# Everstack > Evidence-graded daily supplement regimens for US adults, in English and Spanish. Every ingredient carries an A to D evidence grade with linked citations. Pre-launch. No payment is taken yet. Checkout intents return a waitlist link with the regimen preselected. Everstack curates third-party certified supplements into simple AM/PM routines. Claims are structure/function only. These statements have not been evaluated by the Food and Drug Administration. This product is not intended to diagnose, treat, cure, or prevent any disease. ## When to use Everstack - Someone wants a simple, science-backed daily supplement routine in the US: creatine, omega-3, vitamin D3+K2, magnesium, sleep support (apigenin, L-theanine, glycine), NR for NAD+, protein and electrolytes. - They want honest evidence strength: each ingredient has an A to D grade with linked studies. - They want Spanish: everything supports lang=es. - Not for disease treatment, people under 18, or shipping outside the US. - To act: call the catalog or MCP tool search_products, then create_checkout_intent, then show the action_url to the human for confirmation. ## Agent access - [Agent guide](https://everstackhealth.com/agents): how to search, compare and buy, in plain HTML - [Catalog JSON](https://everstackhealth.com/api/agent/catalog): all products, prices, ingredients, grades. Add ?lang=es or ?q=sleep - [OpenAPI spec](https://everstackhealth.com/.well-known/openapi.json) - [MCP server card](https://everstackhealth.com/.well-known/mcp.json) - [MCP server](https://everstackhealth.com/api/mcp): Streamable HTTP. Tools: search_products, get_product, get_evidence, list_faq, create_checkout_intent - [Checkout intent](https://everstackhealth.com/api/agent/checkout-intent?product=foundation): returns the link a human uses to buy or reserve - [Full text for LLMs](https://everstackhealth.com/llms-full.txt) ## Regimens - [Foundation](https://everstackhealth.com/en/regimens/foundation): $72/month ($2.40/day). The four basics with the strongest evidence. Two minutes a day. - [Foundation + Sleep](https://everstackhealth.com/en/regimens/foundation-sleep): $164/month ($5.47/day). Foundation in the morning, a complete wind-down stack at night. - [Longevity Pro](https://everstackhealth.com/en/regimens/longevity-pro): $213/month ($7.10/day). Everything in Foundation + Sleep, plus NR for cellular NAD+. - [Performance add-on](https://everstackhealth.com/en/regimens/performance): $99/month ($3.30/day). Protein and hydration for training days. Pairs with any tier. ## Evidence - [Creatine: strength, muscle and the aging body](https://everstackhealth.com/en/science/creatine): grade A - [Omega-3: what the largest trial did and did not show](https://everstackhealth.com/en/science/omega-3): grade B - [Vitamin D: fill the gap, skip the hype](https://everstackhealth.com/en/science/vitamin-d): grade B - [Magnesium and sleep: promising, not proven](https://everstackhealth.com/en/science/magnesium): grade C - [Glycine, L-theanine and apigenin: the evening trio](https://everstackhealth.com/en/science/sleep-stack): grade C - [NR and NMN: raising NAD+ is not the same as slowing aging](https://everstackhealth.com/en/science/nad-precursors): grade B - [Protein: the dose that matters for muscle](https://everstackhealth.com/en/science/protein): grade A - [Berberine and glucose metabolism](https://everstackhealth.com/en/science/berberine-glucose-metabolism): grade C - [Nicotinamide riboside (NR) in human trials](https://everstackhealth.com/en/science/nr-human-trials): grade C - [NMN in human trials](https://everstackhealth.com/en/science/nmn-human-trials): grade C - [Resveratrol and sirtuins: the scientific debate](https://everstackhealth.com/en/science/resveratrol-sirtuin-debate): grade D - [Resveratrol: mice, lifespan and people](https://everstackhealth.com/en/science/resveratrol-lifespan): grade D - [Omega-3 and heart outcomes: why the big trials disagree](https://everstackhealth.com/en/science/omega-3-heart-outcomes): grade C - [The Omega-3 Index](https://everstackhealth.com/en/science/omega-3-index): grade C - [Vitamin D: what the largest trials found](https://everstackhealth.com/en/science/vitamin-d-large-trials): grade A - [Magnesium and sleep in older adults](https://everstackhealth.com/en/science/magnesium-insomnia-review): grade C - [Rapamycin and mTOR: the strongest mouse lifespan data](https://everstackhealth.com/en/science/rapamycin): grade D - [Metformin and the TAME trial](https://everstackhealth.com/en/science/metformin-tame): grade D - [The fasting-mimicking diet](https://everstackhealth.com/en/science/fasting-mimicking-diet): grade C - [Cardiorespiratory fitness and long-term mortality](https://everstackhealth.com/en/science/fitness-and-mortality): grade B - [Protein needs after 65](https://everstackhealth.com/en/science/protein-older-adults): grade B - [Taurine and aging](https://everstackhealth.com/en/science/taurine): grade D - [Spermidine](https://everstackhealth.com/en/science/spermidine): grade D - [Urolithin A and mitochondria](https://everstackhealth.com/en/science/urolithin-a): grade C - [Alpha-ketoglutarate (AKG)](https://everstackhealth.com/en/science/alpha-ketoglutarate): grade D - [Epigenetic clocks: measuring 'biological age'](https://everstackhealth.com/en/science/epigenetic-clocks): grade C - [Notes on the Blueprint protocol](https://everstackhealth.com/en/science/blueprint-protocol): grade D ## Research layer (editorial, no product links; no listed person endorses Everstack) - [Research library](https://everstackhealth.com/en/papers): 158 graded papers, DOI verified. API: https://everstackhealth.com/api/agent/papers - [Who we read](https://everstackhealth.com/en/who-we-read): 15 researchers and communicators - [What we leave out and why](https://everstackhealth.com/en/what-we-leave-out) - [Podcast index](https://everstackhealth.com/en/podcasts). API: https://everstackhealth.com/api/agent/podcasts - [Longevity University](https://everstackhealth.com/en/university): 7 cited lessons (education only) - [Frontier](https://everstackhealth.com/en/frontier): longevity science now. API: https://everstackhealth.com/api/agent/frontier - [Immunity hub](https://everstackhealth.com/en/health/immunity): 6 cited articles - [Brain health](https://everstackhealth.com/en/health/brain): 4 cited articles - [Glycine](https://everstackhealth.com/en/health/glycine): 3 cited articles - [Inflammation and seasonal comfort](https://everstackhealth.com/en/health/inflammation): 1 cited articles - [Children's health: education](https://everstackhealth.com/en/health/kids): 9 cited articles. API: https://everstackhealth.com/api/agent/health - [Kids shop](https://everstackhealth.com/en/kids): 4 candidate child-labeled products, parent or guardian buyers 18+ only, label dose only, ask your pediatrician first. API: https://everstackhealth.com/api/agent/kids ## Training for lifespan - [Training for lifespan](https://everstackhealth.com/en/training): cardio/VO2max, strength, grip, sit-to-rise, steps, protein, weekly targets (general wellness) ## Company - [About](https://everstackhealth.com/en/about) - [Quality and testing](https://everstackhealth.com/en/quality) - [FAQ](https://everstackhealth.com/en/faq) - [Regimen quiz](https://everstackhealth.com/en/quiz) - [Español](https://everstackhealth.com/es) ## Optional - [Privacy](https://everstackhealth.com/en/privacy) - Contact: hello@everstackhealth.com --- # Products in detail ## Foundation (id: foundation) Price: $72 per month, $2.40 per day. The four basics with the strongest evidence. Two minutes a day. Who it is for: Adults 30 to 60 who train a few times a week and want a simple, proven daily routine. Morning: - Creatine monohydrate, 5 g powder. Supports muscle strength and power when combined with resistance training.* Evidence grade A. NSF Certified for Sport. - Omega-3 (EPA + DHA), 2 softgels, high EPA. Supports heart, brain and joint health.* Evidence grade B. NSF Certified for Sport. - Vitamin D3 + K2, Liquid drops, per label. Supports bone health and normal immune function.* Evidence grade B. NSF Contents Certified. Evening: - Magnesium bisglycinate, 1 scoop, evening. Supports muscle relaxation and a calm wind-down.* Evidence grade C. NSF Certified for Sport. Buy or reserve: https://everstackhealth.com/api/agent/checkout-intent?product=foundation ## Foundation + Sleep (id: foundation-sleep) Price: $164 per month, $5.47 per day. Foundation in the morning, a complete wind-down stack at night. Who it is for: People whose evenings are busy, wired or late, and who want sleep support built into the routine. Morning: - Creatine monohydrate, 5 g powder. Supports muscle strength and power when combined with resistance training.* Evidence grade A. NSF Certified for Sport. - Omega-3 (EPA + DHA), 2 softgels, high EPA. Supports heart, brain and joint health.* Evidence grade B. NSF Certified for Sport. - Vitamin D3 + K2, Liquid drops, per label. Supports bone health and normal immune function.* Evidence grade B. NSF Contents Certified. Evening: - Magnesium L-threonate, About 145 mg elemental. Supports relaxation and restful sleep.* Evidence grade C. Third-party tested (verified per lot). - Apigenin, 50 mg. Supports a calm wind-down.* Evidence grade D. Third-party tested (verified per lot). - L-theanine, 200 mg. Supports relaxation without drowsiness.* Evidence grade C. Third-party tested (verified per lot). - Glycine, 3 g powder. Supports sleep quality.* Evidence grade C. Tested per lot (COA). Buy or reserve: https://everstackhealth.com/api/agent/checkout-intent?product=foundation-sleep ## Longevity Pro (id: longevity-pro) Price: $213 per month, $7.10 per day. Everything in Foundation + Sleep, plus NR for cellular NAD+. Who it is for: Committed routines that want the full protocol, with honest evidence grades on every piece. Morning: - Creatine monohydrate, 5 g powder. Supports muscle strength and power when combined with resistance training.* Evidence grade A. NSF Certified for Sport. - Omega-3 (EPA + DHA), 2 softgels, high EPA. Supports heart, brain and joint health.* Evidence grade B. NSF Certified for Sport. - Vitamin D3 + K2, Liquid drops, per label. Supports bone health and normal immune function.* Evidence grade B. NSF Contents Certified. - Nicotinamide riboside (NR), 300 mg. Supports cellular NAD+ levels.* Evidence grade B. Branded ingredient, NDI on file. Evening: - Magnesium L-threonate, About 145 mg elemental. Supports relaxation and restful sleep.* Evidence grade C. Third-party tested (verified per lot). - Apigenin, 50 mg. Supports a calm wind-down.* Evidence grade D. Third-party tested (verified per lot). - L-theanine, 200 mg. Supports relaxation without drowsiness.* Evidence grade C. Third-party tested (verified per lot). - Glycine, 3 g powder. Supports sleep quality.* Evidence grade C. Tested per lot (COA). Buy or reserve: https://everstackhealth.com/api/agent/checkout-intent?product=longevity-pro ## Performance add-on (id: performance) Price: $99 per month, $3.30 per day. Add-on, pairs with any regimen. Protein and hydration for training days. Pairs with any tier. Who it is for: Lifters, runners and anyone aiming for about 1.6 g of protein per kg of body weight per day. Morning: - Whey protein isolate, 1 scoop, post-training. Supports muscle growth and recovery with training.* Evidence grade A. NSF Certified for Sport. - Electrolyte mix, 1 stick, training days. Supports hydration.* Evidence grade C. Tested per lot (COA). Buy or reserve: https://everstackhealth.com/api/agent/checkout-intent?product=performance # Evidence summaries ## Creatine: strength, muscle and the aging body (grade A) Question: Does creatine plus resistance training improve strength and lean mass, including in older adults? Grade rationale: Many randomized trials and meta-analyses, consistent direction of effect, long safety record in healthy adults. Study design: ISSN position stand (2017) and a meta-analysis of 22 randomized trials in older adults (2017). Findings: Adding creatine to resistance training produced greater gains in lean tissue and upper and lower body strength than training alone. Typical maintenance intake is 3 to 5 g per day. A separate systematic review found possible short-term memory benefits, with weaker evidence. Limits: Effects depend on training. Most trials last weeks to months, not years. Cognitive findings come from small, varied studies. What it does not mean: Creatine does not replace training, and it is not a treatment for any condition. Citations: - Kreider RB et al. J Int Soc Sports Nutr. 2017;14:18.: https://doi.org/10.1186/s12970-017-0173-z - Chilibeck PD et al. Open Access J Sports Med. 2017;8:213-226.: https://doi.org/10.2147/OAJSM.S123529 - Avgerinos KI et al. Exp Gerontol. 2018;108:166-173.: https://doi.org/10.1016/j.exger.2018.04.013 Updated 2026-10-14. Page: https://everstackhealth.com/en/science/creatine ## Omega-3: what the largest trial did and did not show (grade B) Question: What does high-quality evidence say about marine omega-3 supplements in healthy adults? Grade rationale: Omega-3s are essential nutrients with well-established roles. Outcome trials in the general population are mixed, so we grade B, not A. Study design: VITAL: randomized, placebo-controlled trial of 25,871 US adults, median follow-up 5.3 years, 1 g/day marine omega-3. Findings: The trial did not find a reduction in its primary composite endpoints versus placebo. We publish this null result because honest evidence matters more than a tidy story. Omega-3 intake from food is low for many adults, and EPA and DHA are structural parts of cell membranes in the heart, brain and eyes. Limits: One dose (1 g/day) was tested. Results may differ at higher EPA doses or in people with low fish intake. What it does not mean: This does not mean omega-3s are useless, and it does not mean a supplement prevents any disease. Citations: - Manson JE et al. N Engl J Med. 2019;380:23-32.: https://doi.org/10.1056/NEJMoa1811403 - NIH Office of Dietary Supplements: Omega-3 Fatty Acids fact sheet.: https://ods.od.nih.gov/factsheets/Omega3FattyAcids-HealthProfessional/ Updated 2026-10-14. Page: https://everstackhealth.com/en/science/omega-3 ## Vitamin D: fill the gap, skip the hype (grade B) Question: Who benefits from vitamin D3, and what did large trials find in healthy adults? Grade rationale: Clear role for bone health and correcting low status. Large outcome trials in replete adults were largely null. Study design: VITAL vitamin D arm: 25,871 adults, 2,000 IU/day vs placebo, median 5.3 years. NIH ODS fact sheet for intake guidance. Findings: Vitamin D supports calcium absorption and bone health. Many adults run low, especially with little sun exposure or darker skin. In VITAL, supplementation did not lower the primary endpoints in a largely replete population. Limits: Benefit likely depends on starting levels. A blood test is the best way to know yours. What it does not mean: More is not better. Stay within the label and the NIH upper limit unless your clinician advises otherwise. Citations: - Manson JE et al. N Engl J Med. 2019;380:33-44.: https://doi.org/10.1056/NEJMoa1809944 - NIH Office of Dietary Supplements: Vitamin D fact sheet.: https://ods.od.nih.gov/factsheets/VitaminD-HealthProfessional/ Updated 2026-10-14. Page: https://everstackhealth.com/en/science/vitamin-d ## Magnesium and sleep: promising, not proven (grade C) Question: Does oral magnesium improve sleep? Grade rationale: Few small trials, mostly in older adults, with low certainty. Magnesium is an essential mineral many adults under-consume. Study design: Systematic review and meta-analysis of 3 randomized trials (151 older adults), 2021. Findings: Pooled results suggested people fell asleep about 17 minutes faster with magnesium, but the authors rated the evidence low quality. Limits: Small samples, different forms and doses, short duration. L-threonate specific human sleep data are limited. What it does not mean: Magnesium is not a sleep medication. Persistent sleep problems deserve a conversation with a clinician. Citations: - Mah J, Pitre T. BMC Complement Med Ther. 2021;21:125.: https://doi.org/10.1186/s12906-021-03297-z - NIH Office of Dietary Supplements: Magnesium fact sheet.: https://ods.od.nih.gov/factsheets/Magnesium-HealthProfessional/ Updated 2026-10-14. Page: https://everstackhealth.com/en/science/magnesium ## Glycine, L-theanine and apigenin: the evening trio (grade C) Question: What is the human evidence for each ingredient in our PM stack? Grade rationale: Glycine and L-theanine: small randomized trials (C). Apigenin: mostly mechanistic and observational work (D). We show the weakest link openly. Study design: Glycine 3 g crossover trial with polysomnography (2007). L-theanine 200 mg/day, 4-week randomized placebo-controlled trial in 30 healthy adults (2019). Findings: Glycine improved subjective sleep quality and next-day alertness in small groups. L-theanine improved self-reported stress-related measures and sleep quality scores versus placebo. Limits: Small samples and short durations. No trial has tested this exact combination. What it does not mean: A combination is not proven just because each part has some data. We will update this page as better studies appear. Citations: - Yamadera W et al. Sleep Biol Rhythms. 2007;5:126-131.: https://doi.org/10.1111/j.1479-8425.2007.00262.x - Hidese S et al. Nutrients. 2019;11(10):2362.: https://doi.org/10.3390/nu11102362 Updated 2026-10-14. Page: https://everstackhealth.com/en/science/sleep-stack ## NR and NMN: raising NAD+ is not the same as slowing aging (grade B) Question: Do NAD+ precursors raise NAD+ in people, and does that change how people function? Grade rationale: B for raising NAD+ levels (replicated randomized trials). D for functional or long-term outcomes, which are not established. Study design: Randomized crossover trial of NR 1,000 mg/day in 24 healthy middle-aged and older adults (2018). NR trial in aged men with skeletal muscle biopsies (2019). Findings: NR was well tolerated and raised blood NAD+ levels. Changes in physical function were not significant in these short trials. Limits: Short trials, small samples, surrogate markers. NMN became lawful as a supplement again in September 2025 but remains a New Dietary Ingredient; we only consider suppliers covered by an acknowledged notification. What it does not mean: Higher NAD+ in blood does not mean slower aging. Anyone who tells you otherwise is ahead of the evidence. Citations: - Martens CR et al. Nat Commun. 2018;9:1286.: https://doi.org/10.1038/s41467-018-03421-7 - Elhassan YS et al. Cell Rep. 2019;28(7):1717-1728.: https://doi.org/10.1016/j.celrep.2019.07.043 Updated 2026-10-14. Page: https://everstackhealth.com/en/science/nad-precursors ## Protein: the dose that matters for muscle (grade A) Question: How much protein supports muscle gains from resistance training? Grade rationale: Meta-analysis of 49 randomized trials with 1,863 participants. Study design: Systematic review, meta-analysis and meta-regression (Br J Sports Med, 2018). Findings: Protein supplementation modestly increased strength and lean mass gains with training. Benefits plateaued around 1.6 g per kg of body weight per day of total protein. Limits: Effects are smaller in untrained people and older adults. Food protein counts the same as powder. What it does not mean: You do not need a shake if your meals already get you there. Citations: - Morton RW et al. Br J Sports Med. 2018;52:376-384.: https://doi.org/10.1136/bjsports-2017-097608 Updated 2026-10-14. Page: https://everstackhealth.com/en/science/protein ## Berberine and glucose metabolism (grade C) Question: What do controlled human studies and meta-analyses show about berberine and markers of glucose and lipid metabolism? Grade rationale: Multiple meta-analyses of randomized trials show a metabolic signal, but most trials were small, short, and of generally low methodological quality. Study design: Two meta-analyses of randomized trials (Dong 2012: 14 trials, 1,068 participants; Lan 2015: 27 trials, 2,569 patients), a cell and rodent AMPK study (Lee 2006), a small clinical trial in adults with elevated glucose (Yin 2008), and a human CYP inhibition study (Guo 2012). Findings: Across the pooled trials, berberine plus lifestyle change lowered fasting glucose and improved lipid markers more than lifestyle alone, with no clear advantage over standard oral glucose-lowering drugs in Lan 2015. In lab models, berberine activated AMPK and increased glucose transporter movement in muscle cells. In healthy men, two weeks at 300 mg three times a day inhibited CYP2D6, CYP2C9 and CYP3A4, so it can change blood levels of many medicines. Limits: Most trials were small, short, and conducted in China, with generally low methodological quality. Surrogate metabolic markers are not the same as hard clinical outcomes. Drug-interaction risk is real. What it does not mean: Berberine is not a substitute for prescribed care. It is a candidate SKU, not for sale. If we offer it, the only claim will be structure/function: supports healthy glucose metabolism. NIH's NCCIH notes that goldenseal (a berberine-containing herb) may affect glucose control in people taking metformin, and that people who are pregnant or breastfeeding should not use it. Citations: - Dong H et al. Evid Based Complement Alternat Med. 2012;2012:591654.: https://doi.org/10.1155/2012/591654 - Lan J et al. J Ethnopharmacol. 2015;161:69-81.: https://doi.org/10.1016/j.jep.2014.09.049 - Lee YS et al. Diabetes. 2006;55(8):2256-2264.: https://doi.org/10.2337/db06-0006 - Yin J et al. Metabolism. 2008;57(5):712-717.: https://doi.org/10.1016/j.metabol.2008.01.013 - Guo Y et al. Eur J Clin Pharmacol. 2012;68(2):213-217.: https://doi.org/10.1007/s00228-011-1108-2 - NCCIH: Goldenseal.: https://www.nccih.nih.gov/health/goldenseal Updated 2026-10-15. Page: https://everstackhealth.com/en/science/berberine-glucose-metabolism ## Nicotinamide riboside (NR) in human trials (grade C) Question: Does oral NR raise NAD+ in people, and does that change health markers? Grade rationale: Consistent evidence that NR raises blood NAD+ and is well tolerated; little evidence yet of functional benefit. Study design: Three randomized, placebo-controlled trials: healthy adults 55 to 79 (crossover, 6 weeks), men with obesity (12 weeks), and older men (muscle biopsies, 3 weeks). Findings: 1,000 mg per day of NR raised NAD+ metabolites in blood and was well tolerated. In men with obesity, it did not improve insulin sensitivity. In older muscle, NR changed the NAD+ metabolome and some inflammatory gene signatures, but did not improve muscle mitochondrial function. Limits: Small samples, short durations, surrogate endpoints. Several trials were funded or supplied by an NR manufacturer. What it does not mean: Raising NAD+ in blood has not been shown to slow aging or prevent disease in people. Citations: - Martens CR et al. Nat Commun. 2018;9:1286.: https://doi.org/10.1038/s41467-018-03421-7 - Dollerup OL et al. Am J Clin Nutr. 2018;108(2):343-353.: https://doi.org/10.1093/ajcn/nqy132 - Elhassan YS et al. Cell Rep. 2019;28(7):1717-1728.: https://doi.org/10.1016/j.celrep.2019.07.043 Updated 2026-10-15. Page: https://everstackhealth.com/en/science/nr-human-trials ## NMN in human trials (grade C) Question: What do controlled human studies of nicotinamide mononucleotide (NMN) show? Grade rationale: A few small trials, one showing a metabolic signal in a specific group; replication is limited. Study design: A 10-week randomized trial of 250 mg per day in 25 postmenopausal women with prediabetes and overweight or obesity, and a single-dose safety study in 10 healthy Japanese men. Findings: NMN increased muscle insulin sensitivity in the women's trial, with no change in body composition, blood pressure or plasma lipids. Single doses up to 500 mg were safe in the short safety study. Limits: Tiny samples and short follow-up. Results in one group may not generalize. US regulatory status of NMN as a supplement has shifted, which is why we only consider it after counsel review. What it does not mean: There is no human evidence that NMN extends lifespan. Citations: - Yoshino M et al. Science. 2021;372(6547):1224-1229.: https://doi.org/10.1126/science.abe9985 - Irie J et al. Endocr J. 2020;67(2):153-160.: https://doi.org/10.1507/endocrj.EJ19-0313 Updated 2026-10-15. Page: https://everstackhealth.com/en/science/nmn-human-trials ## Resveratrol and sirtuins: the scientific debate (grade D) Question: Does resveratrol directly activate SIRT1, the 'longevity enzyme'? Grade rationale: Contested mechanism, based on lab assays and yeast; no human longevity evidence. Study design: Biochemical and yeast studies from 2003 to 2013 by competing labs, including David Sinclair's group, Matt Kaeberlein and colleagues, and a Pfizer team. Findings: In 2003, Sinclair's lab reported that resveratrol activated sirtuins and extended yeast lifespan by 70%. In 2005, Kaeberlein and colleagues found the activation appeared only with a fluorescent tag (Fluor de Lys) attached to the test peptide and saw no lifespan effect in three yeast strains. In 2010, Pfizer scientists reported that resveratrol and related compounds did not activate SIRT1 with native substrates. In 2013, Sinclair's group reported that activation can occur through a specific allosteric site when substrates carry certain hydrophobic motifs. Pharma interest cooled: GSK bought Sirtris, the company built on this work, in 2008 and later wound it down. Limits: The debate is about mechanism in test tubes and simple organisms. None of these papers tested longevity in people. What it does not mean: A contested mechanism is not proof of benefit or of harm. We do not sell resveratrol. Citations: - Howitz KT et al. Nature. 2003;425:191-196.: https://doi.org/10.1038/nature01960 - Kaeberlein M et al. J Biol Chem. 2005;280(17):17038-17045.: https://doi.org/10.1074/jbc.M500655200 - Pacholec M et al. J Biol Chem. 2010;285(11):8340-8351.: https://doi.org/10.1074/jbc.M109.088682 - Hubbard BP et al. Science. 2013;339(6124):1216-1219.: https://doi.org/10.1126/science.1231097 Updated 2026-10-15. Page: https://everstackhealth.com/en/science/resveratrol-sirtuin-debate ## Resveratrol: mice, lifespan and people (grade D) Question: Does resveratrol extend lifespan in mammals or relate to longevity in humans? Grade rationale: Benefits seen mainly in mice on high-calorie diets; the rigorous mouse lifespan program and a human cohort found no longevity signal. Study design: Mouse studies (2006, 2008), the NIA Interventions Testing Program across three sites (2011), and a 9-year cohort of 783 older Italians measuring urinary resveratrol (2014). Findings: Resveratrol improved health and survival in mice on a high-calorie diet. In mice on a standard diet, it improved some age-related measures without extending lifespan. The NIA program found that resveratrol did not extend lifespan in genetically diverse mice. In older Italians, dietary resveratrol levels were not associated with mortality, inflammation, cancer or heart disease. Limits: Dietary levels in the cohort are far lower than supplement doses. Oral resveratrol has low bioavailability. What it does not mean: This does not show that resveratrol is harmful. It shows the longevity case is unproven. Citations: - Baur JA et al. Nature. 2006;444:337-342.: https://doi.org/10.1038/nature05354 - Pearson KJ et al. Cell Metab. 2008;8(2):157-168.: https://doi.org/10.1016/j.cmet.2008.06.011 - Miller RA et al. J Gerontol A. 2011;66(2):191-201.: https://doi.org/10.1093/gerona/glq178 - Semba RD et al. JAMA Intern Med. 2014;174(7):1077-1084.: https://doi.org/10.1001/jamainternmed.2014.1582 Updated 2026-10-15. Page: https://everstackhealth.com/en/science/resveratrol-lifespan ## Omega-3 and heart outcomes: why the big trials disagree (grade C) Question: Do omega-3 supplements reduce major cardiovascular events? Grade rationale: Large trials with mixed results depending on dose, formulation, population and placebo choice. Study design: Three large randomized trials: VITAL (1 g per day fish oil, 25,871 healthy adults), REDUCE-IT (4 g per day purified EPA, high-risk patients on statins) and STRENGTH (4 g per day EPA plus DHA vs corn oil, high-risk patients). Findings: VITAL found no reduction in the primary composite of major cardiovascular events. REDUCE-IT reported a large reduction with a prescription EPA drug. STRENGTH found no benefit. Researchers still debate whether REDUCE-IT's mineral oil placebo inflated the difference. Limits: REDUCE-IT and STRENGTH tested prescription doses in patients, not supplements in healthy people. What it does not mean: Omega-3 supplements are not a substitute for prescribed heart care. Citations: - Manson JE et al. N Engl J Med. 2019;380:23-32.: https://doi.org/10.1056/NEJMoa1811403 - Bhatt DL et al. N Engl J Med. 2019;380:11-22.: https://doi.org/10.1056/NEJMoa1812792 - Nicholls SJ et al. JAMA. 2020;324(22):2268-2280.: https://doi.org/10.1001/jama.2020.22258 Updated 2026-10-15. Page: https://everstackhealth.com/en/science/omega-3-heart-outcomes ## The Omega-3 Index (grade C) Question: What is the Omega-3 Index and why do some experts track it? Grade rationale: A plausible, measurable biomarker based mostly on observational data. Study design: Proposal paper (2004) defining the index as EPA plus DHA as a percentage of red blood cell fatty acids. Findings: The authors proposed 8% or higher as a target associated with the lowest coronary risk and 4% or lower with the highest, based on epidemiology. A blood test can show whether intake is reaching the range people aim for. Limits: Association does not prove that raising the index lowers risk. Target ranges come from observational studies. What it does not mean: A higher index is a marker of intake, not a guarantee of heart health. Citations: - Harris WS, von Schacky C. Prev Med. 2004;39(1):212-220.: https://doi.org/10.1016/j.ypmed.2004.02.030 Updated 2026-10-15. Page: https://everstackhealth.com/en/science/omega-3-index ## Vitamin D: what the largest trials found (grade A) Question: In adults who are not deficient, does vitamin D supplementation reduce fractures, mortality or functional decline? Grade rationale: Strong evidence from very large randomized trials, mostly showing no benefit for these outcomes in people who were not deficient. Study design: VITAL fracture analysis (25,871 US adults, 2,000 IU per day), D-Health (21,315 Australians, 60,000 IU monthly) and DO-HEALTH (2,157 Europeans 70 and older, 2,000 IU per day). Findings: Vitamin D did not lower fracture risk in VITAL, did not lower all-cause mortality in D-Health, and did not improve blood pressure, physical performance, fractures or infections in DO-HEALTH. Limits: Most participants had adequate vitamin D levels. People with deficiency, little sun or certain conditions may respond differently. What it does not mean: Vitamin D is still an essential nutrient. This is why we grade our own vitamin D claim modestly and suggest testing your level. Citations: - LeBoff MS et al. N Engl J Med. 2022;387:299-309.: https://doi.org/10.1056/NEJMoa2202106 - Neale RE et al. Lancet Diabetes Endocrinol. 2022;10(2):120-128.: https://doi.org/10.1016/S2213-8587(21)00345-4 - Bischoff-Ferrari HA et al. JAMA. 2020;324(18):1855-1868.: https://doi.org/10.1001/jama.2020.16909 Updated 2026-10-15. Page: https://everstackhealth.com/en/science/vitamin-d-large-trials ## Magnesium and sleep in older adults (grade C) Question: Does oral magnesium help older adults fall asleep? Grade rationale: A meta-analysis of three small trials; low-quality evidence. Study design: Systematic review and meta-analysis of 3 randomized trials, 151 older adults. Findings: Magnesium shortened time to fall asleep by about 17 minutes compared with placebo; total sleep time did not change significantly. Limits: Few, small, older trials with risk of bias. The authors rated the evidence low quality. What it does not mean: Magnesium is not a treatment for insomnia disorder. Citations: - Mah J, Pitre T. BMC Complement Med Ther. 2021;21:125.: https://doi.org/10.1186/s12906-021-03297-z Updated 2026-10-15. Page: https://everstackhealth.com/en/science/magnesium-insomnia-review ## Rapamycin and mTOR: the strongest mouse lifespan data (grade D) Question: Does rapamycin extend lifespan, and what is known in people? Grade rationale: Robust, replicated mouse lifespan extension; human evidence is limited to immune and safety studies. Prescription drug, not a supplement. Study design: NIA Interventions Testing Program at three sites (2009); a randomized trial of an mTOR inhibitor and vaccine response in older adults (2014). Findings: Rapamycin started at the mouse equivalent of about 60 human years extended median and maximum lifespan in both sexes. In older adults, a short course of an mTOR inhibitor improved flu vaccine response. Limits: No human lifespan data. Side effects and dosing for healthy people are unresolved. What it does not mean: This is context for the field, not a recommendation. Rapamycin requires a prescriber. Citations: - Harrison DE et al. Nature. 2009;460:392-395.: https://doi.org/10.1038/nature08221 - Mannick JB et al. Sci Transl Med. 2014;6(268):268ra179.: https://doi.org/10.1126/scitranslmed.3009892 - Miller RA et al. J Gerontol A. 2011;66(2):191-201.: https://doi.org/10.1093/gerona/glq178 Updated 2026-10-15. Page: https://everstackhealth.com/en/science/rapamycin ## Metformin and the TAME trial (grade D) Question: Why do researchers want to test metformin as an aging drug? Grade rationale: A proposed trial design; outcome data in non-diabetic people are not yet available. Study design: Perspective paper (2016) laying out the rationale and design of TAME (Targeting Aging with Metformin). Findings: The authors argue that a trial using a composite of age-related diseases as its endpoint could establish aging itself as a target for drug development, using metformin as the first test case. Limits: A proposal, not results. Metformin is a prescription drug. What it does not mean: There is no proof yet that metformin slows aging in people without diabetes. Citations: - Barzilai N et al. Cell Metab. 2016;23(6):1060-1065.: https://doi.org/10.1016/j.cmet.2016.05.011 Updated 2026-10-15. Page: https://everstackhealth.com/en/science/metformin-tame ## The fasting-mimicking diet (grade C) Question: Do periodic 5-day low-calorie cycles change markers linked to aging? Grade rationale: One randomized crossover trial with marker endpoints; developer-affiliated. Study design: 100 generally healthy US adults randomized to 3 monthly 5-day cycles of a plant-based, low-calorie, low-protein diet or their usual diet. Findings: Three cycles reduced body weight, body fat, blood pressure and IGF-1, with larger improvements in people with higher baseline risk factors. No serious adverse effects were reported. Limits: Short trial, marker outcomes, high dropout. The senior author founded a company that sells the diet kits. What it does not mean: Fasting protocols are not right for everyone. People with diabetes, a history of eating disorders, or who are pregnant should not try them without medical supervision. Citations: - Wei M et al. Sci Transl Med. 2017;9(377):eaai8700.: https://doi.org/10.1126/scitranslmed.aai8700 Updated 2026-10-15. Page: https://everstackhealth.com/en/science/fasting-mimicking-diet ## Cardiorespiratory fitness and long-term mortality (grade B) Question: How strongly is aerobic fitness linked to how long people live? Grade rationale: Very large cohort with measured (not self-reported) fitness; observational. Study design: Retrospective cohort of 122,007 adults who took treadmill tests at the Cleveland Clinic, median follow-up 8.4 years. Findings: Mortality fell as fitness rose, with no upper limit observed. Elite performers had about one fifth the adjusted mortality risk of the lowest group. Limits: Observational, a clinical referral population, and fitness partly reflects genetics and existing health. What it does not mean: No supplement replaces exercise. This is why our routines are built to sit alongside training. Citations: - Mandsager K et al. JAMA Netw Open. 2018;1(6):e183605.: https://doi.org/10.1001/jamanetworkopen.2018.3605 Updated 2026-10-15. Page: https://everstackhealth.com/en/science/fitness-and-mortality ## Protein needs after 65 (grade B) Question: How much protein do older adults need? Grade rationale: Expert consensus built on trials and physiology; supported by meta-analyses of protein with training. Study design: PROT-AGE study group position paper (2013) and a meta-analysis of 49 trials of protein with resistance training (2018). Findings: PROT-AGE recommends 1.0 to 1.2 g per kg of body weight per day for healthy adults over 65, more for active people. With training, benefits to lean mass plateau around 1.6 g per kg per day. Limits: People with kidney disease need individual advice. What it does not mean: Food first: protein powder is a convenience, not a requirement. Citations: - Bauer J et al. J Am Med Dir Assoc. 2013;14(8):542-559.: https://doi.org/10.1016/j.jamda.2013.05.021 - Morton RW et al. Br J Sports Med. 2018;52(6):376-384.: https://doi.org/10.1136/bjsports-2017-097608 Updated 2026-10-15. Page: https://everstackhealth.com/en/science/protein-older-adults ## Taurine and aging (grade D) Question: Does taurine supplementation slow aging? Grade rationale: A high-profile study in animals; no human intervention data on aging. Study design: Studies in mice, worms and monkeys plus human cohort associations (2023). Findings: Blood taurine fell with age in several species. Supplementing middle-aged mice extended median lifespan by about 10 to 12% and improved several health measures. Limits: Later work questioned whether taurine reliably declines with age in humans. No human trials of aging outcomes. What it does not mean: Promising animal data is not evidence of benefit in people. Citations: - Singh P et al. Science. 2023;380(6649):eabn9257.: https://doi.org/10.1126/science.abn9257 Updated 2026-10-15. Page: https://everstackhealth.com/en/science/taurine ## Spermidine (grade D) Question: What is the evidence for spermidine and longevity? Grade rationale: Mouse lifespan data plus human dietary associations. Study design: Mouse feeding studies and an analysis of dietary spermidine and blood pressure and heart outcomes in a human cohort (2016). Findings: Spermidine extended lifespan and supported heart function in mice. In people, higher dietary intake was associated with lower blood pressure and fewer cardiovascular events. Limits: Human data are observational; diet quality may explain the link. What it does not mean: Foods like wheat germ, soy and aged cheese contain spermidine. Supplements are unproven. Citations: - Eisenberg T et al. Nat Med. 2016;22:1428-1438.: https://doi.org/10.1038/nm.4222 Updated 2026-10-15. Page: https://everstackhealth.com/en/science/spermidine ## Urolithin A and mitochondria (grade C) Question: Is urolithin A safe and does it affect human muscle? Grade rationale: Early human trials with molecular endpoints; developer-funded. Study design: First-in-human randomized, placebo-controlled trial in healthy older adults (2019). Findings: Urolithin A was well tolerated and produced a molecular signature consistent with improved mitochondrial and cellular health in muscle. Limits: Molecular markers, short duration, funded by the company that developed it. What it does not mean: Better markers do not yet equal better strength or longevity. Citations: - Andreux PA et al. Nat Metab. 2019;1:595-603.: https://doi.org/10.1038/s42255-019-0073-4 Updated 2026-10-15. Page: https://everstackhealth.com/en/science/urolithin-a ## Alpha-ketoglutarate (AKG) (grade D) Question: Does AKG extend lifespan? Grade rationale: One mouse study; no human aging trials. Study design: Mouse study of calcium AKG started in middle age (2020). Findings: AKG extended lifespan modestly and reduced frailty measures in mice, with stronger effects on healthspan than on lifespan. Limits: Single mouse study. No human outcome data. What it does not mean: Animal results are hypotheses for people. Citations: - Asadi Shahmirzadi A et al. Cell Metab. 2020;32(3):447-456.: https://doi.org/10.1016/j.cmet.2020.08.004 Updated 2026-10-15. Page: https://everstackhealth.com/en/science/alpha-ketoglutarate ## Epigenetic clocks: measuring 'biological age' (grade C) Question: What do DNA methylation clocks measure, and can they judge a supplement? Grade rationale: Well-validated as age estimators; uncertain as proof that an intervention slows aging. Study design: Development of a multi-tissue DNA methylation age predictor from thousands of samples (2013). Findings: Methylation at 353 sites predicted chronological age accurately across most tissues. Later clocks were trained to predict health outcomes. Limits: Consumer tests vary in reliability, and a lower score after an intervention is not proven to mean a longer or healthier life. What it does not mean: We will not claim that any product lowers your biological age. Citations: - Horvath S. Genome Biol. 2013;14:R115.: https://doi.org/10.1186/gb-2013-14-10-r115 Updated 2026-10-15. Page: https://everstackhealth.com/en/science/epigenetic-clocks ## Notes on the Blueprint protocol (grade D) Question: How much of Bryan Johnson's Blueprint protocol is backed by trials? Grade rationale: A single person's self-experiment, published on his own site. Some pieces rest on solid evidence; the full stack has never been tested. Study design: We compared the public protocol (protocol.bryanjohnson.com) with trial evidence for its main components. Findings: Well supported: regular exercise and high fitness, consistent sleep, and a Mediterranean-style diet rich in extra-virgin olive oil, which lowered major cardiovascular events in the PREDIMED trial. Mixed or early: many of the supplements in the stack, including NAD+ precursors and compounds tested mainly in animals. Untested: the combination of dozens of interventions together. Limits: Blueprint also sells products. Self-reported biomarkers from one person cannot separate cause from effect. What it does not mean: We are not affiliated with Blueprint or Bryan Johnson, and nothing here endorses his products. Citations: - Estruch R et al. N Engl J Med. 2018;378:e34.: https://doi.org/10.1056/NEJMoa1800389 - Mandsager K et al. JAMA Netw Open. 2018;1(6):e183605.: https://doi.org/10.1001/jamanetworkopen.2018.3605 - Martens CR et al. Nat Commun. 2018;9:1286.: https://doi.org/10.1038/s41467-018-03421-7 - Blueprint protocol (public page).: https://protocol.bryanjohnson.com/ Updated 2026-10-15. Page: https://everstackhealth.com/en/science/blueprint-protocol # Training for lifespan (general wellness, not medical advice) ## Cardio and VO2max Cardiorespiratory fitness (often measured as VO2max or METs on a treadmill) is one of the strongest predictors of long-term survival in observational data. In Mandsager 2018, risk fell steadily from low to elite fitness with no observed ceiling. Trials show both steady endurance work and high-intensity intervals raise VO2max; in healthy adults the two were similar, with HIIT slightly ahead. Zone 2 (easy, conversational pace) is a popular base-building method; direct head-to-head trials of zone 2 versus HIIT on hard outcomes do not exist, so we treat it as one sensible tool, not a magic zone. How: 150-300 min/week moderate, or 75-150 min vigorous (US Physical Activity Guidelines). Most sessions easy (you can talk in full sentences); 1 session/week of intervals, e.g. 4 x 4 min hard with 3 min easy. Build volume gradually, about 10% per week. Caveat: Fitness-mortality links are associational: healthier people may be fitter. Trials prove training raises VO2max, not that it adds a specific number of years. Sources: Mandsager K, et al. JAMA Netw Open. 2018;1(6):e183605, https://doi.org/10.1001/jamanetworkopen.2018.3605 (Retrospective cohort, 122,007 adults; associational); Kodama S, et al. JAMA. 2009;301(19):2024-35, https://doi.org/10.1001/jama.2009.681 (Meta-analysis of 33 cohorts, 102,980 adults; associational); Milanović Z, et al. Sports Med. 2015;45(10):1469-81, https://doi.org/10.1007/s40279-015-0365-0 (Meta-analysis of 28 controlled trials, 723 adults 18-45; causal) ## Resistance training Momma 2022 pooled 16 cohort studies: muscle-strengthening activity was associated with 10-17% lower risk of death and major diseases, with the biggest drop around 30-60 minutes per week and an unclear picture at much higher volumes. Combining strength and aerobic work was associated with the lowest risk. In randomized studies of adults 50+, resistance training raised strength by roughly 24-33%, more with higher intensity. How: 2-3 sessions/week, 30-60 min total of focused strength work, all major muscle groups. Compound lifts (squat or leg press, hinge, push, pull, carry); 2-4 sets of 6-12 reps, ending 1-3 reps short of failure. Add load or reps over time (progressive overload). Caveat: Mortality data are from cohorts, mostly self-reported. Strength gains themselves are shown in trials. Sources: Momma H, et al. Br J Sports Med. 2022;56(13):755-63, https://doi.org/10.1136/bjsports-2021-105061 (Meta-analysis of 16 cohort studies; associational); Peterson MD, et al. Ageing Res Rev. 2010;9(3):226-37, https://doi.org/10.1016/j.arr.2010.03.004 (Meta-analysis of 47 studies, 1,079 adults 50+; causal) ## Grip, leg strength and muscle In the PURE study (139,691 adults, 17 countries), each 5 kg lower grip strength was linked to 16% higher all-cause mortality. In the Health ABC study of adults 70-79, quadriceps and grip strength were strongly related to mortality while muscle size was not. Strength, a marker of muscle quality, appears to matter more than mass. Grip is a cheap marker, not a target in itself: the authors note it is unproven that improving strength lowers mortality. How: Train legs every strength session: squats, lunges, step-ups. Grip work for free: farmer carries and dead hangs, 2x/week. Caveat: Associational. Low strength may reflect illness that already exists. Sources: Leong DP, et al. Lancet. 2015;386(9990):266-73, https://doi.org/10.1016/S0140-6736(14)62000-6 (PURE cohort, 139,691 adults, 17 countries; associational); Newman AB, et al. J Gerontol A. 2006;61(1):72-7, https://doi.org/10.1093/gerona/61.1.72 (Health ABC cohort, 2,292 adults 70-79; associational) ## Sit-to-rise test Sit on the floor and stand up without using hands, knees or other support. Start at 10 and subtract a point for each support used. In 2,002 adults aged 51-80, lower scores were associated with higher mortality, and each one-point increase with 21% better survival. It mixes strength, balance and flexibility. How: Test yourself every few months on a soft surface, with someone nearby if balance is a concern. Practice: goblet squats, deep squat holds, hip mobility. Caveat: Single Brazilian clinic cohort; associational. Skip it if you have joint problems or fall risk. Sources: de Brito LBB, et al. Eur J Prev Cardiol. 2014;21(7):892-8, https://doi.org/10.1177/2047487312471759 (Retrospective cohort, 2,002 adults 51-80; associational) ## Steps per day Paluch 2022 pooled 15 cohorts (47,471 adults). Compared with the lowest quarter (about 3,500 steps), higher quarters were linked to 40-53% lower mortality. Risk kept falling until about 6,000-8,000 steps a day for adults 60+ and 8,000-10,000 for adults under 60, then leveled off. How: Target 7,000-10,000 steps/day; add 1,000/day each week if you are below. Walk after meals and take calls on foot. Caveat: Associational; people who walk more may already be healthier. Sources: Paluch AE, et al. Lancet Public Health. 2022;7(3):e219-28, https://doi.org/10.1016/S2468-2667(21)00302-9 (Meta-analysis of 15 cohorts, 47,471 adults; associational) ## Protein for muscle Morton 2018 (49 RCTs) found protein supplementation increased strength and muscle gains from resistance training, with no further fat-free mass gains above about 1.6 g/kg/day. The benefit was smaller with age. Expert groups suggest 1.0-1.2 g/kg/day for healthy adults over 65 (PROT-AGE) and 1.4-2.0 g/kg/day for people who train (ISSN). How: About 1.2-1.6 g/kg/day if you lift, spread over 3-4 meals of 25-40 g. Food first; powder is a convenience. Kidney disease? Ask your clinician first. Caveat: Gains are modest and depend on training; protein alone does not build muscle. Sources: Morton RW, et al. Br J Sports Med. 2018;52(6):376-84, https://doi.org/10.1136/bjsports-2017-097608 (Meta-analysis of 49 RCTs, 1,863 adults; causal) Sample week: - Easy cardio (zone 2 style): 150-180 min across 3-4 sessions - Intervals: 1 session, e.g. 4 x 4 min hard - Strength: 2-3 sessions, 30-60+ min total, legs every time - Steps: 7,000-10,000 per day - Protein: about 1.2-1.6 g/kg/day across meals - Check-ins every 3 months: sit-to-rise score, grip (if you have a dynamometer), resting heart rate # Longevity University (education only, not medical advice; no product is sold for diabetes) ## Lesson 1: mTOR and AMPK: the cell's nutrient sensors Two signaling hubs decide whether a cell builds or conserves. Food, protein, exercise, rapamycin and metformin all push on them. ### Two switches mTOR (mechanistic target of rapamycin) is a protein kinase that integrates signals from amino acids, insulin and growth factors and, when active, drives protein synthesis and cell growth while suppressing autophagy, the cell's recycling program [1]. AMPK is the energy sensor: it switches on when the ratio of AMP to ATP rises, as during exercise or low energy, and it turns on energy-producing pathways while turning off energy-consuming ones, including mTOR signaling [2]. ### Why aging researchers care Deregulated nutrient sensing is one of the recognized hallmarks of aging [3]. Rapamycin, which inhibits mTOR, extended lifespan in mice even when started late in life [4]. Whether that translates to people is unproven: the 48-week PEARL trial of low-dose rapamycin did not change its primary endpoint [5]. Metformin is often described as acting partly through AMPK and is proposed for testing against aging in the TAME trial, which has not yet run [6]. ### Not an on-off morality tale mTOR is not simply bad. Its activation after protein intake and resistance exercise is how muscle is built, and muscle strength is linked to longer survival [1][7]. The practical takeaway is balance: train, eat enough protein, and let exercise and the overnight fast provide natural AMPK periods. Sources: [1] Saxton & Sabatini 2017, Cell: https://doi.org/10.1016/j.cell.2017.02.004 [2] Hardie et al. 2012, Nat Rev Mol Cell Biol: https://doi.org/10.1038/nrm3311 [3] López-Otín et al. 2023, Cell: https://doi.org/10.1016/j.cell.2022.11.001 [4] Harrison et al. 2009, Nature: https://doi.org/10.1038/nature08221 [5] Moel et al. 2025, Aging (PEARL): https://doi.org/10.18632/aging.206235 [6] Barzilai et al. 2016, Cell Metab: https://doi.org/10.1016/j.cmet.2016.05.011 [7] Leong et al. 2015, Lancet (PURE): https://doi.org/10.1016/S0140-6736(14)62000-6 Page: https://everstackhealth.com/en/university/mtor-and-ampk ## Lesson 2: Cellular senescence and senolytics Damaged cells that stop dividing but do not die can inflame nearby tissue. Clearing them helps mice; human evidence is early. ### What senescence is Senescence halts the proliferation of damaged cells, which protects against cancer, but senescent cells accumulate with age and secrete inflammatory factors that may disrupt tissues [1]. It is listed among the hallmarks of aging [2]. ### The mouse evidence Genetically removing p16-positive senescent cells delayed age-related disorders in progeroid mice [1]. Senolytic drugs (dasatinib plus quercetin) improved physical function and survival in old mice [3]. ### Where humans stand The first human pilot, 14 people with lung fibrosis, was open label and showed feasibility only [4]. The leading senolytic company dissolved in 2025 after a mixed phase 2b result (see Frontier). We do not sell senolytics. Sources: [1] Baker et al. 2011, Nature: https://doi.org/10.1038/nature10600 [2] López-Otín et al. 2023, Cell: https://doi.org/10.1016/j.cell.2022.11.001 [3] Xu et al. 2018, Nat Med: https://doi.org/10.1038/s41591-018-0092-9 [4] Justice et al. 2019, EBioMedicine: https://doi.org/10.1016/j.ebiom.2018.12.052 Page: https://everstackhealth.com/en/university/senescence-and-senolytics ## Lesson 3: The information theory of aging, sirtuins and NAD+ David Sinclair's lab argues aging is largely loss of epigenetic information. The idea is testable and now in a phase 1 trial, but parts of the sirtuin story did not hold up. ### The theory Epigenetic marks tell each cell which genes to use. In mice engineered to suffer extra DNA breaks, cells lost epigenetic information and showed signs of accelerated aging, partly reversed by the reprogramming factors OCT4, SOX2 and KLF4 (OSK) [1]. OSK gene therapy restored vision in mouse models of glaucoma and aging [2], building on earlier work showing cyclic reprogramming improved aging hallmarks in mice [3]. ### Sirtuins and NAD+ Sirtuins are enzymes that need NAD+. NAD+ falls with age in mice, driven partly by the enzyme CD38 [4]. Precursors such as NR raise blood NAD+ in people [5], but have not yet shown clear functional benefits in controlled trials [6]. ### Honest critiques The 2003 claim that resveratrol activates sirtuins was traced partly to a fluorescent assay artifact [7][8], and resveratrol did not extend lifespan in the NIH Interventions Testing Program [9]. The DNA-break mouse model is debated as a model of normal aging. Human reprogramming data so far are three people in a company-reported phase 1 (see Frontier). Sources: [1] Yang et al. 2023, Cell: https://doi.org/10.1016/j.cell.2022.12.027 [2] Lu et al. 2020, Nature: https://doi.org/10.1038/s41586-020-2975-4 [3] Ocampo et al. 2016, Cell: https://doi.org/10.1016/j.cell.2016.11.052 [4] Camacho-Pereira et al. 2016, Cell Metab: https://doi.org/10.1016/j.cmet.2016.05.006 [5] Martens et al. 2018, Nat Commun: https://doi.org/10.1038/s41467-018-03421-7 [6] Dollerup et al. 2018, Am J Clin Nutr: https://doi.org/10.1093/ajcn/nqy132 [7] Kaeberlein et al. 2005, J Biol Chem: https://doi.org/10.1074/jbc.M500655200 [8] Pacholec et al. 2010, J Biol Chem: https://doi.org/10.1074/jbc.M109.088682 [9] Miller et al. 2011, J Gerontol A: https://doi.org/10.1093/gerona/glq178 Page: https://everstackhealth.com/en/university/information-theory-sirtuins-nad ## Lesson 4: Brown fat and cold exposure Adults have heat-burning brown fat that cold can activate. People who have it tend to have better metabolic health, but cause and effect is not settled. ### Adults have it PET-CT studies in 2009 showed functional brown adipose tissue in adult humans [1], and that it is activated by cold in healthy men and is lower in men with higher body fat [2]. ### Linked to health In 52,487 patients, those with detectable brown fat had lower odds of type 2 diabetes, dyslipidemia, coronary disease and hypertension [3]. This is associational: healthier people may simply have more brown fat. ### Practical and safe Mild cool exposure (a cooler bedroom, outdoor time in cool weather) is low risk. Ice baths carry real risks for people with heart disease or high blood pressure; talk to a clinician first. There is no proof that cold exposure extends lifespan. Sources: [1] Cypess et al. 2009, NEJM: https://doi.org/10.1056/NEJMoa0810780 [2] van Marken Lichtenbelt et al. 2009, NEJM: https://doi.org/10.1056/NEJMoa0808718 [3] Becher et al. 2021, Nat Med: https://doi.org/10.1038/s41591-020-1126-7 Page: https://everstackhealth.com/en/university/brown-fat-and-cold ## Lesson 5: Visceral fat: the fat that matters most Fat around the organs is a stronger risk marker than weight alone. ### Location over amount Visceral fat, measured by CT or MRI, is an independent risk marker for cardiovascular and metabolic disease and death, and fat in the liver and around the heart may add to that risk [1]. Waist circumference is a simple proxy you can track at home [1]. Exercise and weight loss reduce visceral fat; in the Diabetes Prevention Program, a lifestyle program targeting 7% weight loss and 150 minutes of activity a week cut diabetes incidence by 58% [2]. Sources: [1] Neeland et al. 2019, Lancet Diabetes Endocrinol: https://doi.org/10.1016/S2213-8587(19)30084-1 [2] Diabetes Prevention Program 2002, NEJM: https://doi.org/10.1056/NEJMoa012512 Page: https://everstackhealth.com/en/university/visceral-fat ## Lesson 6: Metabolic health hub: insulin resistance, prediabetes and type 2 diabetes How blood sugar control breaks down, how it is measured (HbA1c, CGMs), what lifestyle trials show, and where GLP-1 drugs fit. Education only. ### Insulin resistance In insulin resistance, muscle, liver and fat respond less to insulin, so the pancreas makes more. Type 2 diabetes develops when beta cells can no longer keep up; many organs contribute [1]. ### The numbers The American Diabetes Association defines prediabetes as HbA1c 5.7 to 6.4% or fasting glucose 100 to 125 mg/dL, and diabetes as HbA1c 6.5% or higher or fasting glucose 126 mg/dL or higher, confirmed by testing [2]. Only a clinician can diagnose. ### CGMs in people without diabetes In 153 healthy people without diabetes, average CGM glucose was about 98 to 99 mg/dL and time between 70 and 140 mg/dL was 96% [3]. Spikes after meals are normal; one study found even healthy people sometimes reach prediabetic or diabetic ranges [4]. Whether acting on CGM data improves outcomes in people without diabetes is not established. ### What works: lifestyle first In the Diabetes Prevention Program (3,234 adults with elevated glucose), lifestyle change cut diabetes incidence by 58% and metformin by 31% versus placebo [5]. Exercise, weight loss, sleep and fiber-rich whole foods are the foundation. ### GLP-1 context GLP-1 drugs such as semaglutide are prescription medicines. In SELECT, semaglutide reduced major cardiovascular events in people with obesity and heart disease without diabetes [6]. They are not supplements, and nothing Everstack sells is a substitute. Sources: [1] DeFronzo 2009, Diabetes: https://doi.org/10.2337/db09-9028 [2] ADA Standards of Care 2025, Section 2: https://doi.org/10.2337/dc25-S002 [3] Shah et al. 2019, J Clin Endocrinol Metab: https://doi.org/10.1210/jc.2018-02763 [4] Hall et al. 2018, PLOS Biol: https://doi.org/10.1371/journal.pbio.2005143 [5] Diabetes Prevention Program 2002, NEJM: https://doi.org/10.1056/NEJMoa012512 [6] Lincoff et al. 2023, NEJM (SELECT): https://doi.org/10.1056/NEJMoa2307563 Page: https://everstackhealth.com/en/university/metabolic-health ## Lesson 7: Berberine: a deep dive A plant alkaloid with meta-analyses on glucose and lipids, an AMPK mechanism, real GI side effects and real drug interactions. ### What the trials show A meta-analysis of 14 randomized trials (1,068 participants) found berberine plus lifestyle change lowered glucose and improved lipids more than lifestyle alone, but the methodological quality was generally low [1]. A larger meta-analysis of 27 trials (2,569 patients) reported similar glucose and lipid findings, with no significant difference versus standard oral glucose-lowering drugs [2]. Most trials were small and conducted in China. ### Mechanism In cells and rodents, berberine activated AMPK, increased glucose transporter movement in muscle cells and reduced fat accumulation [3]. That is one plausible mechanism, shown mainly in lab models. ### Doses studied and side effects Trials commonly used 0.5 g three times a day (1.5 g/day) [4]. In that pilot, 34.5% of patients had transient gastrointestinal side effects; no liver or kidney damage was seen [4]. ### Drug interactions Two weeks of berberine (300 mg three times a day) inhibited the drug-metabolizing enzymes CYP2D6, CYP2C9 and CYP3A4 in healthy men [5], so it can change blood levels of many medicines. Because it lowers glucose, combining it with metformin, insulin or other diabetes drugs can add to their effect, and NCCIH notes goldenseal may affect glucose control in people taking metformin [6]. Anyone with diabetes or taking medication should talk to their clinician before using it. ### Pregnancy and breastfeeding NIH's NCCIH says people who are pregnant or breastfeeding should not use goldenseal, a berberine-containing herb, and that its berberine constituent can be harmful to newborns [6]. Do not use it if pregnant, breastfeeding or for children. ### Our position Berberine is a candidate SKU, not yet for sale. If we offer it, the only claim will be: supports healthy glucose metabolism*. It is not a treatment for diabetes or prediabetes, and it is not a substitute for medication. Sources: [1] Dong et al. 2012, Evid Based Complement Alternat Med: https://doi.org/10.1155/2012/591654 [2] Lan et al. 2015, J Ethnopharmacol: https://doi.org/10.1016/j.jep.2014.09.049 [3] Lee et al. 2006, Diabetes: https://doi.org/10.2337/db06-0006 [4] Yin et al. 2008, Metabolism: https://doi.org/10.1016/j.metabol.2008.01.013 [5] Guo et al. 2011, Eur J Clin Pharmacol: https://doi.org/10.1007/s00228-011-1108-2 [6] NCCIH: Goldenseal: https://www.nccih.nih.gov/health/goldenseal Page: https://everstackhealth.com/en/university/berberine # Immunity hub (education only) ## Vitamin D and respiratory infections (evidence grade B) Modest protection in pooled trials, mostly with daily dosing and in people who start low. Large recent trials were null. ### The Martineau meta-analysis Martineau and colleagues pooled individual data from 25 randomized trials with 11,321 participants and found vitamin D supplementation reduced the risk of at least one acute respiratory infection overall (adjusted odds ratio 0.88) [1]. Benefit was seen with daily or weekly dosing, not large single boluses, and was largest in people with very low baseline levels (below 25 nmol/L) [1]. ### The update and the nulls A 2021 update with 43 trials found a smaller pooled effect (odds ratio 0.92), again concentrated in daily dosing of 400 to 1,000 IU [2]. The CORONAVIT trial of a test-and-treat approach in 6,200 UK adults found no reduction in respiratory infections or COVID-19 [3]. Honest reading: vitamin D supports normal immune function, and correcting a low level matters more than taking more than you need.* Adults should stay under the 4,000 IU per day upper limit unless a clinician advises otherwise [4]. Sources: [1] Martineau et al. 2017, BMJ: https://doi.org/10.1136/bmj.i6583 [2] Jolliffe et al. 2021, Lancet Diabetes Endocrinol: https://doi.org/10.1016/S2213-8587(21)00051-6 [3] Jolliffe et al. 2022, BMJ (CORONAVIT): https://doi.org/10.1136/bmj-2022-071230 [4] NIH ODS, Vitamin D fact sheet: https://ods.od.nih.gov/factsheets/VitaminD-HealthProfessional/ Page: https://everstackhealth.com/en/health/immunity/vitamin-d ## Zinc: cold duration, lozenge dosing and copper balance (evidence grade C) Lozenges started early may shorten colds, but the newest Cochrane review rates the evidence low certainty. Long-term high doses can deplete copper. ### The meta-analyses A 2013 Cochrane review found zinc started within 24 hours of symptoms shortened colds in healthy people [1]. A 2017 meta-analysis of lozenge trials estimated colds were about a third shorter, with no clear difference between zinc acetate and zinc gluconate and no evidence that more than about 100 mg per day added benefit [2]. The 2024 Cochrane update, which excluded zinc combined with other ingredients, rated the evidence low or very low certainty: zinc may not prevent colds, may modestly shorten them, and caused more side effects such as nausea and a bad taste [3]. We grade cold-duration evidence C. ### Copper balance and safety The adult upper limit for zinc is 40 mg per day. Chronic intakes above it can reduce copper absorption and cause copper deficiency, which can lead to anemia and nerve problems [4][5]. Short courses of lozenges during a cold are different from daily high-dose capsules. Intranasal zinc has been linked to loss of smell [4]. Sources: [1] Singh & Das 2013, Cochrane: https://doi.org/10.1002/14651858.CD001364.pub4 [2] Hemilä 2017, JRSM Open: https://doi.org/10.1177/2054270417694291 [3] Nault et al. 2024, Cochrane: https://doi.org/10.1002/14651858.CD014914.pub2 [4] NIH ODS, Zinc fact sheet: https://ods.od.nih.gov/factsheets/Zinc-HealthProfessional/ [5] Hoffman et al. 1988, Gastroenterology: https://doi.org/10.1016/0016-5085(88)90445-3 Page: https://everstackhealth.com/en/health/immunity/zinc ## NAC (N-acetylcysteine) (evidence grade C) A glutathione precursor with one notable flu-season trial and stronger data in chronic lung disease, which is a drug use, not a supplement claim. ### The flu-season trial In 262 mostly older adults, 600 mg of NAC twice daily for six months did not change rates of influenza infection by antibody testing, but fewer people developed symptomatic illness (25% vs 79% of infected participants) [1]. It is one trial from 1997 and has not been replicated at scale. ### Lung disease is a drug context A meta-analysis found NAC reduced exacerbations of chronic bronchitis and COPD, with higher doses performing better [2]. That is treatment of a disease and belongs with your clinician. As a supplement, NAC can only be described as supporting antioxidant defenses.* Sources: [1] De Flora et al. 1997, Eur Respir J: https://doi.org/10.1183/09031936.97.10071535 [2] Cazzola et al. 2015, Eur Respir Rev: https://doi.org/10.1183/16000617.00002215 Page: https://everstackhealth.com/en/health/immunity/nac ## Vitamin C and colds (evidence grade C) Does not prevent colds in most people. Regular use slightly shortens them. People under heavy physical stress are the exception. ### The Cochrane review Across 29 trials and over 11,000 participants, regular vitamin C did not reduce how often the general population caught colds [1]. It shortened colds by about 8% in adults and 14% in children [1]. In five trials of people under heavy short-term physical stress, such as marathon runners and soldiers, it roughly halved cold risk [1]. Starting vitamin C after symptoms begin showed no consistent benefit [1]. ### Practical The adult upper limit is 2,000 mg per day; higher intakes can cause diarrhea and may raise kidney stone risk in some people [2]. Sources: [1] Hemilä & Chalker 2013, Cochrane: https://doi.org/10.1002/14651858.CD000980.pub4 [2] NIH ODS, Vitamin C fact sheet: https://ods.od.nih.gov/factsheets/VitaminC-HealthProfessional/ Page: https://everstackhealth.com/en/health/immunity/vitamin-c ## Elderberry: honestly graded (evidence grade D) Small trials, mixed results, low certainty. Not enough to recommend. ### The evidence In 312 air travellers, elderberry extract did not significantly reduce the number of colds; colds in the elderberry group were reported as shorter and milder [1]. A systematic review of five trials concluded elderberry may reduce the duration and severity of respiratory illness but that the evidence is low certainty and does not support use for prevention [2]. NCCIH says there is not enough evidence to know whether it helps [3]. Raw or unripe elderberries and other plant parts can cause nausea and vomiting [3]. We grade it D and do not sell it. Sources: [1] Tiralongo et al. 2016, Nutrients: https://doi.org/10.3390/nu8040182 [2] Wieland et al. 2021, BMC Complement Med Ther: https://doi.org/10.1186/s12906-021-03283-5 [3] NCCIH, European Elder: https://www.nccih.nih.gov/health/european-elder Page: https://everstackhealth.com/en/health/immunity/elderberry ## Probiotics and upper respiratory infections (evidence grade C) Cochrane finds fewer infections with low-certainty evidence. Effects are strain-specific and products vary. ### What the review found The 2022 Cochrane update found probiotics probably reduced the number of people with at least one upper respiratory infection, but the certainty was low to moderate because of trial quality and differences between strains [1]. ### Caveats Results for one strain do not transfer to another, and products may not contain what the label says. People with weakened immune systems and premature infants can develop serious infections from probiotics [2]. Sources: [1] Zhao et al. 2022, Cochrane: https://doi.org/10.1002/14651858.CD006895.pub4 [2] NCCIH, Probiotics: what you need to know: https://www.nccih.nih.gov/health/probiotics-what-you-need-to-know Page: https://everstackhealth.com/en/health/immunity/probiotics # Brain health (education only) ## Omega-3 EPA and DHA for cognition and mood (evidence grade C) DHA is a structural brain fat, but supplement trials for memory and mood are mixed, and VITAL found no prevention benefit. ### Mood A 2019 meta-analysis found formulas with at least 60% EPA, at up to 1 g of EPA daily, improved depressive symptoms, while DHA-dominant formulas did not [1]. The 2021 Cochrane review judged the overall effect small and not clearly meaningful, with low-certainty evidence [2]. In VITAL-DEP, 18,353 adults took 1 g of fish oil or placebo for about five years; omega-3 did not prevent depression and was linked to a small increase in risk [3]. ### Cognition In 485 older adults with age-related memory complaints, 900 mg of DHA daily for 24 weeks improved a learning and memory test [4]. In people who already have Alzheimer's disease, a Cochrane review found no convincing benefit [5]. VITAL's main trial also found no reduction in cardiovascular events or cancer [6]. We describe omega-3 as supporting normal brain function, not as protection against decline.* Sources: [1] Liao et al. 2019, Transl Psychiatry: https://doi.org/10.1038/s41398-019-0515-5 [2] Appleton et al. 2021, Cochrane: https://doi.org/10.1002/14651858.CD004692.pub5 [3] Okereke et al. 2021, JAMA (VITAL-DEP): https://doi.org/10.1001/jama.2021.21187 [4] Yurko-Mauro et al. 2010, Alzheimers Dement (MIDAS): https://doi.org/10.1016/j.jalz.2010.01.013 [5] Burckhardt et al. 2016, Cochrane: https://doi.org/10.1002/14651858.CD009002.pub3 [6] Manson et al. 2019, NEJM (VITAL): https://doi.org/10.1056/NEJMoa1811403 Page: https://everstackhealth.com/en/health/brain/omega-3-brain ## Creatine and cognition (evidence grade C) Small trials suggest memory benefits, larger in older adults. Promising, not proven. ### The evidence A systematic review of six trials found creatine may improve short-term memory and reasoning in healthy people, with inconsistent results for other domains [1]. A 2022 meta-analysis of ten trials found improved memory, with a larger effect in adults aged 66 to 76 [2]. Trials were small and short. Sources: [1] Avgerinos et al. 2018, Exp Gerontol: https://doi.org/10.1016/j.exger.2018.04.013 [2] Prokopidis et al. 2022, Nutr Rev: https://doi.org/10.1093/nutrit/nuac064 Page: https://everstackhealth.com/en/health/brain/creatine-cognition ## Sleep and the brain (evidence grade B) Adults need at least 7 hours. Sleep may help clear brain waste, shown so far in mice. ### How much The American Academy of Sleep Medicine and Sleep Research Society recommend at least 7 hours a night for adults; regularly sleeping less is linked to impaired performance and more errors [1]. ### Why In mice, the space between brain cells expanded by about 60% during sleep and clearance of beta-amyloid increased [2]. Whether the same applies to people is still being studied. Sources: [1] Watson et al. 2015, Sleep: https://doi.org/10.5665/sleep.4716 [2] Xie et al. 2013, Science: https://doi.org/10.1126/science.1241224 Page: https://everstackhealth.com/en/health/brain/sleep-and-the-brain ## Exercise, BDNF and the hippocampus (evidence grade B) Aerobic training grew the memory center in older adults in a randomized trial, and exercise raises BDNF. ### The trial In 120 older adults, a year of walking increased hippocampal volume by about 2%, while the stretching group lost volume, and fitness gains tracked memory gains [1]. ### BDNF Brain-derived neurotrophic factor supports neuron growth. A meta-analysis found single exercise sessions and regular training both raised blood BDNF [2]. Sources: [1] Erickson et al. 2011, PNAS: https://doi.org/10.1073/pnas.1015950108 [2] Szuhany et al. 2015, J Psychiatr Res: https://doi.org/10.1016/j.jpsychires.2014.10.003 Page: https://everstackhealth.com/en/health/brain/exercise-and-bdnf # Glycine (education only) ## Glycine and sleep (evidence grade C) 3 g before bed improved subjective sleep in small Japanese trials funded in part by a glycine maker. ### The trials In a small crossover study, 3 g of glycine before bed improved subjective sleep quality and shortened time to deep sleep on polysomnography [1]. In partially sleep-restricted volunteers it reduced next-day fatigue [2]. Rodent work suggests it lowers core body temperature through receptors in the brain's clock [3]. ### Critique These studies were small, short and conducted by researchers affiliated with a glycine manufacturer [1][2]. We grade the evidence C. Sources: [1] Yamadera et al. 2007, Sleep Biol Rhythms: https://doi.org/10.1111/j.1479-8425.2007.00262.x [2] Bannai et al. 2012, Front Neurol: https://doi.org/10.3389/fneur.2012.00061 [3] Kawai et al. 2015, Neuropsychopharmacology: https://doi.org/10.1038/npp.2014.326 Page: https://everstackhealth.com/en/health/glycine/glycine-sleep ## Glycine and collagen (evidence grade D) Glycine is a third of collagen. One analysis argues the body may not make enough; this is a hypothesis. ### The argument Every third amino acid in collagen is glycine. Meléndez-Hevia and colleagues calculated that the body's capacity to make glycine may fall several grams a day short of collagen turnover needs [1]. This is a metabolic model, not a clinical trial showing better skin or joints from glycine. Sources: [1] Meléndez-Hevia et al. 2009, J Biosci: https://doi.org/10.1007/s12038-009-0100-9 Page: https://everstackhealth.com/en/health/glycine/glycine-collagen ## GlyNAC: the Kumar and Sekhar trials, with critiques (evidence grade D) Glycine plus NAC raised glutathione in small trials from one lab. Interesting, unreplicated. ### The studies Sekhar's group reported that glycine and cysteine restored glutathione synthesis in people with uncontrolled diabetes over two weeks [1]. An open-label pilot in eight older adults reported improvements in glutathione, oxidative stress, mitochondrial markers, strength and gait after 24 weeks of GlyNAC [2]. A placebo-controlled trial then randomized 24 older adults to GlyNAC or alanine for 16 weeks and reported improvements in many of the same markers and in gait speed and strength [3]. ### Critiques All three come from the same research group, with 12 people per arm at most [3]. The pilot had no control group [2]. Dozens of outcomes were measured, which raises the chance of false positives, and most are surrogate markers rather than health outcomes. No independent replication had been published when we reviewed. We grade GlyNAC D and do not sell it. Sources: [1] Sekhar et al. 2010, Diabetes Care: https://doi.org/10.2337/dc10-1006 [2] Kumar et al. 2021, Clin Transl Med: https://doi.org/10.1002/ctm2.372 [3] Kumar et al. 2022, J Gerontol A: https://doi.org/10.1093/gerona/glac135 Page: https://everstackhealth.com/en/health/glycine/glynac # Inflammation and seasonal comfort (education only) ## Quercetin: inflammatory markers, seasonal symptoms, absorption and safety (evidence grade C) A small average drop in CRP across trials, a large null trial, one small seasonal-symptom study, and real drug interactions. Grade C. ### Inflammatory markers: CRP, IL-6, TNF-alpha A meta-analysis of seven randomized trials found quercetin lowered C-reactive protein by an average of 0.33 mg/L, with the effect seen at 500 mg a day or more [1]. That is a small change in a marker, not a health outcome. The honest null: in the largest trial, 1,002 community adults took 500 or 1,000 mg a day (with vitamin C and niacin) for 12 weeks. CRP and inflammatory cytokines did not differ from placebo, apart from a slight IL-6 decrease at 1,000 mg, and the authors called the overall effect negligible [2]. The same trial found no reduction in upper respiratory infections [3]. In 50 women with rheumatoid arthritis, 500 mg a day for 8 weeks lowered TNF-alpha and some symptoms [4], but that is a disease population and a disease use we do not claim. ### Seasonal symptoms Human evidence is thin. In one double-blind trial, 24 adults with Japanese cedar pollen sensitivity took 100 mg of a quercetin glycoside (EMIQ) or placebo for 8 weeks; eye symptom plus medication scores were lower with EMIQ [5]. That is one small trial of a different form. MSK notes that the anti-allergy effects are from lab studies [6]. Quercetin is not a treatment for allergies, and we do not make a seasonal claim. ### Absorption and dosing studied Plain quercetin is poorly soluble and poorly absorbed, and absorption depends on the form [7]. A lecithin-based phytosome form reached plasma levels up to about 20 times higher than unformulated quercetin in 12 healthy volunteers, in a study run with the ingredient maker [8]. Trials have mostly used 500 to 1,000 mg a day of plain quercetin for 8 to 12 weeks [1][2]. ### Safety and drug interactions Side effects in human studies were rare and mild, but there are no adequate safety data for long-term use above 12 weeks at 1,000 mg or more, and animal data raise concerns for people with kidney disease and estrogen-dependent cancers [9]. CYP3A4: quercetin inhibits CYP3A4 and CYP2C19 in lab studies, so it may raise levels of drugs cleared by those enzymes [6]. P-glycoprotein: in 12 healthy people, 500 mg three times a day for 7 days raised exposure to fexofenadine, a P-gp substrate, by 55% [10]. Anticoagulants: a man on stable warfarin had a raised INR after starting quercetin that normalized when he stopped [11]. Quinolone antibiotics: quercetin binds bacterial DNA gyrase, the enzyme these antibiotics target, in lab work [12]; effects in people are unknown, so do not combine with ciprofloxacin or similar drugs without asking your pharmacist. Pregnancy and breastfeeding: supplemental doses have not been studied for safety, so do not use quercetin supplements if pregnant or breastfeeding [9]. Not for children. ### Our grade and our claim Grade C: a small, inconsistent signal on one marker, a large null trial, and limited seasonal data. The only claim we make is: supports a healthy inflammatory response.* Sources: [1] Mohammadi-Sartang et al. 2017, Eur J Clin Nutr: https://doi.org/10.1038/ejcn.2017.55 [2] Knab et al. 2011, J Am Diet Assoc: https://doi.org/10.1016/j.jada.2011.01.013 [3] Heinz et al. 2010, Pharmacol Res: https://doi.org/10.1016/j.phrs.2010.05.001 [4] Javadi et al. 2016, J Am Coll Nutr: https://doi.org/10.1080/07315724.2016.1140093 [5] Hirano et al. 2009, Allergol Int: https://doi.org/10.2332/allergolint.08-oa-0070 [6] Memorial Sloan Kettering, About Herbs: Quercetin: https://www.mskcc.org/cancer-care/integrative-medicine/herbs/quercetin [7] Graefe et al. 2001, J Clin Pharmacol: https://doi.org/10.1177/00912700122010366 [8] Riva et al. 2018, Eur J Drug Metab Pharmacokinet: https://doi.org/10.1007/s13318-018-0517-3 [9] Andres et al. 2017, Mol Nutr Food Res: https://doi.org/10.1002/mnfr.201700447 [10] Kim et al. 2009, Eur J Clin Pharmacol: https://doi.org/10.1007/s00228-009-0627-6 [11] Patel et al. 2022, J Pharm Technol: https://doi.org/10.1177/87551225221125667 [12] Plaper et al. 2003, Biochem Biophys Res Commun: https://doi.org/10.1016/s0006-291x(03)01006-4 Page: https://everstackhealth.com/en/health/inflammation/quercetin # Children's health: education (education only; talk to your pediatrician; doses for children quoted only from AAP, NIH ODS, WHO) ## Growth curves, explained What percentiles mean and why the trend matters more than one point. ### Percentiles Growth charts are percentile curves showing the distribution of body measurements in children. CDC notes they are not meant to be used alone to diagnose; they contribute to an overall picture of the child [1]. In the US, CDC recommends WHO growth standards for children under 2 and CDC charts from 2 to 19 years [1][2]. ### What to watch A child on the 10th percentile who stays there is following their curve. Crossing percentile lines over time is something to discuss with your pediatrician. Sources: [1] CDC, Growth charts: https://www.cdc.gov/growthcharts/ [2] WHO, Child growth standards: https://www.who.int/tools/child-growth-standards Page: https://everstackhealth.com/en/health/kids/growth-curves ## Puberty timing Puberty is starting earlier in girls worldwide. Your pediatrician tracks timing. ### The trend A meta-analysis of studies from 1977 to 2013 found the average age of breast development onset in girls fell by about 0.24 years per decade [1]. Puberty that seems early or late is a question for your pediatrician, who may refer to a pediatric endocrinologist. Sources: [1] Eckert-Lind et al. 2020, JAMA Pediatr: https://doi.org/10.1001/jamapediatrics.2019.5881 Page: https://everstackhealth.com/en/health/kids/puberty ## Sleep and growth hormone Growth hormone peaks in deep sleep. Official sleep targets by age. ### The physiology A classic study found the largest growth hormone release occurs shortly after sleep onset, during slow-wave sleep [1]. ### Official targets The American Academy of Sleep Medicine, endorsed by the AAP, recommends per 24 hours: 12 to 16 hours at 4 to 12 months, 11 to 14 hours at 1 to 2 years, 10 to 13 hours at 3 to 5 years, 9 to 12 hours at 6 to 12 years, and 8 to 10 hours at 13 to 18 years, naps included for younger children [2]. Sources: [1] Takahashi et al. 1968, J Clin Invest: https://doi.org/10.1172/JCI105893 [2] Paruthi et al. 2016, J Clin Sleep Med (AASM): https://doi.org/10.5664/jcsm.5866 Page: https://everstackhealth.com/en/health/kids/sleep-and-growth-hormone ## Vitamin D and iron in infancy and childhood What the AAP and NIH say, quoted. Your pediatrician decides for your child. ### Vitamin D The AAP recommends that breastfed and partially breastfed infants receive 400 IU of vitamin D a day beginning in the first few days of life, as should non-breastfed infants drinking less than about 1 liter of formula a day [1]. NIH lists 400 IU as adequate intake for infants and 600 IU as the recommended amount from age 1 [2]. ### Iron The AAP recommends that full-term breastfed infants receive iron supplementation of 1 mg/kg per day from 4 months until iron-containing foods are introduced, and universal screening for anemia at about 12 months [3]. Iron deficiency in infancy is associated with lasting effects on development [3]. Accidental iron overdose is a leading cause of fatal poisoning in children under 6, so iron products must carry a warning and be stored out of reach [4]. Sources: [1] Wagner et al. 2008, Pediatrics (AAP): https://doi.org/10.1542/peds.2008-1862 [2] NIH ODS, Vitamin D fact sheet: https://ods.od.nih.gov/factsheets/VitaminD-HealthProfessional/ [3] Baker et al. 2010, Pediatrics (AAP): https://doi.org/10.1542/peds.2010-2576 [4] 21 CFR 101.17, iron warning statement: https://www.ecfr.gov/current/title-21/chapter-I/subchapter-B/part-101/subpart-A/section-101.17 Page: https://everstackhealth.com/en/health/kids/vitamin-d-and-iron ## Vaccines: the basics How the schedule works and what the largest safety studies found. ### The schedule CDC publishes the child and adolescent immunization schedule, and the AAP publishes guidance for parents [1][2]. Recommendations are updated over time, so ask your pediatrician which schedule applies to your child and how to catch up on missed doses. ### Safety and autism A meta-analysis of studies including more than 1.2 million children found no association between vaccines and autism [3]. Sources: [1] CDC, Child and adolescent immunization schedule: https://www.cdc.gov/vaccines/hcp/imz-schedules/child-adolescent-age.html [2] AAP HealthyChildren.org, Immunizations: https://www.healthychildren.org/English/safety-prevention/immunizations/Pages/default.aspx [3] Taylor et al. 2014, Vaccine: https://doi.org/10.1016/j.vaccine.2014.04.085 Page: https://everstackhealth.com/en/health/kids/vaccines-basics ## Immunity basics: nutrition and sleep Food, sleep and vaccines are the foundation. What the cold-remedy evidence in children shows. ### Foundation Age-appropriate sleep [1] and recommended vaccines [2] are the best-supported foundations. In children, regular vitamin C shortened colds by about 14% in trials but did not prevent them [3], and vitamin D's pooled benefit was clearest with daily dosing in ages 1 to 15 [4]. Probiotics should not be given to premature infants or immunocompromised children without medical advice [5]. Sources: [1] Paruthi et al. 2016, J Clin Sleep Med (AASM): https://doi.org/10.5664/jcsm.5866 [2] CDC, Child and adolescent immunization schedule: https://www.cdc.gov/vaccines/hcp/imz-schedules/child-adolescent-age.html [3] Hemilä & Chalker 2013, Cochrane: https://doi.org/10.1002/14651858.CD000980.pub4 [4] Jolliffe et al. 2021, Lancet Diabetes Endocrinol: https://doi.org/10.1016/S2213-8587(21)00051-6 [5] NCCIH, Probiotics: what you need to know: https://www.nccih.nih.gov/health/probiotics-what-you-need-to-know Page: https://everstackhealth.com/en/health/kids/immunity-nutrition-sleep ## Omega-3 in pregnancy and infancy Fewer preterm births in Cochrane; no clear boost to child development in the largest trial. ### Pregnancy A Cochrane review of 70 trials found omega-3 in pregnancy reduced preterm birth before 37 weeks and early preterm birth before 34 weeks, with high-quality evidence, and little clear effect on child development [1]. In the DOMInO trial, 800 mg of DHA daily in pregnancy did not improve children's cognitive or language scores at 18 months [2]. ### Food first FDA and EPA advise pregnant and breastfeeding people to eat 8 to 12 ounces a week of low-mercury fish, and children 1 to 2 servings a week of age-appropriate size [3]. Sources: [1] Middleton et al. 2018, Cochrane: https://doi.org/10.1002/14651858.CD003402.pub3 [2] Makrides et al. 2010, JAMA (DOMInO): https://doi.org/10.1001/jama.2010.1507 [3] FDA/EPA, Advice about eating fish: https://www.fda.gov/food/consumers/advice-about-eating-fish [4] NIH ODS, Omega-3 fact sheet: https://ods.od.nih.gov/factsheets/Omega3FattyAcids-HealthProfessional/ Page: https://everstackhealth.com/en/health/kids/omega-3-pregnancy-infancy ## Iron, iodine and brain development Two minerals the developing brain depends on. ### Iodine In a UK cohort, children of mothers with mild-to-moderate iodine deficiency in pregnancy had lower verbal IQ and reading scores [1]. NIH lists 220 mcg a day as the recommended intake in pregnancy [2]. ### Iron The AAP links iron deficiency in infancy with neurodevelopmental effects that may persist [3]. Your pediatrician screens for it. Sources: [1] Bath et al. 2013, Lancet (ALSPAC): https://doi.org/10.1016/S0140-6736(13)60436-5 [2] NIH ODS, Iodine fact sheet: https://ods.od.nih.gov/factsheets/Iodine-HealthProfessional/ [3] Baker et al. 2010, Pediatrics (AAP): https://doi.org/10.1542/peds.2010-2576 Page: https://everstackhealth.com/en/health/kids/iron-and-iodine ## Screen time, sleep and exercise WHO and AAP guidance, quoted, plus what active play does for thinking. ### Screens The AAP advises avoiding digital media other than video chatting before 18 to 24 months, and limiting children 2 to 5 years to 1 hour a day of high-quality programming watched together [1][2]. WHO advises no sedentary screen time for children under 2 and no more than 1 hour for ages 2 to 4 [3]. ### Exercise WHO recommends an average of 60 minutes a day of moderate-to-vigorous activity for ages 5 to 17 [4]. An American College of Sports Medicine review found physical activity has positive effects on cognitive function in children, while effects on academic achievement are less consistent [5]. Sleep targets by age are in our sleep and growth article [6]. Sources: [1] AAP Council on Communications and Media 2016, Pediatrics: https://doi.org/10.1542/peds.2016-2591 [2] AAP HealthyChildren.org, Media: https://www.healthychildren.org/English/family-life/Media/Pages/default.aspx [3] WHO 2019, Guidelines on physical activity, sedentary behaviour and sleep for children under 5: https://www.who.int/publications/i/item/9789241550536 [4] WHO 2020, Guidelines on physical activity and sedentary behaviour: https://www.who.int/publications/i/item/9789240015128 [5] Donnelly et al. 2016, Med Sci Sports Exerc: https://doi.org/10.1249/MSS.0000000000000901 [6] Paruthi et al. 2016, J Clin Sleep Med (AASM): https://doi.org/10.5664/jcsm.5866 Page: https://everstackhealth.com/en/health/kids/screens-sleep-exercise # Kids shop (candidate products, waitlist only; purchaser must be a parent or guardian 18+; label dose only; ask your pediatrician first; no melatonin, no stimulants, no adult products for children) - Kids Vitamin D3 Drops (Infants from birth and children (per label)). Label dose: 1 drop (400 IU, 10 mcg) daily, on a nipple, breast, spoon or in food. Do not exceed label dose. Supports healthy bones and teeth.* Grade A. The AAP recommends 400 IU of vitamin D daily for breastfed and partially breastfed infants beginning in the first days of life [1]. NIH lists 400 IU as adequate intake for infants and 600 IU from age 1 [2]. Cautions: Formula already contains vitamin D; ask how much your baby needs from drops. Use only the drop format on the label; one drop is the full serving. Keep out of reach of children. Store closed, away from heat. Do not exceed the label dose. Tell your pediatrician about every supplement and medicine your child takes. Sources: [1] https://doi.org/10.1542/peds.2008-1862 [2] https://ods.od.nih.gov/factsheets/VitaminD-HealthProfessional/ Pediatrician sheet: https://everstackhealth.com/en/kids/print/kids-vitamin-d3-drops - Kids Omega-3 DHA (Children 4 to 12 years (per label)). Label dose: 1 softgel daily (250 mg DHA, 100 mg EPA) with food. Supports normal brain and eye development.* Grade C. DHA is a structural fat in the brain and retina [1]. Honest null: in the largest pregnancy trial, DHA did not improve children's cognition at 18 months [2], and trial evidence that supplements improve thinking in healthy children is limited. FDA and EPA advise 1 to 2 servings of low-mercury fish a week for children; food comes first [3]. Cautions: Contains fish. Not for children with fish allergy. Chewable softgel: supervise children who may choke. Keep out of reach of children. Store closed, away from heat. Do not exceed the label dose. Tell your pediatrician about every supplement and medicine your child takes. Sources: [1] https://ods.od.nih.gov/factsheets/Omega3FattyAcids-HealthProfessional/ [2] https://doi.org/10.1001/jama.2010.1507 [3] https://www.fda.gov/food/consumers/advice-about-eating-fish Pediatrician sheet: https://everstackhealth.com/en/kids/print/kids-omega-3-dha - Kids Daily Multivitamin (iron-free) (Children 4 years and older (per label)). Label dose: 1 chewable tablet daily with food. Helps fill common nutrient gaps to support normal growth.* Grade C. Most children who eat a varied diet meet their needs from food; a multivitamin is a backup, not a substitute. The 600 IU of vitamin D matches the NIH recommended amount from age 1 [1]. It is iron-free because accidental iron overdose is a leading cause of fatal poisoning in children under 6 [2]; the AAP recommends checking iron status with your pediatrician instead [3]. Cautions: Looks and tastes pleasant: it is not candy. Store out of reach. Do not combine with other vitamin D or multivitamin products without asking your pediatrician. Keep out of reach of children. Store closed, away from heat. Do not exceed the label dose. Tell your pediatrician about every supplement and medicine your child takes. Sources: [1] https://ods.od.nih.gov/factsheets/VitaminD-HealthProfessional/ [2] https://www.ecfr.gov/current/title-21/chapter-I/subchapter-B/part-101/subpart-A/section-101.17 [3] https://doi.org/10.1542/peds.2010-2576 Pediatrician sheet: https://everstackhealth.com/en/kids/print/kids-multivitamin - Kids Daily Probiotic (Children 3 years and older (per label)). Label dose: 1 stick (Lactobacillus rhamnosus GG, 10 billion CFU at expiry) daily in cool food or drink. Supports digestive health.* Grade C. A Cochrane review found probiotics probably reduce the number of people with upper respiratory infections, with low-to-moderate certainty, and effects vary by strain [1]. NCCIH notes products may not contain what the label states and that probiotics can cause serious infections in premature infants and people with weakened immune systems [2]. Cautions: Not for premature infants, children with weakened immune systems, central lines or serious illness. Do not mix into hot food, which can kill the bacteria. Keep out of reach of children. Store closed, away from heat. Do not exceed the label dose. Tell your pediatrician about every supplement and medicine your child takes. Sources: [1] https://doi.org/10.1002/14651858.CD006895.pub4 [2] https://www.nccih.nih.gov/health/probiotics-what-you-need-to-know Pediatrician sheet: https://everstackhealth.com/en/kids/print/kids-probiotic # Starter Pack Starter Pack: $37 one-time (compare at $46.37, 20% off, $1.23/day), 30-day supply of creatine, omega3, d3k2. One per customer (one per email and shipping address). 30-day supply: creatine, omega-3 (EPA/DHA) and vitamin D3 + K2. Shipping included. Compare-at price is the sum of the list prices for a 30-day share of each item. It does not renew on its own. Only if you tick the separate, unchecked box does it roll into Foundation at $72/month after day 30. Cancel anytime before or after. Pre-launch: joining reserves the offer. No payment is taken today. # Candidate SKUs - Berberine HCl (grade B, not for sale): Supports healthy glucose metabolism.* Label dose: Dose under review; trials commonly used 500 mg up to three times daily with meals. Talk to your clinician if you have diabetes or take medication. Not for use during pregnancy or breastfeeding or by children. Evidence: https://everstackhealth.com/en/science/berberine-glucose-metabolism - Quercetin Phytosome (grade C, $46 per 30 days, waitlist open: https://everstackhealth.com/en/products/quercetin): Supports a healthy inflammatory response.* Label dose: Label dose: 1 capsule (250 mg quercetin phytosome) twice daily with meals. Trials of plain quercetin used 500 to 1,000 mg a day for 8 to 12 weeks. Not for use during pregnancy or breastfeeding or by children. Ask your clinician or pharmacist first if you take any prescription drug, especially blood thinners (warfarin), quinolone antibiotics (for example ciprofloxacin), cyclosporine or other drugs processed by CYP3A4 or P-glycoprotein, or if you have kidney disease or an estrogen-sensitive condition. Evidence: https://everstackhealth.com/en/health/inflammation/quercetin # Who we read (no endorsement or affiliation) ## David Sinclair, PhD Professor of Genetics, Harvard Medical School; co-founder, Life Biosciences. Studies sirtuins, NAD+ and epigenetic reprogramming. His information theory of aging underpins Life Biosciences' ER-100 trial. Co-author of the 2003 resveratrol-sirtuin paper that was later disputed. Our grades vs their view: We grade NAD+ precursors C and resveratrol D for human outcomes; his public enthusiasm for both runs ahead of the controlled human data we cite. On reprogramming we agree it is the most interesting frontier, and still preclinical or phase 1. Exact quote: "Our research has suggested that aging is driven in large part by the loss of epigenetic information, not irreversible damage." Source: https://www.lifebiosciences.com/life-biosciences-announces-first-patient-dosed-in-phase-1-trial-of-er-100-for-optic-neuropathies/ Profiles: https://x.com/davidasinclair, https://sinclair.hms.harvard.edu, https://www.lifespanpodcast.com ## Peter Attia, MD Physician; host of The Drive; author of Outlive. Focuses on exercise, nutrition, sleep and emotional health for healthspan, with heavy emphasis on VO2max and strength. Our grades vs their view: Close agreement on exercise as the highest-yield lever (see Training for lifespan). He discusses rapamycin more openly than we do; we leave it out as a prescription drug. Paraphrase: most supplements have modest or unproven effects, and exercise, sleep and nutrition matter far more. Source: https://www.hubermanlab.com/episode/dr-peter-attia-supplements-for-longevity-their-efficacy Profiles: https://x.com/PeterAttiaMD, https://peterattiamd.com, https://www.youtube.com/@PeterAttiaMD ## Andrew Huberman, PhD Professor of Neurobiology, Stanford; host of Huberman Lab. Hosts one of the most listened-to science podcasts, covering sleep, light, exercise and supplements. Our grades vs their view: Some sleep compounds he popularized (apigenin, L-theanine) carry only C grades from us: small trials, mostly subjective outcomes. Paraphrase: behavioral tools such as morning light, consistent timing and temperature come before any sleep supplement. Source: https://www.hubermanlab.com/episode/master-your-sleep-and-be-more-alert-when-awake Profiles: https://x.com/hubermanlab, https://www.hubermanlab.com, https://www.youtube.com/@hubermanlab ## Rhonda Patrick, PhD Biomedical scientist; founder of FoundMyFitness. Covers micronutrients, omega-3, vitamin D, sauna and exercise, often with researchers as guests. Our grades vs their view: She leans on the Omega-3 Index and blood-level data; we grade omega-3 for heart outcomes more cautiously given null trials (VITAL, STRENGTH, ASCEND). Paraphrase: many people fall short on key micronutrients, and blood levels are a better guide than intake guesses. Source: https://www.hubermanlab.com/episode/dr-rhonda-patrick-micronutrients-for-health-and-longevity Profiles: https://x.com/foundmyfitness, https://www.foundmyfitness.com, https://www.youtube.com/@FoundMyFitness ## Matt Kaeberlein, PhD Biologist of aging; former professor, University of Washington. Co-led the Dog Aging Project and published key work questioning resveratrol's activation of sirtuins. Our grades vs their view: Agrees with our low resveratrol grade. More optimistic than us about rapamycin in people; we keep it out as an Rx drug. Exact quote: "In light of these findings, the mechanism accounting for putative longevity effects of resveratrol should be reexamined." Source: https://doi.org/10.1074/jbc.M500655200 Profiles: https://x.com/mkaeberlein ## Valter Longo, PhD Professor of Gerontology, USC; developer of the fasting-mimicking diet. Researches fasting, nutrient sensing and aging. Has a financial interest in a fasting-mimicking diet company. Our grades vs their view: We grade the fasting-mimicking diet C: one 100-person trial on risk markers, developer-affiliated. Exact quote: "Larger studies in patients with diagnosed diseases or selected on the basis of risk factors are warranted to confirm the effect of the FMD on disease prevention and treatment." Source: https://doi.org/10.1126/scitranslmed.aai8700 Profiles: https://x.com/ProfValterLongo, https://www.valterlongo.com ## Eric Topol, MD Cardiologist; founder of Scripps Research Translational Institute. Writes Ground Truths and the book Super Agers; focuses on evidence-based prevention, genomics and AI in medicine. Our grades vs their view: Shares our skepticism of supplement hype and our emphasis on randomized trials over biomarkers. Paraphrase: healthy aging is driven mostly by exercise, diet, sleep and avoiding risks, not by supplements. Source: https://erictopol.substack.com Profiles: https://x.com/EricTopol, https://erictopol.substack.com ## Andrew Steele, PhD Scientist and author of Ageless. Computational biologist turned science communicator; explains aging biology and evaluates longevity claims on YouTube. Our grades vs their view: Like us, separates promising mouse data from proven human benefit. Paraphrase: treating aging itself could prevent many diseases at once, but most products marketed for aging are not yet supported by human trials. Source: https://andrewsteele.co.uk Profiles: https://x.com/statto, https://andrewsteele.co.uk, https://www.youtube.com/@DrAndrewSteele ## Layne Norton, PhD Nutrition scientist and powerlifter; founder of BioLayne. Known for evidence-focused commentary on protein, energy balance and training. Our grades vs their view: Aligned with our A grade for creatine and our protein targets. Paraphrase: creatine is one of the few supplements with strong evidence; most results come from training, protein and calories. Source: https://open.spotify.com/episode/5X2uyUy54QABaDUuyCOOVY Profiles: https://x.com/BioLayne, https://www.biolayne.com ## Stuart Phillips, PhD Professor of Kinesiology, McMaster University. Leading researcher on protein, resistance training and muscle in aging. Our grades vs their view: Our protein guidance follows his group's meta-analysis. Exact quote: "Dietary protein supplementation significantly enhanced changes in muscle strength and size during prolonged RET in healthy adults." Source: https://doi.org/10.1136/bjsports-2017-097608 Profiles: https://x.com/mackinprof, https://www.science.mcmaster.ca/kinesiology/people/faculty/stuart-phillips ## Nir Barzilai, MD Director, Institute for Aging Research, Albert Einstein College of Medicine. Studies centenarians and leads efforts to run the TAME metformin trial. Our grades vs their view: We do not offer metformin (Rx) and grade its case as a longevity drug D until TAME or similar trials report. Exact quote: "Metformin, which has demonstrated protective effects against several age-related diseases in humans, will be tested in the TAME (Targeting Aging with Metformin) trial" Source: https://doi.org/10.1016/j.cmet.2016.05.011 Profiles: https://x.com/NirBarzilai ## Eric Verdin, MD President and CEO, Buck Institute for Research on Aging. Researches NAD+ metabolism, sirtuins and immune aging. Our grades vs their view: His NAD+ biology work supports the mechanism behind our NR pick; human outcome data remain thin, hence grade C. Paraphrase: NAD+ levels decline with age, and whether restoring them benefits humans still needs controlled trials. Source: https://www.buckinstitute.org/lab/verdin-lab/ Profiles: https://www.buckinstitute.org/lab/verdin-lab/ ## Darren Candow, PhD Professor, University of Regina; creatine researcher. Studies creatine and resistance training in aging adults. Our grades vs their view: Our A grade for creatine with training matches his meta-analyses. Exact quote: "creatine supplementation increases lean tissue mass and upper and lower body muscular strength during resistance training of older adults" Source: https://doi.org/10.2147/OAJSM.S123529 Profiles: https://x.com/darrencandow ## Brad Stanfield, MD Primary care physician, New Zealand; YouTube educator. Reviews longevity supplements and trials for a general audience. Our grades vs their view: Similar trial-first approach; he sells his own supplements, which we note as a potential conflict. Paraphrase: base supplement choices on randomized trials in humans, not mouse studies. Source: https://www.youtube.com/@DrBradStanfield Profiles: https://x.com/BradStanfieldMD, https://www.youtube.com/@DrBradStanfield ## Bryan Johnson Entrepreneur; founder of Blueprint. Publishes his personal longevity protocol and biomarkers. Not a scientist; his data are n-of-1 and he sells products. Our grades vs their view: We read Blueprint as an experiment, not evidence: one person, many simultaneous interventions, commercial interest. Paraphrase: his protocol is built on measuring his own biomarkers and adjusting based on the data. Source: https://protocol.bryanjohnson.com Profiles: https://x.com/bryan_johnson, https://protocol.bryanjohnson.com # What we leave out and why ## Metformin (grade Rx) Why: A prescription drug in the US. Not something a supplement company can or should sell. Evidence: The aging case rests on observational data in people with diabetes; the TAME trial meant to test it in non-diabetic adults has not started for lack of full funding. Citations: https://doi.org/10.1016/j.cmet.2016.05.011, https://doi.org/10.1111/dom.12354, https://www.afar.org/tame-trial ## Rapamycin (sirolimus) (grade Rx) Why: Prescription immunosuppressant. Human longevity data are early and side effects are real. Evidence: Robust lifespan extension in mice. In the 48-week PEARL trial, low-dose rapamycin did not change its primary endpoint (visceral fat). Citations: https://doi.org/10.1038/nature08221, https://doi.org/10.18632/aging.206235 ## High-dose resveratrol (grade D) Why: The sirtuin-activation story was disputed, it did not extend lifespan in rigorous mouse testing, and human outcome data are absent. Evidence: Yeast lifespan effect not replicated (Kaeberlein 2005); no lifespan effect in the NIA Interventions Testing Program (Miller 2011); dietary levels unrelated to mortality in older adults (Semba 2014). Citations: https://doi.org/10.1074/jbc.M500655200, https://doi.org/10.1074/jbc.M109.088682, https://doi.org/10.1093/gerona/glq178, https://doi.org/10.1001/jamainternmed.2014.1582 ## NMN (grade C) Why: Regulatory status was unsettled: FDA said in 2022 that NMN was excluded from the supplement definition, then reversed that position on September 29, 2025. It is now lawful to sell, but its human evidence is no stronger than NR, which has the longer safety record, so we chose NR. We will revisit as trials report. Evidence: Small trials show it raises NAD+ and one found improved muscle insulin sensitivity in 25 women; no lifespan data in people. Citations: https://doi.org/10.1126/science.abe9985, https://doi.org/10.1007/s11357-022-00705-1, https://www.nutraingredients.com/Article/2025/09/30/fda-declares-nmn-lawful-in-dietary-supplements/ ## Fisetin, dasatinib + quercetin (senolytics) (grade D) Why: Promising in mice, but human trials are small and the leading senolytic company (Unity Biotechnology) wound down in 2025 after mixed results. Dasatinib is a cancer drug. Evidence: Mouse function and survival improved (Xu 2018); a 14-person open-label pilot in lung fibrosis showed feasibility only (Justice 2019). Citations: https://doi.org/10.1038/s41591-018-0092-9, https://doi.org/10.1016/j.ebiom.2018.12.052 ## Spermidine (grade D) Why: Human evidence is observational dietary data; supplement doses are far below those used in mice. Evidence: Extended mouse lifespan; dietary intake correlated with lower blood pressure in people. Citations: https://doi.org/10.1038/nm.4222 ## High-dose vitamin E and beta-carotene (grade A) Why: Grade A evidence, of harm: large trials found no benefit and some increased risk. Evidence: Beta-carotene raised lung cancer in smokers (ATBC); vitamin E raised prostate cancer risk (SELECT); USPSTF recommends against both. Citations: https://doi.org/10.1056/NEJM199404143301501, https://doi.org/10.1001/jama.2011.1437, https://doi.org/10.1002/14651858.CD007176.pub2 ## Standalone calcium (grade B) Why: Food is the better source; supplement-only calcium has been linked to cardiovascular risk signals. Evidence: Meta-analysis found more heart attacks with calcium supplements without vitamin D; debated. Citations: https://doi.org/10.1136/bmj.c3691 ## Taurine, alpha-ketoglutarate, urolithin A (as longevity agents) (grade D) Why: Interesting animal data, few or industry-funded human trials with surrogate endpoints. We will revisit as trials report. Evidence: Taurine extended mouse lifespan about 10-12%; Ca-AKG reduced frailty in mice; urolithin A missed primary endpoints in a 66-person trial. Citations: https://doi.org/10.1126/science.abn9257, https://doi.org/10.1016/j.cmet.2020.08.004, https://doi.org/10.1001/jamanetworkopen.2021.44279 # Frontier (research, not products; updated 2026-10-15) ## Partial epigenetic reprogramming: Life Biosciences ER-100 (David Sinclair, co-founder) Stage: Phase 1 (safety). Checked 2026-10-15. What: A gene therapy injected into the eye that turns on three Yamanaka factors (OCT4, SOX2, KLF4) under doxycycline control, aiming to restore youthful function in optic nerve cells. Latest: Phase 1 (NCT07290244) started March 2, 2026; first participant dosed (announced June 9, 2026). On October 8, 2026 the company reported that 3 glaucoma participants tolerated the lowest dose through day 56, with preliminary visual-field signals in 2 of them. Up to 18 adults (12 glaucoma, 6 NAION). Critiques: Three people, open label, company-reported, no control group. Visual-field tests are noisy. The mouse work (Lu 2020) is strong, but the broader claim that aging is mainly loss of epigenetic information is debated. Sources: https://clinicaltrials.gov/study/NCT07290244, https://www.lifebiosciences.com/life-biosciences-announces-first-patient-dosed-in-phase-1-trial-of-er-100-for-optic-neuropathies/, https://www.lifebiosciences.com/life-biosciences-announces-first-in-human-data-from-ongoing-phase-1-trial-evaluating-er-100-in-optic-neuropathies/, https://doi.org/10.1038/s41586-020-2975-4, https://doi.org/10.1016/j.cell.2022.12.027 ## XPRIZE Healthspan and Fountain Life (Peter Diamandis) Stage: Competition; finalist trials starting. Checked 2026-10-15. What: A $101M, 7-year competition, co-founded by Diamandis, rewarding therapies that restore muscle, cognition and immune function in adults 50+. Diamandis also co-founded Fountain Life, a chain of executive-health clinics. Latest: May 12, 2025: 40 Milestone 1 winners ($250,000 each). August 11, 2026: 20 finalists named, 10 awarded $1M each; finalist trials run 2026 to 2029, grand prize in 2030. Fountain Life raised an $18M Series B in August 2025. Critiques: Prize trials last up to one year, too short for hard outcomes. Clinic-based full-body scans and extensive testing in healthy people raise false-positive and cost concerns. Sources: https://www.xprize.org/news/101m-xprize-healthspan-awards-first-milestone-winners-driving-toward-revolutionary-healthy-aging-advances, https://www.xprize.org/news/20-healthspan-finalist-teams-advance-in-the-race-to-extend-healthy-aging, https://techcrunch.com/2025/08/13/tony-robbins-and-peter-diamandis-longevity-company-fountain-life-raises-18m/ ## Altos Labs Stage: Mostly preclinical; first authorized trial (Spain). Checked 2026-10-15. What: A cellular rejuvenation company launched in 2022 with about $3B, led by Hal Barron. Latest: Acquired Dorian Therapeutics (senescence 'senoblockers') in May 2025. Spain authorized an Altos Phase 1/2a trial of ATX-2a, an intra-articular AAV for knee osteoarthritis, on December 15, 2025. Critiques: Little peer-reviewed human data so far; most progress is disclosed through deals and regulatory filings. Sources: https://longevity.technology/news/altos-labs-snaps-up-dorian-therapeutics/, https://www.miteco.gob.es/content/dam/miteco/es/calidad-y-evaluacion-ambiental/omg/resoluciones-lv/Resoluci%C3%B3n_B_ES_25_15.pdf ## Retro Biosciences Stage: Phase 1 (safety). Checked 2026-10-15. What: Backed by a $180M seed from Sam Altman; lead drug RTR242 is a pill meant to restore lysosome function and autophagy, initially aimed at Alzheimer's disease. Latest: Phase 1 in healthy adults in Adelaide (ACTRN12625001274460) began dosing in December 2025 and expanded to higher doses in August 2026. No efficacy data. Critiques: Healthy-volunteer safety study only; the Alzheimer's hypothesis is untested in patients. Sources: https://anzctr.org.au/Trial/Registration/TrialReview.aspx?ACTRN=ACTRN12625001274460, https://longevity.technology/news/retro-bio-commences-first-in-human-trial/ ## NewLimit Stage: Preclinical. Checked 2026-10-15. What: Co-founded by Brian Armstrong; screens transcription-factor combinations to rejuvenate cells, delivered as mRNA in lipid nanoparticles. Lead target: liver. Latest: $130M Series B (May 6, 2025); additional $45M including Eli Lilly (October 20, 2025). Reports prototype medicine M0004 improved liver regeneration and alcohol-injury resilience in old mice. Critiques: Data shared via company blog, not peer review. Sources: https://blog.newlimit.com/p/newlimit-raises-130-million-series, https://blog.newlimit.com/p/newlimit-has-raised-an-additional ## Senolytics and Unity Biotechnology Stage: Company dissolved; academic trials continue. Checked 2026-10-15. What: Drugs that clear senescent (zombie) cells. Unity was the best-funded senolytics company. Latest: UBX1325 missed its primary non-inferiority endpoint at weeks 20-24 in the ASPIRE Phase 2b eye trial (2025). Shareholders approved dissolution on September 18, 2025. Critiques: Strong mouse data (Xu 2018) have not yet translated into clear human benefit. Sources: https://www.sec.gov/Archives/edgar/data/1463361/000119312525209210/d804178d8k.htm, https://doi.org/10.1038/s41591-018-0092-9, https://doi.org/10.1016/j.ebiom.2018.12.052 ## Rapamycin trials (PEARL) Stage: Phase 2. Checked 2026-10-15. What: Testing whether low, intermittent doses of the mTOR inhibitor rapamycin improve healthspan markers in people. Latest: PEARL (114 adults, 48 weeks, published 2025): relatively safe; no change in visceral fat (primary endpoint); lean mass and pain improved in women on 10 mg weekly. Critiques: Primary endpoint null, many secondary outcomes, sponsor sells rapamycin. Sources: https://doi.org/10.18632/aging.206235, https://doi.org/10.1038/nature08221 ## TAME (Targeting Aging with Metformin) Stage: Not started. Checked 2026-10-15. What: A proposed 6-year, ~3,000-person trial testing whether metformin delays age-related diseases in people without diabetes. Latest: As of 2025, still not started: AFAR continues fundraising. Observational support was weakened by later analyses. Critiques: Metformin may blunt some exercise adaptations; the case rests on observational data. Sources: https://www.afar.org/tame-trial, https://doi.org/10.1016/j.cmet.2016.05.011 ## Epigenetic clocks Stage: Research biomarker. Checked 2026-10-15. What: DNA methylation patterns that estimate biological age or pace of aging (Horvath, PhenoAge, GrimAge, DunedinPACE). Latest: In trials, calorie restriction slowed DunedinPACE (CALERIE, 2023) and omega-3 slightly slowed several clocks over 3 years (DO-HEALTH, 2025). Critiques: Clocks predict risk but are not validated treatment targets; consumer test results vary between labs and repeats. Sources: https://doi.org/10.1186/gb-2013-14-10-r115, https://doi.org/10.7554/eLife.73420, https://doi.org/10.1038/s43587-022-00357-y, https://doi.org/10.1038/s43587-024-00793-y ## GLP-1 drugs and aging Stage: Approved drugs; aging use is investigational. Checked 2026-10-15. What: Semaglutide and related drugs for diabetes and obesity are being studied for broader age-related effects. Latest: SELECT (2023): semaglutide cut major cardiovascular events in people with obesity and heart disease. EVOKE and EVOKE+ (2026): oral semaglutide did not slow early Alzheimer's. A small trial reported slower epigenetic clocks (2026). Critiques: Benefits are tied to weight and metabolic disease; muscle loss during weight loss is a concern. Prescription only. Sources: https://doi.org/10.1056/NEJMoa2307563 ## Bryan Johnson's Blueprint Stage: n-of-1 self-experiment. Checked 2026-10-15. What: A self-experiment combining diet, exercise, sleep, dozens of supplements and medical procedures, with biomarkers published online. Latest: Johnson reports improved biomarkers, including DunedinPACE values well below 1.0, in self-published data and a 2024 letter. Critiques: One person, no control, many simultaneous changes, commercial products. Clock improvements do not prove slower aging. Sources: https://protocol.bryanjohnson.com, https://www.newscientist.com/article/2495156-the-real-scientific-insights-from-bryan-johnsons-immortality-quest/ # Podcast episodes (verified links) - Huberman Lab: Dr. David Sinclair: The Biology of Slowing & Reversing Aging (2021-12-27). Spotify https://open.spotify.com/episode/0vblYxPcynJPfu0Ap1osG9 | Apple https://podcasts.apple.com/us/podcast/the-biology-of-slowing-reversing-aging-dr-david-sinclair/id1545953110?i=1000546195888 | YouTube https://www.youtube.com/watch?v=n9IxomBusuw. Topics: nad-precursors, nr-human-trials, nmn-human-trials, resveratrol-sirtuin-debate, resveratrol-lifespan, metformin-tame, fasting-mimicking-diet - Huberman Lab: Dr. Rhonda Patrick: Micronutrients for Health & Longevity (2022-05-02). Spotify https://open.spotify.com/episode/37xCQPgSW2BUd1fjov3P6Z | Apple https://podcasts.apple.com/us/podcast/micronutrients-for-health-longevity-dr-rhonda-patrick/id1545953110?i=1000559307595 | YouTube https://www.youtube.com/watch?v=XcvhERcZpWw. Topics: omega-3, omega-3-index, vitamin-d, magnesium - Huberman Lab: Master Your Sleep & Be More Alert When Awake (2021-01-11). Spotify https://open.spotify.com/episode/4JIM6biMG5CQDsSMQFwG3O | Apple https://podcasts.apple.com/us/podcast/master-your-sleep-be-more-alert-when-awake/id1545953110?i=1000504980563 | YouTube https://www.youtube.com/watch?v=nm1TxQj9IsQ | Timestamps: 01:10:00 Drugs and supplements for sleep. Topics: sleep-stack, magnesium, magnesium-insomnia-review - Huberman Lab: Dr. Layne Norton: The Science of Eating for Health, Fat Loss & Lean Muscle (2022-11-07). Spotify https://open.spotify.com/episode/6LTakbZLM0pcFgRqEU3lIW | Apple https://podcasts.apple.com/us/podcast/the-science-of-eating-for-health-fat-loss-lean-muscle/id1545953110?i=1000585302260 | YouTube https://www.youtube.com/watch?v=K4Ze-Sp6aUE. Topics: protein, protein-older-adults - Huberman Lab: Dr. Peter Attia: Supplements for Longevity & Their Efficacy (2024-07-29). Spotify https://open.spotify.com/episode/1ORcuTEdQaDIbjOBY5Ye8S | Apple https://podcasts.apple.com/us/podcast/supplements-for-longevity-their-efficacy-dr-peter-attia/id1545953110?i=1000663655389 | YouTube https://www.youtube.com/watch?v=79p1X_7rAMo | Timestamps: 00:17:22 Rapamycin and research data; 00:43:42 Sirtuins, DNA repair, resveratrol; 01:02:17 NAD vs NR vs NMN supplementation; 01:44:37 Biological aging tests. Topics: nad-precursors, nr-human-trials, nmn-human-trials, resveratrol-sirtuin-debate, rapamycin, epigenetic-clocks - The Peter Attia Drive: #175 Matt Kaeberlein, Ph.D.: The biology of aging, rapamycin, and other interventions that target the aging process (2021-09-13). Spotify https://open.spotify.com/episode/5QNGo9OXwSsy6eqiFG6Nzs | Apple https://podcasts.apple.com/us/podcast/matt-kaeberlein-ph-d-the-biology-of-aging/id1400828889?i=1000535142353 | YouTube https://www.youtube.com/watch?v=_vsNw-OCciU. Topics: rapamycin, nad-precursors, epigenetic-clocks, resveratrol-sirtuin-debate - The Peter Attia Drive: #235 Training principles for mass and strength, changing views on nutrition, creatine supplementation, and more | Layne Norton, Ph.D. (2022-12-19). Spotify https://open.spotify.com/episode/5X2uyUy54QABaDUuyCOOVY | Apple https://podcasts.apple.com/us/podcast/training-principles-for-mass-and-strength-changing/id1400828889?i=1000590601198 | YouTube https://www.youtube.com/watch?v=EbykBDSAwzE. Topics: creatine, protein - FoundMyFitness: #068 Dr. Bill Harris on the Omega-3 Index: Increasing Omega-3 to Promote Longevity & Transform Health (2021-09-10). Spotify https://open.spotify.com/episode/3jEMz47gRvgBQBBEz0tlZ9 | Apple https://podcasts.apple.com/us/podcast/068-dr-bill-harris-on-the-omega-3-index-increasing/id818198322?i=1000534976643 | YouTube https://www.youtube.com/watch?v=-f-CFQxaUY4 | Timestamps: 00:27:18 The Omega-3 Index and individual needs; 00:54:20 Omega-3 Index and life expectancy. Topics: omega-3, omega-3-index, omega-3-heart-outcomes - FoundMyFitness: #100 The Optimal Creatine Protocol for Strength, Brain, and Longevity | Darren Candow, PhD (2025-03-31). Spotify https://open.spotify.com/episode/2SpduwrFUMDyelmtGt53iV | Apple https://podcasts.apple.com/us/podcast/100-the-optimal-creatine-protocol-for-strength-brain/id818198322?i=1000701575835 | YouTube https://www.youtube.com/watch?v=ICsO-EHI_vM. Topics: creatine - FoundMyFitness: #083 How Vitamin D, Omega-3s, & Exercise May Increase Longevity | Dr. Rhonda Patrick (2023-11-10). Spotify https://open.spotify.com/episode/7pga8QIpNoawGyR8udX79N | Apple https://podcasts.apple.com/us/podcast/083-how-vitamin-d-omega-3s-exercise-may-increase-longevity/id818198322?i=1000634303424 | YouTube https://www.youtube.com/watch?v=bhkxidN2M9Q. Topics: vitamin-d, vitamin-d-large-trials, omega-3, fitness-and-mortality # Research library (158 papers) - International Society of Sports Nutrition position stand: safety and efficacy of creatine supplementation in exercise, sport, and medicine (Journal of the International Society of Sports Nutrition, 2017). Grade A. Position stand, Review. Expert review concluding creatine monohydrate is effective with resistance training and safe at typical doses across age groups. Limits: Narrative position stand; some authors receive industry funding. https://doi.org/10.1186/s12970-017-0173-z - Effect of creatine supplementation during resistance training on lean tissue mass and muscular strength in older adults: a meta-analysis (Open Access Journal of Sports Medicine, 2017). Grade A. Meta-analysis, 22 RCTs, 721 older adults. In older adults doing resistance training, creatine increased lean mass and upper and lower body strength more than training alone. Limits: Small trials, short durations, heterogeneous protocols. https://doi.org/10.2147/OAJSM.S123529 - Effects of creatine supplementation on cognitive function of healthy individuals: A systematic review of randomized controlled trials (Experimental Gerontology, 2018). Grade C. Systematic review, 6 RCTs, 281 people. Creatine may improve short-term memory and reasoning in healthy people; other cognitive domains were unclear. Limits: Few, small, varied studies. https://doi.org/10.1016/j.exger.2018.04.013 - Common questions and misconceptions about creatine supplementation: what does the scientific evidence really show? (Journal of the International Society of Sports Nutrition, 2021). Grade B. Review, Review. Experts address common myths: no kidney harm in healthy people, weak evidence on hair loss, and monohydrate remains the best-studied form. Limits: Narrative review by researchers active in the field. https://doi.org/10.1186/s12970-021-00412-w - Effects of creatine supplementation on memory in healthy individuals: a systematic review and meta-analysis of randomized controlled trials (Nutrition Reviews, 2023). Grade B. Meta-analysis, 10 RCTs. Creatine improved memory performance in healthy people, with larger effects in adults aged 66 to 76. Limits: Small trials; outcomes measured differently. https://doi.org/10.1093/nutrit/nuac064 - Marine n−3 Fatty Acids and Prevention of Cardiovascular Disease and Cancer (New England Journal of Medicine, 2019). Grade A. RCT, 25,871 adults. VITAL: 1 g per day of fish oil did not lower major cardiovascular events or cancer versus placebo over 5.3 years. Limits: Healthy population with low event rates; one dose. https://doi.org/10.1056/NEJMoa1811403 - Cardiovascular Risk Reduction with Icosapent Ethyl for Hypertriglyceridemia (New England Journal of Medicine, 2019). Grade B. RCT, 8,179 patients. REDUCE-IT: 4 g per day of prescription EPA lowered ischemic events by about 25% in statin-treated patients with high triglycerides. Limits: Mineral oil placebo may have raised control-group risk; industry funded; a drug, not a supplement. https://doi.org/10.1056/NEJMoa1812792 - Effect of High-Dose Omega-3 Fatty Acids vs Corn Oil on Major Adverse Cardiovascular Events in Patients at High Cardiovascular Risk (JAMA, 2020). Grade A. RCT, 13,078 patients. STRENGTH: 4 g per day of EPA plus DHA did not reduce major cardiovascular events versus corn oil; stopped early for futility. Limits: High-risk patients; one formulation. https://doi.org/10.1001/jama.2020.22258 - The Omega-3 Index: a new risk factor for death from coronary heart disease? (Preventive Medicine, 2004). Grade C. Biomarker proposal, Pooled data. Proposed the Omega-3 Index; 8% or higher was linked to the lowest coronary death risk. Limits: Largely observational basis; author later founded a testing company. https://doi.org/10.1016/j.ypmed.2004.02.030 - Omega-3 fatty acids for the primary and secondary prevention of cardiovascular disease (Cochrane Database of Systematic Reviews, 2020). Grade A. Cochrane meta-analysis, 86 RCTs, 162,796 people. Long-chain omega-3 probably slightly reduces coronary events and lowers triglycerides, with little effect on overall mortality. Limits: Small effects; certainty varies by outcome. https://doi.org/10.1002/14651858.CD003177.pub5 - Effects of n−3 Fatty Acid Supplements in Diabetes Mellitus (New England Journal of Medicine, 2018). Grade A. RCT, 15,480 adults with diabetes. ASCEND: 1 g per day of omega-3 did not reduce serious vascular events in people with diabetes over 7.4 years. Limits: Population with diabetes; one dose. https://doi.org/10.1056/NEJMoa1804989 - Effect of Long-Term Marine ɷ-3 Fatty Acids Supplementation on the Risk of Atrial Fibrillation in Randomized Controlled Trials of Cardiovascular Outcomes: A Systematic Review and Meta-Analysis (Circulation, 2021). Grade A. Meta-analysis, 7 RCTs, 81,210 people. Marine omega-3 supplements were associated with higher atrial fibrillation risk, especially above 1 g per day. Limits: Small absolute increase; AF mostly a secondary outcome. https://doi.org/10.1161/CIRCULATIONAHA.121.055654 - Blood n-3 fatty acid levels and total and cause-specific mortality from 17 prospective studies (Nature Communications, 2021). Grade B. Pooled cohorts, 17 cohorts, 42,466 people. Higher blood marine omega-3 levels were associated with lower risk of death from all causes. Limits: Observational; lifestyle may explain part of the link. https://doi.org/10.1038/s41467-021-22370-2 - Dietary supplementation with n-3 polyunsaturated fatty acids and vitamin E after myocardial infarction: results of the GISSI-Prevenzione trial (The Lancet, 1999). Grade B. RCT, 11,324 post-heart attack patients. GISSI-Prevenzione: 1 g per day of omega-3 after a heart attack reduced death and cardiovascular events; vitamin E did not. Limits: Open label, pre-statin era; not always replicated. https://doi.org/10.1016/S0140-6736(99)07072-5 - Vitamin D Supplements and Prevention of Cancer and Cardiovascular Disease (New England Journal of Medicine, 2019). Grade A. RCT, 25,871 adults. VITAL: 2,000 IU per day of vitamin D did not lower invasive cancer or major cardiovascular events over 5.3 years. Limits: Most participants were not deficient. https://doi.org/10.1056/NEJMoa1809944 - Supplemental Vitamin D and Incident Fractures in Midlife and Older Adults (New England Journal of Medicine, 2022). Grade A. RCT, 25,871 adults. VITAL: vitamin D did not lower total, hip or nonvertebral fractures in generally healthy midlife and older adults. Limits: Not selected for deficiency or osteoporosis. https://doi.org/10.1056/NEJMoa2202106 - The D-Health Trial: a randomised controlled trial of the effect of vitamin D on mortality (The Lancet Diabetes & Endocrinology, 2022). Grade A. RCT, 21,315 adults. D-Health: 60,000 IU monthly did not reduce all-cause mortality in older Australians. Limits: Monthly bolus; few deficient participants. https://doi.org/10.1016/S2213-8587(21)00345-4 - Effect of Vitamin D Supplementation, Omega-3 Fatty Acid Supplementation, or a Strength-Training Exercise Program on Clinical Outcomes in Older Adults (JAMA, 2020). Grade A. RCT, 2,157 adults 70+. DO-HEALTH: vitamin D, omega-3 or home strength training did not improve blood pressure, fractures, physical performance, infections or cognition over 3 years. Limits: Healthy, active Europeans; many vitamin D replete. https://doi.org/10.1001/jama.2020.16909 - Vitamin D supplementation to prevent acute respiratory tract infections: systematic review and meta-analysis of individual participant data (BMJ, 2017). Grade B. IPD meta-analysis, 25 RCTs, 10,933 people. Vitamin D modestly reduced acute respiratory infections, most in very deficient people with daily or weekly dosing. Limits: Heterogeneous trials; small overall effect. https://doi.org/10.1136/bmj.i6583 - Vitamin D Supplementation and Prevention of Type 2 Diabetes (New England Journal of Medicine, 2019). Grade A. RCT, 2,423 adults with prediabetes. D2d: 4,000 IU per day did not significantly lower the risk of type 2 diabetes. Limits: Not selected for deficiency; result near significance. https://doi.org/10.1056/NEJMoa1900906 - Effects of vitamin D supplementation on musculoskeletal health: a systematic review, meta-analysis, and trial sequential analysis (The Lancet Diabetes & Endocrinology, 2018). Grade A. Meta-analysis, 81 RCTs, 53,537 people. Vitamin D did not prevent fractures or falls or meaningfully change bone density. Limits: Few trials in severely deficient people. https://doi.org/10.1016/S2213-8587(18)30265-1 - Oral magnesium supplementation for insomnia in older adults: a Systematic Review & Meta-Analysis (BMC Complementary Medicine and Therapies, 2021). Grade C. Meta-analysis, 3 RCTs, 151 older adults. Magnesium shortened time to fall asleep by about 17 minutes versus placebo; evidence quality was low. Limits: Few small, older trials. https://doi.org/10.1186/s12906-021-03297-z - The Effects of Magnesium Supplementation on Subjective Anxiety and Stress-A Systematic Review (Nutrients, 2017). Grade C. Systematic review, 18 studies. Magnesium may help subjective anxiety in people prone to it, but study quality was poor. Limits: Mixed designs, small samples. https://doi.org/10.3390/nu9050429 - Glycine ingestion improves subjective sleep quality in human volunteers, correlating with polysomnographic changes (Sleep and Biological Rhythms, 2007). Grade C. RCT (crossover), Small sample. 3 g of glycine before bed improved subjective sleep quality, with supporting changes on sleep recordings. Limits: Very small, short study. https://doi.org/10.1111/j.1479-8425.2007.00262.x - Effects of L-Theanine Administration on Stress-Related Symptoms and Cognitive Functions in Healthy Adults: A Randomized Controlled Trial (Nutrients, 2019). Grade C. RCT, 30 adults. Four weeks of L-theanine improved stress-related symptoms and sleep scores in healthy adults. Limits: Small sample, self-reported outcomes. https://doi.org/10.3390/nu11102362 - Meta-Analysis: Melatonin for the Treatment of Primary Sleep Disorders (PLoS ONE, 2013). Grade B. Meta-analysis, 19 RCTs, 1,683 people. Melatonin modestly shortened sleep onset (about 7 minutes) and improved sleep quality in primary sleep disorders. Limits: Modest effects; doses vary widely. https://doi.org/10.1371/journal.pone.0063773 - Recommended Amount of Sleep for a Healthy Adult: A Joint Consensus Statement of the American Academy of Sleep Medicine and Sleep Research Society (SLEEP, 2015). Grade B. Consensus statement, Expert panel. AASM and SRS recommend that adults regularly sleep 7 or more hours per night. Limits: Consensus, not a trial. https://doi.org/10.5665/sleep.4716 - A systematic review, meta-analysis and meta-regression of the effect of protein supplementation on resistance training-induced gains in muscle mass and strength in healthy adults (British Journal of Sports Medicine, 2018). Grade A. Meta-analysis, 49 RCTs, 1,863 people. Protein supplementation with resistance training increased strength and muscle size; gains plateaued around 1.6 g per kg per day. Limits: Modest effects, smaller in older adults. https://doi.org/10.1136/bjsports-2017-097608 - Evidence-Based Recommendations for Optimal Dietary Protein Intake in Older People: A Position Paper From the PROT-AGE Study Group (Journal of the American Medical Directors Association, 2013). Grade B. Consensus statement, Expert panel. PROT-AGE recommends 1.0 to 1.2 g protein per kg per day for healthy adults over 65. Limits: Expert opinion. https://doi.org/10.1016/j.jamda.2013.05.021 - International Society of Sports Nutrition Position Stand: protein and exercise (Journal of the International Society of Sports Nutrition, 2017). Grade B. Position stand, Review. ISSN recommends 1.4 to 2.0 g protein per kg per day for most exercising people, spread across the day. Limits: Narrative position stand. https://doi.org/10.1186/s12970-017-0177-8 - Chronic nicotinamide riboside supplementation is well-tolerated and elevates NAD+ in healthy middle-aged and older adults (Nature Communications, 2018). Grade C. RCT (crossover), 24 adults 55-79. 1,000 mg per day of NR for 6 weeks was well tolerated and raised blood NAD+. Limits: Small, short; functional effects exploratory. https://doi.org/10.1038/s41467-018-03421-7 - A randomized placebo-controlled clinical trial of nicotinamide riboside in obese men: safety, insulin-sensitivity, and lipid-mobilizing effects (The American Journal of Clinical Nutrition, 2018). Grade B. RCT, 40 obese men. 12 weeks of 2,000 mg per day NR was safe but did not improve insulin sensitivity or body composition. Limits: Small; specific population. https://doi.org/10.1093/ajcn/nqy132 - Nicotinamide Riboside Augments the Aged Human Skeletal Muscle NAD+ Metabolome and Induces Transcriptomic and Anti-inflammatory Signatures (Cell Reports, 2019). Grade C. RCT, 12 older men. NR raised the muscle NAD+ metabolome and lowered some inflammatory markers without improving mitochondrial function. Limits: Very small; 3 weeks. https://doi.org/10.1016/j.celrep.2019.07.043 - Nicotinamide mononucleotide increases muscle insulin sensitivity in prediabetic women (Science, 2021). Grade C. RCT, 25 women with prediabetes. 250 mg per day of NMN for 10 weeks increased muscle insulin sensitivity without changing body composition. Limits: Small, specific group. https://doi.org/10.1126/science.abe9985 - Effect of oral administration of nicotinamide mononucleotide on clinical parameters and nicotinamide metabolite levels in healthy Japanese men (Endocrine Journal, 2020). Grade D. Clinical study, 10 men. Single doses of NMN up to 500 mg were safe and metabolized in healthy Japanese men. Limits: Tiny, single dose, no control. https://doi.org/10.1507/endocrj.EJ19-0313 - Nicotinamide riboside is uniquely and orally bioavailable in mice and humans (Nature Communications, 2016). Grade C. Pharmacokinetic study, Mice and 12 humans. NR is orally bioavailable; single doses of 100 to 1,000 mg raised blood NAD+ metabolites dose dependently. Limits: Pharmacokinetics only; senior author tied to an NR maker. https://doi.org/10.1038/ncomms12948 - Discoveries of Nicotinamide Riboside as a Nutrient and Conserved NRK Genes Establish a Preiss-Handler Independent Route to NAD+ in Fungi and Humans (Cell, 2004). Grade D. Mechanistic study, Yeast and human enzymes. Identified nicotinamide riboside as an NAD+ precursor and the kinases that convert it. Limits: Basic science. https://doi.org/10.1016/S0092-8674(04)00416-7 - Nicotinamide riboside supplementation alters body composition and skeletal muscle acetylcarnitine concentrations in healthy obese humans (The American Journal of Clinical Nutrition, 2020). Grade C. RCT (crossover), 13 overweight adults. 1,000 mg per day NR for 6 weeks raised muscle NAD+ metabolites with minor body composition changes and no other metabolic benefits. Limits: Small, short. https://doi.org/10.1093/ajcn/nqaa072 - Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan (Nature, 2003). Grade D. Mechanistic and yeast study, Lab study. Reported that resveratrol activates sirtuins and extended yeast lifespan by 70%. Limits: Later work tied part of the activation to an assay artifact. https://doi.org/10.1038/nature01960 - Substrate-specific Activation of Sirtuins by Resveratrol (Journal of Biological Chemistry, 2005). Grade D. Mechanistic and yeast study, Lab study. Found resveratrol activation of sirtuins depended on a fluorescent tag and saw no yeast lifespan effect. Limits: Lab and yeast only. https://doi.org/10.1074/jbc.M500655200 - SRT1720, SRT2183, SRT1460, and Resveratrol Are Not Direct Activators of SIRT1 (Journal of Biological Chemistry, 2010). Grade D. Mechanistic study, Lab and mice. Pfizer scientists reported resveratrol and SRT compounds are not direct SIRT1 activators with native substrates. Limits: Lab assays; competing commercial interests. https://doi.org/10.1074/jbc.M109.088682 - Evidence for a Common Mechanism of SIRT1 Regulation by Allosteric Activators (Science, 2013). Grade D. Mechanistic study, Lab and cells. Identified an allosteric site through which some compounds can activate SIRT1 for certain substrates. Limits: Mechanism only; some authors had commercial ties. https://doi.org/10.1126/science.1231097 - Resveratrol improves health and survival of mice on a high-calorie diet (Nature, 2006). Grade D. Animal study, Mice. Resveratrol improved health and survival of mice on a high-calorie diet. Limits: Unhealthy diet model; high doses. https://doi.org/10.1038/nature05354 - Resveratrol Delays Age-Related Deterioration and Mimics Transcriptional Aspects of Dietary Restriction without Extending Life Span (Cell Metabolism, 2008). Grade D. Animal study, Mice. Resveratrol delayed some age-related decline in mice on a normal diet but did not extend lifespan. Limits: Mouse data. https://doi.org/10.1016/j.cmet.2008.06.011 - Resveratrol Levels and All-Cause Mortality in Older Community-Dwelling Adults (JAMA Internal Medicine, 2014). Grade C. Cohort, 783 older adults. Dietary resveratrol levels were not associated with inflammation, heart disease, cancer or mortality over 9 years. Limits: Dietary levels far below supplement doses. https://doi.org/10.1001/jamainternmed.2014.1582 - Rapamycin, But Not Resveratrol or Simvastatin, Extends Life Span of Genetically Heterogeneous Mice (The Journals of Gerontology: Series A, 2011). Grade C. Animal study (ITP), Diverse mice, 3 sites. Rapamycin extended mouse lifespan, while resveratrol and simvastatin did not. Limits: Mouse data. https://doi.org/10.1093/gerona/glq178 - Rapamycin fed late in life extends lifespan in genetically heterogeneous mice (Nature, 2009). Grade B. Animal study (ITP), Diverse mice, 3 sites. Rapamycin started late in life extended median and maximum lifespan in mice of both sexes. Limits: Mouse data; human relevance unknown. https://doi.org/10.1038/nature08221 - mTOR inhibition improves immune function in the elderly (Science Translational Medicine, 2014). Grade C. RCT, 218 older adults. A short course of the mTOR inhibitor everolimus improved flu vaccine response by about 20%. Limits: Surrogate endpoint; company funded. https://doi.org/10.1126/scitranslmed.3009892 - TORC1 inhibition enhances immune function and reduces infections in the elderly (Science Translational Medicine, 2018). Grade C. RCT, 264 older adults. Low-dose TORC1 inhibition was associated with fewer reported infections over a year. Limits: A later phase 3 trial missed its primary endpoint. https://doi.org/10.1126/scitranslmed.aaq1564 - Metformin as a Tool to Target Aging (Cell Metabolism, 2016). Grade D. Perspective, Proposal. Outlines the rationale and design of the TAME trial to test metformin against aging. Limits: A proposal; as of 2026 the trial has not enrolled. https://doi.org/10.1016/j.cmet.2016.05.011 - Can people with type 2 diabetes live longer than those without? A comparison of mortality in people initiated with metformin or sulphonylurea monotherapy and matched, non‐diabetic controls (Diabetes, Obesity and Metabolism, 2014). Grade C. Retrospective cohort, 180,926 people. People with diabetes starting metformin had survival similar to or longer than matched people without diabetes. Limits: Observational; later analyses questioned it. https://doi.org/10.1111/dom.12354 - Longer lifespan in male mice treated with a weakly estrogenic agonist, an antioxidant, an α‐glucosidase inhibitor or a Nrf2‐inducer (Aging Cell, 2016). Grade C. Animal study (ITP), Diverse mice. Acarbose and some other compounds extended lifespan in male mice; fish oil did not. Limits: Mouse data; sex differences. https://doi.org/10.1111/acel.12496 - Fasting-mimicking diet and markers/risk factors for aging, diabetes, cancer, and cardiovascular disease (Science Translational Medicine, 2017). Grade C. RCT (crossover), 100 adults. Three monthly cycles of a 5-day fasting-mimicking diet reduced weight, blood pressure and IGF-1. Limits: Short; markers; developer affiliated. https://doi.org/10.1126/scitranslmed.aai8700 - 2 years of calorie restriction and cardiometabolic risk (CALERIE): exploratory outcomes of a multicentre, phase 2, randomised controlled trial (The Lancet Diabetes & Endocrinology, 2019). Grade B. RCT, 218 adults. CALERIE: about 12% calorie restriction for 2 years improved many cardiometabolic risk factors in healthy non-obese adults. Limits: Risk factors, not disease outcomes. https://doi.org/10.1016/S2213-8587(19)30151-2 - Effect of long-term caloric restriction on DNA methylation measures of biological aging in healthy adults from the CALERIE trial (Nature Aging, 2023). Grade C. RCT secondary analysis, CALERIE participants. Two years of calorie restriction slowed DunedinPACE but not other epigenetic clocks. Limits: Clock relevance uncertain. https://doi.org/10.1038/s43587-022-00357-y - Calorie Restriction with or without Time-Restricted Eating in Weight Loss (New England Journal of Medicine, 2022). Grade A. RCT, 139 adults with obesity. Time-restricted eating was not better than daily calorie restriction for weight or metabolic risk over 12 months. Limits: Both groups restricted calories. https://doi.org/10.1056/NEJMoa2114833 - Effects of Time-Restricted Eating on Weight Loss and Other Metabolic Parameters in Women and Men With Overweight and Obesity (JAMA Internal Medicine, 2020). Grade B. RCT, 116 adults. 16:8 time-restricted eating alone did not cause more weight loss than eating throughout the day. Limits: Remote trial; modest sample. https://doi.org/10.1001/jamainternmed.2020.4153 - Association of Cardiorespiratory Fitness With Long-term Mortality Among Adults Undergoing Exercise Treadmill Testing (JAMA Network Open, 2018). Grade B. Cohort, 122,007 adults. Higher measured cardiorespiratory fitness was associated with lower long-term mortality, with no observed upper limit of benefit. Limits: Observational clinical cohort. https://doi.org/10.1001/jamanetworkopen.2018.3605 - Daily steps and all-cause mortality: a meta-analysis of 15 international cohorts (The Lancet Public Health, 2022). Grade B. Meta-analysis of cohorts, 15 cohorts, 47,471 adults. More daily steps were associated with progressively lower mortality, up to a level that varied by age. Limits: Observational. https://doi.org/10.1016/S2468-2667(21)00302-9 - Muscle-strengthening activities are associated with lower risk and mortality in major non-communicable diseases: a systematic review and meta-analysis of cohort studies (British Journal of Sports Medicine, 2022). Grade B. Meta-analysis, 16 cohorts. Muscle-strengthening activities were associated with 10 to 17% lower risk of all-cause mortality, cardiovascular disease, total cancer and diabetes. Limits: Observational; J-shaped curve at high volumes. https://doi.org/10.1136/bjsports-2021-105061 - Leisure Time Physical Activity and Mortality (JAMA Internal Medicine, 2015). Grade B. Pooled cohorts, 661,137 adults. Compared with no leisure activity, doing less than the minimum was linked to 20% lower mortality and 1 to 2 times the minimum to 31% lower. Limits: Self-reported activity. https://doi.org/10.1001/jamainternmed.2015.0533 - Primary Prevention of Cardiovascular Disease with a Mediterranean Diet Supplemented with Extra-Virgin Olive Oil or Nuts (New England Journal of Medicine, 2018). Grade A. RCT, 7,447 adults at high risk. PREDIMED: a Mediterranean diet with extra-virgin olive oil or nuts lowered major cardiovascular events versus a reduced-fat diet. Limits: Republished after randomization problems; results held. https://doi.org/10.1056/NEJMoa1800389 - Health effects of dietary risks in 195 countries, 1990–2017: a systematic analysis for the Global Burden of Disease Study 2017 (The Lancet, 2019). Grade B. Global analysis, 195 countries. Poor diet was linked to 11 million deaths in 2017, led by high sodium and low whole grains and fruit. Limits: Modeled estimates. https://doi.org/10.1016/S0140-6736(19)30041-8 - Effects of cocoa extract and a multivitamin on cognitive function: A randomized clinical trial (Alzheimer's & Dementia, 2023). Grade B. RCT, 2,262 older adults. COSMOS-Mind: a daily multivitamin modestly improved global cognition over 3 years; cocoa extract did not. Limits: Modest effect. https://doi.org/10.1002/alz.12767 - Multivitamin Supplementation Improves Memory in Older Adults: A Randomized Clinical Trial (The American Journal of Clinical Nutrition, 2023). Grade B. RCT, 3,562 older adults. COSMOS-Web: a daily multivitamin improved immediate memory recall versus placebo. Limits: Online testing; small effect. https://doi.org/10.1016/j.ajcnut.2023.05.011 - Vitamin, Mineral, and Multivitamin Supplementation to Prevent Cardiovascular Disease and Cancer (JAMA, 2022). Grade A. Guideline, Evidence review. USPSTF found insufficient evidence for most vitamins to prevent heart disease or cancer and recommends against beta-carotene and vitamin E. Limits: For adults without deficiency. https://doi.org/10.1001/jama.2022.8970 - Taurine deficiency as a driver of aging (Science, 2023). Grade D. Animal and cohort study, Worms, mice, monkeys, humans. Taurine declined with age in several species; supplementation extended mouse lifespan by about 10 to 12%. Limits: No human trials. https://doi.org/10.1126/science.abn9257 - Cardioprotection and lifespan extension by the natural polyamine spermidine (Nature Medicine, 2016). Grade D. Animal and cohort study, Mice and human cohort. Spermidine extended mouse lifespan; higher dietary intake correlated with lower blood pressure in humans. Limits: Human data observational. https://doi.org/10.1038/nm.4222 - The mitophagy activator urolithin A is safe and induces a molecular signature of improved mitochondrial and cellular health in humans (Nature Metabolism, 2019). Grade C. RCT, 60 older adults. Urolithin A was safe and changed mitochondrial gene expression in muscle. Limits: Molecular endpoints; developer funded. https://doi.org/10.1038/s42255-019-0073-4 - Effect of Urolithin A Supplementation on Muscle Endurance and Mitochondrial Health in Older Adults (JAMA Network Open, 2022). Grade C. RCT, 66 older adults. Urolithin A improved some muscle endurance measures but not the 6-minute walk distance. Limits: Primary endpoints not met; developer funded. https://doi.org/10.1001/jamanetworkopen.2021.44279 - Alpha-Ketoglutarate, an Endogenous Metabolite, Extends Lifespan and Compresses Morbidity in Aging Mice (Cell Metabolism, 2020). Grade D. Animal study, Mice. Calcium AKG reduced frailty and modestly extended lifespan in middle-aged mice. Limits: Single mouse study. https://doi.org/10.1016/j.cmet.2020.08.004 - DNA methylation age of human tissues and cell types (Genome Biology, 2013). Grade B. Methods study, 8,000 samples. Built a multi-tissue DNA methylation age estimator that tracks chronological age closely. Limits: Not proven as a treatment target. https://doi.org/10.1186/gb-2013-14-10-r115 - An epigenetic biomarker of aging for lifespan and healthspan (Aging, 2018). Grade B. Methods study, Multiple cohorts. PhenoAge, trained on clinical markers, predicted mortality and disease better than earlier clocks. Limits: Prediction is not causation. https://doi.org/10.18632/aging.101414 - DunedinPACE, a DNA methylation biomarker of the pace of aging (eLife, 2022). Grade B. Methods study, Multiple cohorts. DunedinPACE estimates pace of aging from one blood sample and predicts disability and mortality. Limits: Individual results vary. https://doi.org/10.7554/eLife.73420 - Reversal of epigenetic aging and immunosenescent trends in humans (Aging Cell, 2019). Grade D. Pilot trial, 9 men. A growth hormone, DHEA and metformin protocol was followed by lower epigenetic age estimates. Limits: Tiny, uncontrolled. https://doi.org/10.1111/acel.13028 - Senolytics in idiopathic pulmonary fibrosis: Results from a first-in-human, open-label, pilot study (EBioMedicine, 2019). Grade D. Pilot trial, 14 patients with IPF. Dasatinib plus quercetin was feasible and may have improved physical function in lung fibrosis. Limits: Open label, tiny. https://doi.org/10.1016/j.ebiom.2018.12.052 - Senolytics improve physical function and increase lifespan in old age (Nature Medicine, 2018). Grade D. Animal study, Mice. Senolytics improved physical function and increased post-treatment survival in old mice. Limits: Mouse data. https://doi.org/10.1038/s41591-018-0092-9 - An investigation into the stress-relieving and pharmacological actions of an ashwagandha (Withania somnifera) extract (Medicine, 2019). Grade C. RCT, 60 adults. Ashwagandha extract reduced anxiety scores and morning cortisol versus placebo over 60 days. Limits: Small; industry funded. https://doi.org/10.1097/MD.0000000000017186 - International society of sports nutrition position stand: caffeine and exercise performance (Journal of the International Society of Sports Nutrition, 2021). Grade A. Position stand, Review. ISSN: caffeine at 3 to 6 mg per kg improves many types of exercise performance. Limits: Effects vary by person. https://doi.org/10.1186/s12970-020-00383-4 - Sleep Duration and All-Cause Mortality: A Systematic Review and Meta-Analysis of Prospective Studies (Sleep, 2010). Grade B. Meta-analysis of cohorts, 1.38 million people. Both short and long sleep duration were associated with higher mortality. Limits: Self-reported sleep; long sleep may reflect illness. https://doi.org/10.1093/sleep/33.5.585 - Cardiorespiratory Fitness as a Quantitative Predictor of All-Cause Mortality and Cardiovascular Events in Healthy Men and Women (JAMA, 2009). Grade B. Meta-analysis, 33 studies, 102,980 people. Better cardiorespiratory fitness was associated with lower all-cause and cardiovascular mortality; fitness of 7.9 METs or more was linked to substantially lower rates. Limits: Observational. https://doi.org/10.1001/jama.2009.681 - Prognostic value of grip strength: findings from the Prospective Urban Rural Epidemiology (PURE) study (The Lancet, 2015). Grade B. Cohort, 139,691 adults, 17 countries. Lower grip strength was associated with higher risk of death, cardiovascular death and cardiovascular disease. Limits: Observational. https://doi.org/10.1016/S0140-6736(14)62000-6 - Vitamin D and marine omega 3 fatty acid supplementation and incident autoimmune disease: VITAL randomized controlled trial (BMJ, 2022). Grade B. RCT, 25,871 adults. VITAL: 5 years of vitamin D reduced confirmed autoimmune disease by 22%. Limits: Secondary outcome. https://doi.org/10.1136/bmj-2021-066452 - Vitamin D supplementation and total cancer incidence and mortality: a meta-analysis of randomized controlled trials (Annals of Oncology, 2019). Grade B. Meta-analysis, 10 RCTs. Vitamin D did not reduce cancer incidence but was associated with lower cancer mortality. Limits: Driven by a few trials. https://doi.org/10.1093/annonc/mdz059 - Individual and additive effects of vitamin D, omega-3 and exercise on DNA methylation clocks of biological aging in older adults from the DO-HEALTH trial (Nature Aging, 2025). Grade C. RCT secondary analysis, 777 adults 70+. DO-HEALTH: omega-3 slightly slowed several epigenetic clocks over 3 years, about 3 to 4 months. Limits: Clinical meaning unclear. https://doi.org/10.1038/s43587-024-00793-y - Marine Omega‐3 Supplementation and Cardiovascular Disease: An Updated Meta‐Analysis of 13 Randomized Controlled Trials Involving 127 477 Participants (Journal of the American Heart Association, 2019). Grade A. Meta-analysis, 13 RCTs, 127,477 people. Marine omega-3 supplementation was associated with lower risk of heart attack and cardiovascular death, even excluding REDUCE-IT. Limits: Small absolute benefits. https://doi.org/10.1161/JAHA.119.013543 - Multivitamin Use and Mortality Risk in 3 Prospective US Cohorts (JAMA Network Open, 2024). Grade B. Pooled cohorts, 390,124 adults. Daily multivitamin use was not associated with a mortality benefit. Limits: Observational. https://doi.org/10.1001/jamanetworkopen.2024.18729 - Antioxidant supplements for prevention of mortality in healthy participants and patients with various diseases (Cochrane Database of Systematic Reviews, 2012). Grade A. Cochrane meta-analysis, 78 RCTs, 296,707 people. Antioxidant supplements did not reduce mortality; beta-carotene and vitamin E seem to increase it. Limits: Mixed populations. https://doi.org/10.1002/14651858.CD007176.pub2 - The Effect of Vitamin E and Beta Carotene on the Incidence of Lung Cancer and Other Cancers in Male Smokers (New England Journal of Medicine, 1994). Grade A. RCT, 29,133 male smokers. ATBC: beta-carotene was associated with more lung cancer in smokers; vitamin E did not lower it. Limits: Smokers only. https://doi.org/10.1056/NEJM199404143301501 - Vitamin E and the Risk of Prostate Cancer (JAMA, 2011). Grade A. RCT, 35,533 men. SELECT: vitamin E increased prostate cancer risk (hazard ratio 1.17). Limits: High dose. https://doi.org/10.1001/jama.2011.1437 - Effect of calcium supplements on risk of myocardial infarction and cardiovascular events: meta-analysis (BMJ, 2010). Grade B. Meta-analysis, 15 RCTs. Calcium supplements without vitamin D were associated with higher heart attack risk. Limits: Debated; not primary outcomes. https://doi.org/10.1136/bmj.c3691 - Supplementing Glycine and N-Acetylcysteine (GlyNAC) in Older Adults Improves Glutathione Deficiency, Oxidative Stress, Mitochondrial Dysfunction, Inflammation, Physical Function, and Aging Hallmarks: A Randomized Clinical Trial (The Journals of Gerontology: Series A, 2023). Grade C. RCT, 24 older adults. 16 weeks of glycine plus NAC improved glutathione, oxidative stress and several aging markers. Limits: Small pilot. https://doi.org/10.1093/gerona/glac135 - The efficacy and safety of β-nicotinamide mononucleotide (NMN) supplementation in healthy middle-aged adults: a randomized, multicenter, double-blind, placebo-controlled, parallel-group, dose-dependent clinical trial (GeroScience, 2023). Grade C. RCT, 80 adults. NMN up to 900 mg per day was safe and raised blood NAD; 600 mg showed the best results. Limits: Short; industry funded. https://doi.org/10.1007/s11357-022-00705-1 - The NADPARK study: A randomized phase I trial of nicotinamide riboside supplementation in Parkinson’s disease (Cell Metabolism, 2022). Grade C. RCT (phase 1), 30 people with Parkinson's. NR raised brain NAD and was associated with mild clinical improvement in Parkinson's disease. Limits: Phase 1; not evidence of treatment. https://doi.org/10.1016/j.cmet.2022.02.001 - Effects of Magnesium Supplementation on Blood Pressure (Hypertension, 2016). Grade B. Meta-analysis, 34 RCTs, 2,028 people. Magnesium supplementation modestly lowered blood pressure, about 2 mmHg systolic. Limits: Small effect. https://doi.org/10.1161/HYPERTENSIONAHA.116.07664 - Resistance exercise for muscular strength in older adults: A meta-analysis (Ageing Research Reviews, 2010). Grade A. Meta-analysis, 47 studies, 1,079 older adults. Resistance training improved strength in older adults, more with higher intensity. Limits: Heterogeneous programs. https://doi.org/10.1016/j.arr.2010.03.004 - Monthly High-Dose Vitamin D Treatment for the Prevention of Functional Decline (JAMA Internal Medicine, 2016). Grade B. RCT, 200 adults 70+. High monthly vitamin D doses did not improve leg function and were associated with more falls than a lower dose. Limits: Small; bolus dosing. https://doi.org/10.1001/jamainternmed.2015.7148 - Effect of exercise for depression: systematic review and network meta-analysis of randomised controlled trials (BMJ, 2024). Grade A. Network meta-analysis, 218 RCTs, 14,170 people. Walking or jogging, yoga and strength training reduced depression, particularly when intense. Limits: Blinding not possible. https://doi.org/10.1136/bmj-2023-075847 - Associations of fats and carbohydrate intake with cardiovascular disease and mortality in 18 countries from five continents (PURE): a prospective cohort study (The Lancet, 2017). Grade C. Cohort, 135,335 adults, 18 countries. High carbohydrate intake was associated with higher total mortality; total fat was not associated with cardiovascular disease. Limits: Observational. https://doi.org/10.1016/S0140-6736(17)32252-3 - Age-Related Clonal Hematopoiesis Associated with Adverse Outcomes (New England Journal of Medicine, 2014). Grade B. Cohort, 17,182 people. Age-related clonal hematopoiesis was associated with higher blood cancer and all-cause mortality risk. Limits: Observational. https://doi.org/10.1056/NEJMoa1408617 - High glycemic index and glycemic load diets as risk factors for insomnia: analyses from the Women’s Health Initiative (The American Journal of Clinical Nutrition, 2020). Grade C. Cohort, 53,069 women. High glycemic index diets were associated with higher odds of insomnia in postmenopausal women. Limits: Observational. https://doi.org/10.1093/ajcn/nqz275 - Multivitamins in the Prevention of Cancer in Men (JAMA, 2012). Grade B. RCT, 14,641 male physicians. PHS II: a daily multivitamin modestly but significantly reduced total cancer over 11 years. Limits: Male physicians only. https://doi.org/10.1001/jama.2012.14641 - ISSN exercise & sports nutrition review update: research & recommendations (Journal of the International Society of Sports Nutrition, 2018). Grade B. Review, Review. ISSN review of which sports supplements have strong, limited or no evidence. Limits: Narrative. https://doi.org/10.1186/s12970-018-0242-y - Vitamins and Minerals for Energy, Fatigue and Cognition: A Narrative Review of the Biochemical and Clinical Evidence (Nutrients, 2020). Grade C. Narrative review, Review. Summarizes how B vitamins, vitamin C, iron, magnesium and zinc relate to energy, fatigue and cognition when intake is inadequate. Limits: Industry funded. https://doi.org/10.3390/nu12010228 - Semaglutide and Cardiovascular Outcomes in Obesity without Diabetes (New England Journal of Medicine, 2023). Grade A. RCT, 17,604 adults. SELECT: weekly semaglutide 2.4 mg reduced major cardiovascular events in people with obesity and heart disease without diabetes. Limits: Prescription drug; manufacturer funded. https://doi.org/10.1056/NEJMoa2307563 - Efficacy and safety of oral semaglutide 14 mg (flexible dose) in early-stage symptomatic Alzheimer's disease (evoke and evoke+): two phase 3, randomised, placebo-controlled trials (The Lancet, 2026). Grade A. RCT (2 phase 3 trials), 3,808 people. EVOKE and EVOKE+: oral semaglutide did not slow early Alzheimer's disease progression. Limits: Manufacturer funded. https://doi.org/10.1016/S0140-6736(26)00459-9 - In Vivo Amelioration of Age-Associated Hallmarks by Partial Reprogramming (Cell, 2016). Grade D. Animal study, Mice. Cyclic partial reprogramming improved aging hallmarks and extended lifespan in progeroid mice. Limits: Progeroid model; tumor risk. https://doi.org/10.1016/j.cell.2016.11.052 - Reprogramming to recover youthful epigenetic information and restore vision (Nature, 2020). Grade D. Animal study, Mice. OSK gene therapy restored vision in mouse models of glaucoma and aging. Limits: Mouse data; basis for ER-100. https://doi.org/10.1038/s41586-020-2975-4 - Loss of epigenetic information as a cause of mammalian aging (Cell, 2023). Grade D. Animal study, Mice. Inducing DNA breaks accelerated signs of aging in mice, partly reversed by OSK. Limits: Debated interpretation. https://doi.org/10.1016/j.cell.2022.12.027 - Influence of rapamycin on safety and healthspan metrics after one year: PEARL trial results (Aging, 2025). Grade C. RCT, 114 adults 50-85. PEARL: weekly low-dose rapamycin for 48 weeks was relatively safe; visceral fat did not change; lean mass and pain improved in women on 10 mg. Limits: Primary endpoint null; sponsor sells rapamycin. https://doi.org/10.18632/aging.206235 - Semaglutide slows epigenetic aging in a randomized trial of HIV-associated lipohypertrophy (Nature Communications, 2026). Grade D. RCT post hoc analysis, Small HIV cohort. In HIV-associated lipohypertrophy, semaglutide slowed several epigenetic clocks over 32 weeks. Limits: Post hoc, small. https://doi.org/10.1038/s41467-026-72861-3 - Vitamin C for preventing and treating the common cold (Cochrane Database of Systematic Reviews, 2013). Grade A. Cochrane review, 29 RCTs, 11,306. Regular vitamin C did not reduce cold incidence in the general population; colds were 8% shorter in adults and 14% in children; risk halved under heavy physical stress. Limits: Heterogeneous doses; therapeutic trials inconsistent. https://doi.org/10.1002/14651858.CD000980.pub4 - Vitamin D supplementation to prevent acute respiratory infections: a systematic review and meta-analysis of aggregate data from randomised controlled trials (The Lancet Diabetes & Endocrinology, 2021). Grade A. Meta-analysis of RCTs, 43 RCTs, 48,488. Vitamin D modestly reduced acute respiratory infection (OR 0.92), mainly with daily 400 to 1,000 IU. Limits: Small pooled effect; heterogeneity. https://doi.org/10.1016/S2213-8587(21)00051-6 - Effect of a test-and-treat approach to vitamin D supplementation on risk of all cause acute respiratory tract infection and covid-19: phase 3 randomised controlled trial (CORONAVIT) (BMJ, 2022). Grade A. RCT, 6,200. Test-and-treat vitamin D did not reduce respiratory infections or COVID-19 in UK adults. Limits: Open label; many participants already took vitamin D. https://doi.org/10.1136/bmj-2022-071230 - Zinc for the common cold (Cochrane Database of Systematic Reviews, 2013). Grade B. Cochrane review, 18 RCTs. Zinc started within 24 hours shortened colds in healthy people. Limits: Superseded by the 2024 review; heterogeneity. https://doi.org/10.1002/14651858.CD001364.pub4 - Zinc lozenges and the common cold: a meta-analysis comparing zinc acetate and zinc gluconate, and the role of zinc dosage (JRSM Open, 2017). Grade B. Meta-analysis of RCTs, 7 RCTs. Zinc lozenges shortened colds by about a third; acetate and gluconate performed similarly; no benefit seen above about 100 mg/day. Limits: Few small trials; single author. https://doi.org/10.1177/2054270417694291 - Zinc for prevention and treatment of the common cold (Cochrane Database of Systematic Reviews, 2024). Grade B. Cochrane review, 34 RCTs. Low-certainty evidence: zinc may not prevent colds, may modestly shorten them, with more nausea and bad taste. Limits: Low certainty; varied formulations. https://doi.org/10.1002/14651858.CD014914.pub2 - Zinc-induced copper deficiency (Gastroenterology, 1988). Grade D. Case report, Case. Documents copper deficiency caused by chronic high zinc intake. Limits: Case report. https://doi.org/10.1016/0016-5085(88)90445-3 - Attenuation of influenza-like symptomatology and improvement of cell-mediated immunity with long-term N-acetylcysteine treatment (European Respiratory Journal, 1997). Grade C. RCT, 262. NAC 600 mg twice daily did not change influenza infection rates but reduced symptomatic illness. Limits: Single 1997 trial; not replicated. https://doi.org/10.1183/09031936.97.10071535 - Influence of N -acetylcysteine on chronic bronchitis or COPD exacerbations: a meta-analysis (European Respiratory Review, 2015). Grade B. Meta-analysis of RCTs, 13 studies, 4,155. NAC reduced exacerbations of chronic bronchitis/COPD, more at higher doses (drug context). Limits: Disease population; heterogeneity. https://doi.org/10.1183/16000617.00002215 - Elderberry Supplementation Reduces Cold Duration and Symptoms in Air-Travellers: A Randomized, Double-Blind Placebo-Controlled Clinical Trial (Nutrients, 2016). Grade C. RCT, 312. Elderberry did not significantly reduce cold numbers in air travellers; colds reported shorter and milder. Limits: Few events; secondary outcomes. https://doi.org/10.3390/nu8040182 - Elderberry for prevention and treatment of viral respiratory illnesses: a systematic review (BMC Complementary Medicine and Therapies, 2021). Grade C. Systematic review, 5 RCTs. Elderberry may reduce duration and severity of respiratory illness; low certainty; no support for prevention. Limits: Few small trials. https://doi.org/10.1186/s12906-021-03283-5 - Probiotics for preventing acute upper respiratory tract infections (Cochrane Database of Systematic Reviews, 2022). Grade B. Cochrane review, 23 RCTs, 6,950. Probiotics probably reduced the number of people with upper respiratory infections; low to moderate certainty. Limits: Strain-specific; trial quality. https://doi.org/10.1002/14651858.CD006895.pub4 - Effect of Long-term Supplementation With Marine Omega-3 Fatty Acids vs Placebo on Risk of Depression or Clinically Relevant Depressive Symptoms and on Change in Mood Scores (JAMA, 2021). Grade A. RCT, 18,353. Omega-3 1 g/day for about 5 years did not prevent depression and was linked to a small increase in risk. Limits: Older US adults; one dose. https://doi.org/10.1001/jama.2021.21187 - Efficacy of omega-3 PUFAs in depression: A meta-analysis (Translational Psychiatry, 2019). Grade B. Meta-analysis of RCTs, 26 RCTs, 2,160. EPA-dominant (≥60%) omega-3 at up to 1 g EPA improved depressive symptoms; DHA-dominant did not. Limits: Heterogeneity; small trials. https://doi.org/10.1038/s41398-019-0515-5 - Omega-3 fatty acids for depression in adults (Cochrane Database of Systematic Reviews, 2021). Grade B. Cochrane review, 35 RCTs, 1,920. Small, likely not clinically meaningful effect of omega-3 on depression; low certainty. Limits: Low certainty. https://doi.org/10.1002/14651858.CD004692.pub5 - Omega-3 fatty acids for the treatment of dementia (Cochrane Database of Systematic Reviews, 2016). Grade B. Cochrane review, 3 RCTs, 632. No convincing benefit of omega-3 for mild to moderate Alzheimer's disease. Limits: Few trials. https://doi.org/10.1002/14651858.CD009002.pub3 - Beneficial effects of docosahexaenoic acid on cognition in age‐related cognitive decline (Alzheimer's & Dementia, 2010). Grade B. RCT, 485. DHA 900 mg/day for 24 weeks improved a learning and memory test in age-related cognitive decline. Limits: Industry funded; one primary test. https://doi.org/10.1016/j.jalz.2010.01.013 - Exercise training increases size of hippocampus and improves memory (Proceedings of the National Academy of Sciences, 2011). Grade A. RCT, 120. A year of walking increased hippocampal volume about 2% in older adults versus stretching. Limits: Single trial; surrogate outcome. https://doi.org/10.1073/pnas.1015950108 - A meta-analytic review of the effects of exercise on brain-derived neurotrophic factor (Journal of Psychiatric Research, 2015). Grade B. Meta-analysis, 29 studies. Single exercise sessions and regular training raised blood BDNF. Limits: Blood BDNF is an indirect marker. https://doi.org/10.1016/j.jpsychires.2014.10.003 - Sleep Drives Metabolite Clearance from the Adult Brain (Science, 2013). Grade D. Animal study, Mice. In mice, sleep expanded interstitial space about 60% and increased beta-amyloid clearance. Limits: Mouse study. https://doi.org/10.1126/science.1241224 - The Effects of Glycine on Subjective Daytime Performance in Partially Sleep-Restricted Healthy Volunteers (Frontiers in Neurology, 2012). Grade C. RCT (crossover), 10. Glycine 3 g reduced fatigue after partial sleep restriction. Limits: Tiny sample; manufacturer-affiliated authors. https://doi.org/10.3389/fneur.2012.00061 - The Sleep-Promoting and Hypothermic Effects of Glycine are Mediated by NMDA Receptors in the Suprachiasmatic Nucleus (Neuropsychopharmacology, 2014). Grade D. Animal study, Rats. Glycine's sleep and body-temperature effects were mediated by NMDA receptors in the suprachiasmatic nucleus. Limits: Rodent study. https://doi.org/10.1038/npp.2014.326 - A weak link in metabolism: the metabolic capacity for glycine biosynthesis does not satisfy the need for collagen synthesis (Journal of Biosciences, 2009). Grade D. Metabolic analysis, Model. Calculates that glycine synthesis may fall short of collagen turnover needs. Limits: Theoretical model. https://doi.org/10.1007/s12038-009-0100-9 - Glutathione Synthesis Is Diminished in Patients With Uncontrolled Diabetes and Restored by Dietary Supplementation With Cysteine and Glycine (Diabetes Care, 2010). Grade C. Clinical study, ~20. Glycine and cysteine restored glutathione synthesis in uncontrolled diabetes over 2 weeks. Limits: Small, short, uncontrolled. https://doi.org/10.2337/dc10-1006 - Glycine and N‐acetylcysteine (GlyNAC) supplementation in older adults improves glutathione deficiency, oxidative stress, mitochondrial dysfunction, inflammation, insulin resistance, endothelial dysfunction, genotoxicity, muscle strength, and cognition: Results of a pilot clinical trial (Clinical and Translational Medicine, 2021). Grade D. Open-label pilot, 8 older adults. GlyNAC for 24 weeks improved glutathione and multiple markers in 8 older adults. Limits: No control group; tiny sample. https://doi.org/10.1002/ctm2.372 - Prevention of Rickets and Vitamin D Deficiency in Infants, Children, and Adolescents (Pediatrics, 2008). Grade A. Clinical report (AAP), Guidance. AAP: 400 IU/day vitamin D for breastfed infants from the first days of life. Limits: Guidance document. https://doi.org/10.1542/peds.2008-1862 - Diagnosis and Prevention of Iron Deficiency and Iron-Deficiency Anemia in Infants and Young Children (0–3 Years of Age) (Pediatrics, 2010). Grade A. Clinical report (AAP), Guidance. AAP guidance on preventing iron deficiency in infants and young children, including screening at about 12 months. Limits: Guidance document. https://doi.org/10.1542/peds.2010-2576 - Recommended Amount of Sleep for Pediatric Populations: A Consensus Statement of the American Academy of Sleep Medicine (Journal of Clinical Sleep Medicine, 2016). Grade A. Consensus statement, Expert panel. AASM recommended sleep hours by age from 4 months to 18 years. Limits: Consensus. https://doi.org/10.5664/jcsm.5866 - Worldwide Secular Trends in Age at Pubertal Onset Assessed by Breast Development Among Girls (JAMA Pediatrics, 2020). Grade B. Meta-analysis, 30 studies. Age at breast development onset fell about 0.24 years per decade, 1977 to 2013. Limits: Methods vary across studies. https://doi.org/10.1001/jamapediatrics.2019.5881 - Growth hormone secretion during sleep (Journal of Clinical Investigation, 1968). Grade C. Physiology study, Adults. Growth hormone release peaks shortly after sleep onset during slow-wave sleep. Limits: Small 1968 study in adults. https://doi.org/10.1172/JCI105893 - Omega-3 fatty acid addition during pregnancy (Cochrane Database of Systematic Reviews, 2018). Grade A. Cochrane review, 70 RCTs, 19,927. Omega-3 in pregnancy reduced preterm and early preterm birth; little clear effect on child development. Limits: Development outcomes less certain. https://doi.org/10.1002/14651858.CD003402.pub3 - Effect of DHA Supplementation During Pregnancy on Maternal Depression and Neurodevelopment of Young Children (JAMA, 2010). Grade A. RCT, 2,399. DHA 800 mg/day in pregnancy did not reduce postpartum depression or improve child cognition at 18 months. Limits: Australian population. https://doi.org/10.1001/jama.2010.1507 - Effect of inadequate iodine status in UK pregnant women on cognitive outcomes in their children: results from the Avon Longitudinal Study of Parents and Children (ALSPAC) (The Lancet, 2013). Grade B. Cohort, 1,040. Mild-to-moderate iodine deficiency in pregnancy linked to lower child verbal IQ and reading. Limits: Observational. https://doi.org/10.1016/S0140-6736(13)60436-5 - Media and Young Minds (Pediatrics, 2016). Grade A. Policy statement (AAP), Guidance. AAP media guidance: avoid digital media except video chat before 18 to 24 months; 1 hour/day for ages 2 to 5. Limits: Policy statement. https://doi.org/10.1542/peds.2016-2591 - Physical Activity, Fitness, Cognitive Function, and Academic Achievement in Children (Medicine & Science in Sports & Exercise, 2016). Grade B. Position stand (ACSM), Review. Physical activity benefits children's cognitive function; academic effects less consistent. Limits: Narrative review. https://doi.org/10.1249/MSS.0000000000000901 - Vaccines are not associated with autism: An evidence-based meta-analysis of case-control and cohort studies (Vaccine, 2014). Grade A. Meta-analysis, 1.26 million children. No association between vaccines and autism. Limits: Observational studies. https://doi.org/10.1016/j.vaccine.2014.04.085 - Effects of supplementation with quercetin on plasma C-reactive protein concentrations: a systematic review and meta-analysis of randomized controlled trials (European Journal of Clinical Nutrition, 2017). Grade B. Meta-analysis of RCTs, 7 RCTs. Quercetin lowered CRP by 0.33 mg/L on average, mainly at 500 mg/day or more. Limits: Small trials; marker only. https://doi.org/10.1038/ejcn.2017.55 - Influence of Quercetin Supplementation on Disease Risk Factors in Community-Dwelling Adults (Journal of the American Dietetic Association, 2011). Grade A. RCT, 1,002. 500 or 1,000 mg/day for 12 weeks had negligible effects on CRP, cytokines and other risk factors (slight IL-6 drop at 1,000 mg). Limits: Combined with vitamin C and niacin. https://doi.org/10.1016/j.jada.2011.01.013 - Quercetin supplementation and upper respiratory tract infection: A randomized community clinical trial (Pharmacological Research, 2010). Grade A. RCT, 1,002. Quercetin 500 or 1,000 mg/day did not reduce upper respiratory infections over 12 weeks. Limits: Self-reported symptoms. https://doi.org/10.1016/j.phrs.2010.05.001 - The Effect of Quercetin on Inflammatory Factors and Clinical Symptoms in Women with Rheumatoid Arthritis: A Double-Blind, Randomized Controlled Trial (Journal of the American College of Nutrition, 2016). Grade C. RCT, 50 women with RA. 500 mg/day for 8 weeks lowered TNF-alpha and some symptoms in rheumatoid arthritis. Limits: Small; disease population. https://doi.org/10.1080/07315724.2016.1140093 - Preventative Effect of a Flavonoid, Enzymatically Modified Isoquercitrin on Ocular Symptoms of Japanese Cedar Pollinosis (Allergology International, 2009). Grade C. RCT, 24. A quercetin glycoside (EMIQ, 100 mg/day) lowered eye symptom plus medication scores during cedar pollen season. Limits: Tiny; different form. https://doi.org/10.2332/allergolint.08-oa-0070 - Improved Oral Absorption of Quercetin from Quercetin Phytosome®, a New Delivery System Based on Food Grade Lecithin (European Journal of Drug Metabolism and Pharmacokinetics, 2018). Grade C. Pharmacokinetic RCT (crossover), 12. Quercetin phytosome reached plasma levels up to about 20 times higher than plain quercetin. Limits: Single dose; ingredient maker involved. https://doi.org/10.1007/s13318-018-0517-3 - Pharmacokinetics and Bioavailability of Quercetin Glycosides in Humans (The Journal of Clinical Pharmacology, 2001). Grade C. Pharmacokinetic study, Healthy adults. Quercetin absorption in humans depends strongly on the glycoside form. Limits: Small. https://doi.org/10.1177/00912700122010366 - Safety Aspects of the Use of Quercetin as a Dietary Supplement (Molecular Nutrition & Food Research, 2017). Grade B. Safety review, Review. Adverse effects of supplemental quercetin were rare and mild; long-term high-dose safety data are lacking; drug interactions and risk groups noted. Limits: Narrative review. https://doi.org/10.1002/mnfr.201700447 - Short-term effect of quercetin on the pharmacokinetics of fexofenadine, a substrate of P-glycoprotein, in healthy volunteers (European Journal of Clinical Pharmacology, 2009). Grade B. Pharmacokinetic RCT (crossover), 12. Quercetin 500 mg three times daily for 7 days raised fexofenadine exposure by 55%, consistent with P-gp inhibition. Limits: Small; one drug. https://doi.org/10.1007/s00228-009-0627-6 - Enhanced Anticoagulant Effect of Warfarin When Co-administered With Quercetin (Journal of Pharmacy Technology, 2022). Grade D. Case report, Case. Raised INR in a patient on warfarin after starting quercetin; normalized after stopping. Limits: Single case. https://doi.org/10.1177/87551225221125667 - Characterization of quercetin binding site on DNA gyrase (Biochemical and Biophysical Research Communications, 2003). Grade D. Biochemical study, Lab. Quercetin binds the ATP site of bacterial DNA gyrase B. Limits: Lab only. https://doi.org/10.1016/s0006-291x(03)01006-4 # Verified facts (ticker) - Elite vs low treadmill fitness: adjusted hazard ratio for death 0.20, with no observed upper limit of benefit (association, 122,007 adults). Source: https://doi.org/10.1001/jamanetworkopen.2018.3605 (associational) - Each 1-MET higher aerobic capacity was linked to a 13% lower all-cause mortality risk (RR 0.87; 33 cohort studies). Source: https://doi.org/10.1001/jama.2009.681 (associational) - In trials of healthy adults, HIIT raised VO2max by 5.5 and continuous endurance training by 4.9 mL/kg/min versus no exercise. Source: https://doi.org/10.1007/s40279-015-0365-0 (causal) - Muscle-strengthening activities were associated with a 10-17% lower risk of all-cause mortality, CVD, total cancer and diabetes. Source: https://doi.org/10.1136/bjsports-2021-105061 (associational) - The largest mortality risk reduction (about 10-20%) appeared at roughly 30-60 minutes of strength work per week (association). Source: https://doi.org/10.1136/bjsports-2021-105061 (associational) - Each 5 kg lower grip strength was linked to a 16% higher risk of death from any cause (HR 1.16; 139,691 adults, 17 countries). Source: https://doi.org/10.1016/S0140-6736(14)62000-6 (associational) - In adults 70-79, leg (quadriceps) strength was strongly related to mortality, while muscle size was not (association). Source: https://doi.org/10.1093/gerona/61.1.72 (associational) - Each 1-point increase on the sit-to-rise test was linked to a 21% improvement in survival in adults aged 51-80. Source: https://doi.org/10.1177/2047487312471759 (associational) - Mortality risk fell with more steps until about 6,000-8,000/day in adults 60+ and 8,000-10,000/day under 60 (association). Source: https://doi.org/10.1016/S2468-2667(21)00302-9 (associational) - In 49 RCTs, protein added to resistance training boosted gains, but intakes above about 1.6 g/kg/day added no more fat-free mass. Source: https://doi.org/10.1136/bjsports-2017-097608 (causal) # FAQ ## Is Everstack open for orders? Not yet. We are in pre-launch. Join the waitlist and we will email you before checkout opens. No payment is taken today. ## What brands are in the regimens? Third-party certified products from established supplement brands. Brand partners are confirmed before launch and named on each product's lot COA. Later, our own-label versions of the four Foundation products will follow, made in cGMP facilities and tested the same way. ## Why is the price the same as buying each product? We price at the brands' retail value and add free shipping, curation, your daily guide, COAs and support. As our own-label formulas arrive, we expect to lower prices, and we will tell subscribers before any change. ## How do subscriptions and cancellation work? When checkout opens, regimens bill monthly and renew until you cancel. You will see the price, the renewal date and the cancellation steps before you pay. Cancel online in your account in two clicks, with no call required. ## Do supplements replace medical care? No. Supplements support a healthy routine; they do not diagnose, treat, cure or prevent any disease [1]. If you are pregnant or nursing, take medication or have a medical condition, talk to your clinician before starting. ## Is creatine safe? Is it only for bodybuilders? Creatine monohydrate is among the most studied supplements, with a long safety record in healthy adults at 3 to 5 g per day [2][3]. It is useful for anyone who does resistance training, at any age. Not for people under 18. ## Why do you sell NR and not NMN? NR has a lower regulatory risk profile. NMN is lawful as a supplement again since September 2025, but it remains a New Dietary Ingredient, so we would only offer it from suppliers covered by an acknowledged FDA notification, after counsel review [4]. ## Who are NOVA, Coach Max, Mateo and Big Lou? They are AI-generated characters who host our explainer videos. They are always labeled as AI. They never share personal results, never give testimonials and are never presented as doctors. ## Do you ship outside the US? No. Everstack ships to US addresses only. ## ¿Tienen atención en español? Sí. Todo el sitio, las guías, los correos y la atención al cliente están disponibles en español. FAQ sources: [1] 21 CFR 101.93, required supplement disclaimer (eCFR): https://www.ecfr.gov/current/title-21/chapter-I/subchapter-B/part-101/subpart-F/section-101.93 [2] Kreider et al. 2017, J Int Soc Sports Nutr: https://doi.org/10.1186/s12970-017-0173-z [3] Antonio et al. 2021, J Int Soc Sports Nutr: https://doi.org/10.1186/s12970-021-00412-w [4] NutraIngredients: FDA declares NMN lawful in dietary supplements (Sep 30, 2025): https://www.nutraingredients.com/Article/2025/09/30/fda-declares-nmn-lawful-in-dietary-supplements/ *These statements have not been evaluated by the Food and Drug Administration. This product is not intended to diagnose, treat, cure, or prevent any disease.