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Longevity University / 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.

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Human chromosomes (grey) with telomeres lit at their tips (white)
Human chromosomes (grey) with telomeres lit at their tips (white). Image: U.S. Department of Energy Human Genome Program, Public domain

Education only, not medical advice. Talk to your clinician before changing medication or if you have a condition.

Information theory of agingHypothesis: damage and stress scramble epigenetic marks; OSK factors may restore them. Shown in mice; in phase 1 in humans. NAD+ fuels sirtuins.Young epigenomeright genes ondamageScrambled epigenomeblurred cell identityOSKRestored?mice yes; humans ?NAD+ → sirtuins (repair, epigenome)NAD+ falls with age (CD38). Resveratrol: activation disputed.
Information theory of aging. Hypothesis: damage and stress scramble epigenetic marks; OSK factors may restore them. Shown in mice; in phase 1 in humans. NAD+ fuels sirtuins.

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).

Check your understanding

1. Do NAD+ precursors raise NAD+ in human blood?
  1. Yes, but functional benefits are unproven
  2. No
Tap to reveal the answer

Answer: a. See [5] and [6].

Sources

  1. Yang et al. 2023, Cell. doi.org/10.1016/j.cell.2022.12.027
  2. Lu et al. 2020, Nature. doi.org/10.1038/s41586-020-2975-4
  3. Ocampo et al. 2016, Cell. doi.org/10.1016/j.cell.2016.11.052
  4. Camacho-Pereira et al. 2016, Cell Metab. doi.org/10.1016/j.cmet.2016.05.006
  5. Martens et al. 2018, Nat Commun. doi.org/10.1038/s41467-018-03421-7
  6. Dollerup et al. 2018, Am J Clin Nutr. doi.org/10.1093/ajcn/nqy132
  7. Kaeberlein et al. 2005, J Biol Chem. doi.org/10.1074/jbc.M500655200
  8. Pacholec et al. 2010, J Biol Chem. doi.org/10.1074/jbc.M109.088682
  9. Miller et al. 2011, J Gerontol A. doi.org/10.1093/gerona/glq178

DOIs verified against Crossref on 2026-10-15.

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