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categories: ["people", "longevity"]categories: ["people", "longevity"]tags: ["aging", "sirtuins", "nad", "epigenetics", "reprogramming", "biogerontology"]tags: ["aging", "sirtuins", "nad", "epigenetics", "reprogramming", "biogerontology"]summary: "Australian-American biologist at Harvard known for sirtuin and NAD+ research, the information theory of aging, and disputes over the strength of his public claims."summary: "Australian-American biologist at Harvard known for sirtuin and NAD+ research, the information theory of aging, and disputes over the strength of his public claims."updated: "2026-07-27"updated: "2026-10-29"issues: ["The 2024 Academy for Health and Lifespan Research resignations are described without a source.", "The Sirtris acquisition figure is given qualitatively and unsourced."]issues: ["The 2024 Academy for Health and Lifespan Research resignations are described without a source.", "The Sirtris acquisition figure is given qualitatively and unsourced."]------ lines 29–35 → 29–3515 unchanged lines not shown
**David Sinclair** is an Australian-American molecular biologist at Harvard Medical School whose**David Sinclair** is an Australian-American molecular biologist at Harvard Medical School whoselaboratory has worked on yeast aging, sirtuins, NAD+ metabolism andlaboratory has worked on yeast aging, sirtuins, NAD+ metabolism and[[partial-reprogramming|epigenetic rejuvenation]]. He is among the most publicly visible[[partial-reprogramming|epigenetic rejuvenation]]. He is among the most publicly visiblebiogerontologists and the most criticized within the field, with the criticism aimed less at thebiogerontologists and the most criticized within the field. The criticism is aimed less at theunderlying experiments than at how far his public statements travel beyond them.underlying experiments than at how far his public statements travel beyond them. ## Career## Careerlines 44–57 → 44–588 unchanged lines not shown
## Sirtuins and resveratrol## Sirtuins and resveratrol The sirtuins are NAD+-dependent deacetylases; Guarente's laboratory had linked the yeast homologThe sirtuins are NAD+-dependent deacetylases. Guarente's laboratory had linked the yeast homologSIR2 to lifespan and to the response to [[caloric-restriction]], and the question was whether smallSIR2 to lifespan and to the response to [[caloric-restriction]], which raised the question ofmolecules could reproduce that response by activating the mammalian equivalents. In 2003 Sinclair's group reported that resveratrol, a polyphenol found in red wine,whether small molecules could reproduce that response by activating the mammalian equivalents. Inactivated SIRT1 and extended yeast lifespan.[^howitz2003] A 2006 paper reported that resveratrol2003 Sinclair's group reported that resveratrol, a polyphenol found in red wine, activated SIRT1and extended yeast lifespan.[^howitz2003] A 2006 paper reported that resveratrolimproved survival in mice fed a high-calorie diet.[^baur2006] Sirtris was founded on this work andimproved survival in mice fed a high-calorie diet.[^baur2006] Sirtris was founded on this work andacquired by GlaxoSmithKline in 2008 for a sum in the hundreds of millions of dollars.acquired by GlaxoSmithKline in 2008 for a sum in the hundreds of millions of dollars. The programme then unravelled. Pfizer scientists reported that the apparent SIRT1 activation was anThe programme then came apart. Pfizer scientists reported that the apparent SIRT1 activation was anartifact of the fluorophore attached to the assay substrate, and did not occur with nativeartifact of the fluorophore attached to the assay substrate, and did not occur with nativepeptides.[^pacholec2010] GSK halted development of its resveratrol formulation in 2010 and closedpeptides.[^pacholec2010] GSK halted development of its resveratrol formulation in 2010 and closedSirtris in 2013. Sinclair and colleagues have continued to argue that allosteric sirtuin activationSirtris in 2013. Sinclair and colleagues have continued to argue that allosteric sirtuin activationlines 61–67 → 62–683 unchanged lines not shown
> [!caution] Contested> [!caution] Contested> Resveratrol's lifespan effects have not replicated consistently in mammals. The US National> Resveratrol's lifespan effects have not replicated consistently in mammals. The US National> Institute on Aging's Interventions Testing Program, which tests compounds across three> Institute on Aging's Interventions Testing Program, which tests compounds across three> genetically heterogeneous mouse cohorts, did not find a lifespan extension for resveratrol —> genetically heterogeneous mouse cohorts, did not find a lifespan extension for resveratrol,> in contrast to its result for [[rapamycin]].> in contrast to its result for [[rapamycin]]. ## NAD+ and the information theory of aging## NAD+ and the information theory of aginglines 70–88 → 71–882 unchanged lines not shown
NAD+ disrupts communication with mitochondria and that raising it with precursors reverses aspectsNAD+ disrupts communication with mitochondria and that raising it with precursors reverses aspectsof that state in mice.[^gomes2013] This work is part of the case for [[nad-precursors]] asof that state in mice.[^gomes2013] This work is part of the case for [[nad-precursors]] asgeroprotectors. Human trials of nicotinamide riboside and nicotinamide mononucleotide have reliablygeroprotectors. Human trials of nicotinamide riboside and nicotinamide mononucleotide have reliablyraised blood NAD+ concentrations; they have not demonstrated functional benefit on aging endpoints.raised blood NAD+ concentrations but have not demonstrated functional benefit on aging endpoints. His broader theoretical claim is the information theory of aging: that aging is driven not by theHis broader theoretical claim is the information theory of aging. It holds that aging is driven byaccumulation of DNA mutations but by the progressive loss of epigenetic information — cellsthe progressive loss of epigenetic information (cells forgetting which genes to express) ratherforgetting which genes to express — and that the information can in principle be restored becausethan by the accumulation of DNA mutations, and that the information can in principle be restoreda backup copy persists. The supporting experiment used mice engineered to sustain repeatedbecause a backup copy persists. The supporting experiment used mice engineered to sustain repeatednon-mutagenic DNA double-strand breaks, which accelerated epigenetic and physiological agingnon-mutagenic DNA double-strand breaks, which accelerated epigenetic and physiological agingmarkers.[^yang2023] Critics have argued that repeated double-strand breaks are a severe andmarkers.[^yang2023] Critics have argued that repeated double-strand breaks are a severe andnon-physiological insult, and that the result shows DNA damage accelerates aging phenotypes rathernon-physiological insult, and that the result shows DNA damage accelerates aging phenotypes ratherthan that ordinary aging is epigenetic in origin. The distinction matters because the therapeuticthan that ordinary aging is epigenetic in origin. The therapeutic programme of resetting theprogramme of resetting the epigenome follows only from the stronger claim, and because theepigenome follows only from the stronger claim, and the readouts used to demonstrate it arereadouts used to demonstrate it are [[epigenetic-clock|DNA methylation clocks]] whose causal status[[epigenetic-clock|DNA methylation clocks]] whose causal status is itself disputed. See [[epigenetic-reprogramming]] and [[hallmarks-of-aging]].is itself disputed. See [[epigenetic-reprogramming]] and [[hallmarks-of-aging]]. ## Reprogramming work## Reprogramming work lines 91–99 → 91–992 unchanged lines not shown
depending on DNA demethylases.[^lu2020] The paper is among the most cited demonstrations thatdepending on DNA demethylases.[^lu2020] The paper is among the most cited demonstrations that[[yamanaka-factors|OSK]] can improve function in a living mammal without erasing cell identity, and[[yamanaka-factors|OSK]] can improve function in a living mammal without erasing cell identity, andit is a foundational reference for the reprogramming companies, including [[altos-labs]] andit is a foundational reference for the reprogramming companies, including [[altos-labs]] and[[newlimit]]. It is also a single tissue in a mouse, using an inducible transgenic system rather[[newlimit]]. It also concerns a single tissue in a mouse and uses an inducible transgenic systemthan a deliverable therapy, and the extrapolation to systemic human rejuvenation is not supportedrather than a deliverable therapy, so it does not support extrapolation to systemic humanby it.rejuvenation. ## Reception## Reception lines 110–119 → 110–11910 unchanged lines not shown
claiming demonstrated age reversal in dogs. A supplement carries no regulatory review of such aclaiming demonstrated age reversal in dogs. A supplement carries no regulatory review of such aclaim, unlike the canine lifespan candidates [[loyal]] is taking through the veterinary regulator.claim, unlike the canine lifespan candidates [[loyal]] is taking through the veterinary regulator.Much of the academy's board resigned in protest and Sinclair stepped down as president. The episodeMuch of the academy's board resigned in protest and Sinclair stepped down as president. The episodeis now the standard citation in arguments that the longevity field's credibility problem isis now the standard example cited by those who argue that the longevity field's credibility problemself-inflicted.is self-inflicted. > [!debate] Where the disagreement actually sits> [!debate] Where the disagreement sits> Almost nobody disputes that NAD+ falls with age or that OSK expression alters epigenetic marks.> Almost nobody disputes that NAD+ falls with age or that OSK expression alters epigenetic marks.> The dispute is whether these are causes or correlates, and whether a mouse eye result licenses> The dispute is whether these are causes or correlates, and whether a mouse eye result licenses> statements about human aging. Sinclair's answer has generally been more confident than his> statements about human aging. Sinclair's answer has generally been more confident than hislines 130–138 → 130–13810 unchanged lines not shown
by regulators who now associate the field with overstatement.by regulators who now associate the field with overstatement. Whether the information theory of aging survives as a causal account or is absorbed as one moreWhether the information theory of aging survives as a causal account or is absorbed as one moreentry in the hallmarks list depends on experiments — reprogramming delivered systemically toentry in the hallmarks list depends on experiments that have not yet been reported: reprogrammingnormally aged animals, with lifespan rather than clock readings as the endpoint — that have not yetdelivered systemically to normally aged animals, with lifespan rather than clock readings as thebeen reported.endpoint. ## See also## See also removed, struck through added, underlinedLine numbers count the serialised markdown of each revision, frontmatter included.
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