#27 – David Sinclair, Ph.D.: Slowing aging – sirtuins, NAD, and the epigenetics of aging

KEYPOINTS

• 01

  Sirtuins came from an unbiased genetic hunt in yeast

  In Lenny Guarente's MIT lab, gene screens for yeast lifespan turned up SIR genes ('silent information regulators'), not the DNA-repair or antioxidant genes the field expected. Sir2, which has counterparts in mammals, controls gene silencing. Sinclair notes that at the time aging was blamed mainly on DNA damage and free radicals, so a gene-silencing protein was a surprise.

• 02

  Sirtuins move to repair damage and neglect their usual jobs

  Sinclair and student Kevin Mills stained the proteins and saw them relocate to the nucleolus, home of the ribosomal DNA, during normal aging and during an accelerated form of aging. His lab and others then showed that sirtuins were both necessary and sufficient to mimic calorie restriction in yeast and mammals. Knocking them out weakens the lifespan benefit, though Sinclair concedes that intense stress can bypass them in yeast.

• 03

  NAD fuels sirtuins, and nicotinamide brakes them

  Sirtuins consume NAD and release nicotinamide (a form of vitamin B3). When his first student, Kevin Bitterman, fed yeast nicotinamide expecting activation, he got inhibition. Sinclair explains it as a negative feedback pocket in the enzyme that senses its own by-product, and says he wouldn't recommend very high doses of nicotinamide. Labs worldwide now use it as a sirtuin inhibitor.

• 04

  Calorie restriction switches on NAD recycling

  PNC1, an NAD-salvage gene previously studied in tuberculosis, was among the most strongly upregulated genes in calorie-restricted yeast. That connected nutrient stress to higher sirtuin activity through NAD.

• 05

  Resveratrol was a proof-of-concept activator, not a drug

  In 2003, Konrad Howitz at Biomol screened compounds and found plant molecules that appeared to activate human SIRT1. The two labs spent about six months trying to disprove it, because true allosteric activators are rare. What convinced Sinclair was that the molecules extended yeast lifespan only when the sirtuin gene was present. Even so, he calls resveratrol 'a terrible molecule' because it dissolves so poorly.

• 06

  Mouse results depended on diet and absorption

  In his 2006 study, middle-aged mice on a high-fat, high-sugar 'Western' diet given resveratrol (about 200 mg/kg/day, by his recollection) lived roughly 20–25% longer than equally fed controls. The NIA's Interventions Testing Program later found no lifespan extension with resveratrol mixed into standard chow, which Sinclair says matches his own data and reflects absorption. He says fat improved blood levels in his studies, so he takes it with oil or yogurt.

• 07

  His personal regimen comes with explicit uncertainty

  Sinclair takes about a gram of resveratrol, reasoning that if it doesn't work at a gram it won't work at more. He also takes metformin at a low dose because the pathways overlap and stacking compounds is 'unknown territory', plus NMN. He doubts resveratrol will add even five years to his life, but believes it may delay cardiovascular disease.

• 08

  Aging as loss of analog information

  Sinclair previewed an unpublished 'unifying theory'. DNA is digital and stays largely intact in old animals, he says, while the epigenetic pattern of which genes are switched on is analog and degrades like a scratched CD. Using Waddington's 1950s landscape, he describes cells as marbles jostled out of their valleys until neurons and liver cells lose their identity. His lab was writing up experiments in which manipulating the epigenome produces hallmarks of aging.

• 09

  Old eggs may suffer from low NAD

  Sinclair links egg aneuploidy to faulty spindles. He describes a kinase that controls spindle quality, regulated by the NAD-dependent sirtuin SIRT2, and says giving NAD precursors to older mice produced healthier, more numerous eggs. Whether this applies to sperm is untested. This is mouse work, not a human fertility treatment.