#70–David Sinclair, PhD: How cellular reprogramming could slow our aging clock, & the latest on NAD

KEYPOINTS

• 01

  Sinclair's 'information theory of aging'

  Sinclair, a Harvard geneticist, discussing his book Lifespan, borrows from Claude Shannon's 1940s work on preserving information in noisy communication. He proposes that aging is mainly a loss of epigenetic information, meaning which genes should be on or off in a cell, rather than a loss of the DNA sequence itself. His analogy: the genome is a DVD, and aging is scratches that stop it being read correctly.

• 02

  Sirtuins began as yeast 'silent information regulators'

  SIR stands for silent information regulator. In yeast, the SIR2 gene responds to dietary restriction, heat and starvation. Adding an extra copy extended yeast lifespan by about 30%, an experiment done by then graduate student Matt Kaeberlein. These proteins keep certain genes silent but leave their posts to repair broken DNA. Sinclair argues repeated repair calls gradually scramble the cell's program, and aging yeast lose cellular identity and become sterile.

• 03

  Methylation is the deepest, most stable layer

  Cells mark genes to stay silent for decades by attaching methyl groups to DNA. Sinclair describes histone modifications as more changeable layers above it. The pattern of methylation at a few hundred sites shifts predictably with age, and he says it is very hard to reverse; the only way he knows is the Yamanaka stem cell reprogramming factors.

• 04

  The Horvath clock measures how fast you're aging

  UCLA mathematician Steve Horvath trained algorithms on methylation sites to estimate age, about 95% accurate for chronological age. Sinclair says the clock starts ticking from conception, runs faster with smoking and sedentary living, and is slowed by exercise and calorie restriction. Universal clocks now work across tissues in humans and, from a Harvard group, in mice.

• 05

  Partial reprogramming aims to restore youth without erasing identity

  Fully turning on the Yamanaka factors can be dangerous: Juan Carlos Izpisua Belmonte's Salk lab showed it can cause tumors in mice or kill them within about two days. Sinclair's lab leaves out the fourth factor, MYC, a known cancer gene. It delivers the other three, OCT4, SOX2 and KLF4, in an adeno-associated virus that switches on with the antibiotic doxycycline.

• 06

  Reprogrammed mouse eyes regained vision

  With Bruce Ksander's lab, Sinclair's team tested three models: a crushed optic nerve, raised eye pressure mimicking glaucoma, and naturally aged mice around 12 months old, which they compare to roughly 40-year-old humans. They report regenerated nerves in all three and restored vision in the glaucoma and old mice, measured by whether mice turn their heads to track moving lines. Treated retinal cells had a younger methylation age, with Horvath's help.

• 07

  Peter presses on whether boosters touch the deep clock

  Sinclair says early data suggest rapamycin, NAD boosters and metformin have relatively little effect on the methylation clock and at best slow it, whereas reprogramming appears to reverse it. Peter wonders whether a week-long fast or pulsed rapamycin, which he takes, might shift it. The two imagine a future clock test read from interstitial fluid, much like today's continuous glucose monitors.

• 08

  NAD and the oral-precursor debate

  Sirtuins need NAD as fuel, with resveratrol acting as the 'accelerator.' The body converts NR to NMN to NAD and keeps recycling it. Peter cites Joshua Rabinowitz's Princeton tracer study showing oral NR in mice was mostly converted in the liver, raising blood nicotinamide more than NR. A later human trial using 1,000 mg of NR raised muscle NAD but was not yet peer-reviewed. Sinclair suspects gut microbes strip nicotinamide off NR and NMN.

• 09

  The benefits may be greatest in the least healthy

  Both men note a recurring pattern with metformin, resveratrol and NAD boosters: benefits are clearest in obese or sick mice and people. Peter worries that the health-obsessed people most likely to take these molecules may benefit least. Sinclair agrees the human evidence is incomplete.