NAD+ and Aging: David Sinclair's Bet

David Sinclair has made a career out of trying to reverse aging.

The Harvard geneticist has been at the center of longevity research for over two decades, starting with his work on sirtuins—a family of proteins that seemed to mediate the life-extending effects of caloric restriction. That work was controversial, as we'll see. But Sinclair's current bet is on something more fundamental: a molecule called NAD+.

NAD+ (nicotinamide adenine dinucleotide) is a coenzyme present in every cell of your body. It's essential for metabolism, DNA repair, and cellular signaling. It's also one of the molecules that most consistently declines with age. By the time you're 60, your NAD+ levels may be half what they were at 20.

Sinclair's hypothesis: that decline isn't just a marker of aging—it's a driver. If you could restore NAD+ levels to youthful norms, you might be able to slow or even reverse aspects of aging.

The longevity supplement industry has latched onto this idea with enthusiasm. NMN and NR—NAD+ precursors—are now a billion-dollar market. But does the science support the hype?

It's complicated. Tantalizing but incomplete. A bet on biology that hasn't fully paid off yet.

What NAD+ Does

NAD+ is everywhere in metabolism.

In its oxidized form (NAD+) and reduced form (NADH), it shuttles electrons between reactions. It's the key electron carrier in glycolysis, the citric acid cycle, and oxidative phosphorylation. Without NAD+, you couldn't extract energy from food.

But that's just the beginning.

DNA repair. Enzymes called PARPs (poly(ADP-ribose) polymerases) use NAD+ as a substrate. When your DNA is damaged—by radiation, oxidation, or replication errors—PARPs detect the break and use NAD+ to build repair scaffolds. More DNA damage means more PARP activity means more NAD+ consumption.

Sirtuins. This family of seven enzymes (SIRT1-7 in mammals) uses NAD+ as a cofactor. Sirtuins regulate gene expression, stress responses, metabolism, and cellular repair processes. They're often called "longevity genes" because activating them extends lifespan in some model organisms.

Cellular signaling. NAD+ participates in signaling pathways that sense nutrient status and coordinate cellular responses.

Immune function. Certain immune cells, particularly during inflammatory responses, consume substantial amounts of NAD+.

NAD+ isn't just a metabolic cog. It's a regulatory hub, connecting cellular energy status to DNA repair, gene expression, and stress responses.

When NAD+ is abundant, cells repair efficiently, regulate genes appropriately, and maintain function. When NAD+ declines, these processes suffer.

The Decline

NAD+ levels drop with age. This is one of the most consistent findings in aging biology.

Studies in mice, rats, worms, and humans show the same pattern: NAD+ in tissues decreases as organisms age. The decline is substantial—often 50% or more by middle age.

Why does it decline?

Increased consumption. DNA damage accumulates with age. More damage means more PARP activity means more NAD+ consumed. Chronic inflammation also consumes NAD+.

Decreased synthesis. The enzymes that make NAD+ become less efficient with age. The salvage pathway, which recycles NAD+ precursors, may slow down.

Altered balance. The ratio between NAD+ synthesis and consumption shifts unfavorably.

The decline creates a vicious cycle. Lower NAD+ means impaired DNA repair, which means more damage, which means more PARP activation, which consumes more NAD+. The system spirals.

The Sirtuins Story

Before NAD+, there were sirtuins.

Sinclair's early fame came from work on SIRT1 and its activators, particularly resveratrol—the compound in red wine that was briefly touted as a longevity drug.

The story started in yeast. A sirtuin called Sir2 extended yeast lifespan when overexpressed. Sir2 required NAD+ to function. The connection between NAD+, sirtuins, and longevity seemed clear.

Caloric restriction, which extends lifespan in many species, appeared to work partly through sirtuins. Restrict calories, raise NAD+ (or NAD+/NADH ratio), activate sirtuins, live longer.

Resveratrol, found in red wine and grape skins, was reported to activate SIRT1 and extend mouse lifespan. GlaxoSmithKline paid $720 million to acquire Sirtris, a company founded to develop sirtuin-activating drugs.

Then came problems.

Replication failures. Several labs couldn't reproduce key findings. The original lifespan extension in worms and flies, reported in a high-profile 2004 paper, turned out to be an artifact of genetic background. When corrected, the effect disappeared.

Mechanistic questions. Whether resveratrol directly activates SIRT1 became contentious. The initial assays used artificial substrates; with natural substrates, the activation was much weaker.

Clinical disappointment. GlaxoSmithKline shut down Sirtris in 2013 after clinical trials of sirtuin activators failed.

The sirtuin hype collapsed. Sinclair's reputation took a hit.

But the NAD+ connection remained interesting—partly because sirtuins were only one of the NAD+-dependent systems affected by age-related decline.

The NAD+ Precursor Strategy

If NAD+ decline drives aging, the obvious intervention is to restore it.

You can't easily take NAD+ as a supplement—it doesn't cross cell membranes well and gets degraded in the gut. But you can take precursors that cells convert into NAD+.

Nicotinamide riboside (NR) is a form of vitamin B3 that enters cells and feeds into the NAD+ salvage pathway. It's sold as Niagen and TRU NIAGEN.

Nicotinamide mononucleotide (NMN) is one step closer to NAD+ in the biosynthesis pathway. It's what Sinclair himself reportedly takes. NMN supplements are widely available.

Nicotinamide (NAM) and niacin are older forms of vitamin B3 that also feed into NAD+ synthesis, but with different pharmacology (niacin causes flushing; NAM may inhibit sirtuins at high doses).

The precursor strategy is simple: supply the building blocks, let cells make more NAD+.

In mice, it works. NR and NMN supplementation raises tissue NAD+ levels and, in various studies, has shown benefits: improved mitochondrial function, enhanced DNA repair, better metabolic health, even extended lifespan in some experiments.

The mouse data is genuinely promising. The human data is much less clear.

Human Trials

The leap from mice to humans is treacherous. Most interventions that extend mouse lifespan fail in humans.

Human trials of NR and NMN have been conducted. They show:

NAD+ precursors are safe. No serious adverse effects at typical supplement doses (500-1000 mg/day for NR, similar for NMN).

They raise blood NAD+ levels. This is expected—the biochemistry works the same in humans as in mice.

Clinical benefits are unclear. Studies have looked for improvements in metabolic markers, insulin sensitivity, exercise performance, cognitive function, and other endpoints. Results are mixed. Some small studies show modest benefits; others show nothing.

No human trial has demonstrated that NAD+ precursors slow aging or extend lifespan. That would require decades of follow-up and enormous cohorts—studies that haven't been done.

What we have instead: surrogate endpoints, short-term studies, and a lot of extrapolation from animal data.

The Sinclair Controversy

David Sinclair is a polarizing figure in aging research.

His supporters credit him with raising the profile of longevity science, pursuing bold hypotheses, and persisting through setbacks. He's built a major research program, trained influential scientists, and kept the field in public view.

His critics argue he's consistently oversold findings, made premature claims, and benefited financially from companies selling products based on preliminary data. The sirtuin-resveratrol episode left scars.

Sinclair's 2019 book Lifespan: Why We Age—and Why We Don't Have To was a bestseller but drew criticism for presenting speculative ideas as more established than they are. His personal supplement regimen—which he discusses publicly—goes beyond what published evidence supports.

The supplement industry amplifies these tensions. NMN and NR sell in the hundreds of millions of dollars annually, marketed with claims that outrun the science. Sinclair's prominence connects him to this industry whether or not he endorses specific products.

The question isn't whether Sinclair is right or wrong. It's whether the science justifies the confidence—and the commercial enterprise built on it.

What the Skeptics Say

Critics of the NAD+ aging hypothesis raise several concerns:

Correlation isn't causation. NAD+ declines with age, but so do hundreds of other molecules. The decline might be a consequence of aging rather than a cause.

Mouse lifespans are uninformative. Mice age in ways that don't translate to humans. Interventions that extend mouse lifespan have mostly failed when tested in people.

The clinical evidence is weak. Years of human trials have not produced clear, replicated benefits. If NAD+ restoration were as powerful as claimed, we should see more signal by now.

Mechanism questions. If NAD+ decline drives aging, through what pathway exactly? The sirtuin story fell apart; the PARP story is complicated; other mechanisms are speculative.

The supplement industry muddies the science. Commercial interests push premature claims. When companies profit from preliminary findings, there's pressure to oversell.

None of this proves NAD+ restoration doesn't work. It means the evidence is weaker than enthusiasts suggest.

What the Evidence Does Support

Let's steelman the hypothesis.

NAD+ is genuinely central to cellular health. It's not a random molecule—it's a core metabolic cofactor involved in hundreds of reactions and multiple regulatory pathways.

The decline is real and substantial. This isn't a small effect or a measurement artifact. NAD+ genuinely drops with age across multiple tissues and species.

Animal data shows functional benefits. NR and NMN improve mitochondrial function, DNA repair, and metabolic health in aged mice. These aren't trivial effects.

The mechanism is plausible. Connecting NAD+ to DNA repair (via PARPs) and gene regulation (via sirtuins) provides mechanistic pathways through which restoration could improve aging phenotypes.

The human safety profile is good. If you're going to experiment on yourself with longevity interventions, NAD+ precursors are among the less risky options.

The case isn't ridiculous. It's just unproven. The gap between "plausible mechanism with animal data" and "demonstrated human longevity benefit" remains uncrossed.

The Broader Context

NAD+ restoration is one thread in a larger tapestry of longevity research.

Other interventions being studied: - Rapamycin (mTOR inhibitor)—the most robust lifespan extender in mice - Metformin—diabetes drug with possible longevity effects - Senolytics—drugs that clear senescent cells - Caloric restriction mimetics—various approaches - Epigenetic reprogramming—Sinclair's newer bet, using Yamanaka factors

NAD+ restoration fits into this landscape as one candidate among many. It's not the only theory of aging and may not be the most important one.

The field as a whole is advancing. Multiple clinical trials are underway. The FDA recently allowed the TAME (Targeting Aging with Metformin) trial, which will test whether metformin delays aging-related diseases. Similar trials for senolytics are in progress.

We may learn within the next decade whether any of these interventions actually slow human aging—or whether the promise dissipates like the sirtuin story.

The Mitochondrial Connection

What does NAD+ have to do with mitochondria?

NAD+ is essential for oxidative phosphorylation. The electron transport chain requires NAD+/NADH cycling. Without adequate NAD+, mitochondrial ATP production suffers.

NAD+ decline impairs mitochondrial function. Low NAD+ means less efficient electron transport, lower ATP output, and potentially more reactive oxygen species production.

Mitochondrial dysfunction may drive NAD+ decline. It's bidirectional—as mitochondria accumulate damage, they may become less efficient at NAD+ synthesis and more prone to NAD+-consuming stress responses.

SIRT3, a mitochondrial sirtuin, depends on NAD+. SIRT3 regulates mitochondrial metabolism and stress resistance. Low NAD+ means less SIRT3 activity means worse mitochondrial function.

The NAD+-mitochondria connection is tight. Restoring NAD+ might help maintain mitochondrial health; maintaining mitochondrial health might help preserve NAD+. They're coupled systems.

The Honest Assessment

Here's where we stand:

The theory is plausible. NAD+ decline is real, substantial, and mechanistically connected to cellular dysfunction.

The animal data is promising. NAD+ precursors improve multiple health parameters in aged mice.

The human data is insufficient. We don't know if NAD+ restoration slows aging in humans. The trials so far haven't shown clear, robust benefits.

The commercial enthusiasm outpaces the science. Millions of people are taking NMN and NR based on limited evidence.

It's a reasonable bet, not a sure thing. If you want to experiment on yourself—and many longevity enthusiasts do—NAD+ precursors are relatively safe and mechanistically reasonable. But don't expect miracles.

Sinclair has bet his reputation on this being real. The longevity supplement industry has bet billions. The outcome is still uncertain.

We're running an uncontrolled experiment on ourselves. In a few decades, we'll know if it worked.

Further Reading

- Yoshino, J., Baur, J. A., & Imai, S. (2018). "NAD+ Intermediates: The Biology and Therapeutic Potential of NMN and NR." Cell Metabolism. - Sinclair, D. A., & LaPlante, M. D. (2019). Lifespan: Why We Age—and Why We Don't Have To. Atria Books. - Martens, C. R., et al. (2018). "Chronic nicotinamide riboside supplementation is well-tolerated and elevates NAD+ in healthy middle-aged and older adults." Nature Communications. - Imai, S., & Guarente, L. (2014). "NAD+ and sirtuins in aging and disease." Trends in Cell Biology.

This is Part 4 of the Mitochondria Mythos series. Next: "Mitophagy: Clearing Out Damaged Mitochondria."