The numbers are specific, and they're his own. Sinclair, a genetics professor at Harvard Medical School and author of the 2019 bestseller Lifespan, reports a homocysteine target under 8 µmol/L, tied to the NAD+ and methylation pathways his research focuses on. He also monitors B12 specifically, for a reason that isn't about B12 deficiency in the usual sense.
The B12 monitoring exists because of a drug, not a supplement. Sinclair's stack includes metformin, 800 mg/day — a prescription medication approved to treat type 2 diabetes, which he takes off-label for its reported effects on longevity-linked pathways. Metformin is a known B12 depleter, working through the ileal transporter mechanism in the gut. That's the specific reason B12 needs tracking on this protocol: not as a general wellness check, but to counter a documented side effect of a drug he's self-administering outside its approved use.
Self-directed stacks can overshoot. Sinclair has said that after supplementing with B12 and folate to counter the metformin depletion, his levels went to roughly double the recommended maximum — his own account of the correction running past the target in the other direction. It's a small, concrete illustration of the general problem with any self-directed protocol: monitoring one drug's side effect with a supplement doesn't guarantee landing in the right range.
The mechanism behind the whole stack has a documented critic. Sinclair's central scientific claim, running through both his research and his public protocol, is that sirtuins (a family of proteins) drive longevity, and that resveratrol activates them. In January 2023, NAD+ researcher Charles Brenner published a peer-reviewed letter in Archives of Gerontology and Geriatrics directly disputing this. Brenner cites research showing sirtuins do not extend lifespan in yeast or flies, and argues that the assay used to show resveratrol activating sirtuins produces a false positive — the measurement method itself, not the biology, is what shows the effect.
The original resveratrol result has a footnote that rarely makes the highlight reel. Brenner also points to a detail about the foundational resveratrol lifespan studies: the effect showed up only in mice fed an unhealthy, calorie-dense diet, not in mice on a normal one. A molecule that helps offset a bad diet is a different, much narrower claim than a molecule that extends healthy lifespan — and it's the second claim that made it into the public conversation.
NMN sits on firmer ground for one specific claim, and no ground yet for the one people actually care about. It's well established that NMN raises NAD+ levels in humans — that part isn't disputed. What hasn't been shown in any human trial is that raising NAD+ this way extends lifespan or reverses aging-related disease. The mouse data on dramatic anti-aging effects is real; whether it translates to people is the open question the marketing around NMN routinely skips past.
None of this means the numbers are wrong — it means they're one person's numbers. Sinclair's stated homocysteine and B12 targets are things he reports doing for himself, cited to his own book and interviews, not a clinical guideline anyone else is bound by. Whether the underlying sirtuin mechanism holds up is a separate, still-contested question from whether tracking homocysteine and B12 is reasonable — plenty of physicians recommend monitoring both for reasons that have nothing to do with sirtuins at all.
Homocysteine and B12 are both markers FixFirst checks automatically if they're on your report, against standard clinical ranges — not Sinclair's stack-specific targets. If you're on metformin for any reason, B12 is worth tracking regardless of what else is in your protocol.