The global supplement market exceeds $150 billion annually. The proportion of that revenue tied to claims with strong human evidence is small. The proportion tied to claims that are mechanistically plausible but unproven is large. The proportion tied to claims that are entirely fictional is uncomfortable.
A three-tier framework helps make sense of the landscape without requiring a PhD in biochemistry every time a new molecule trends.
Tier 1: well-evidenced in humans, broadly applicable
These are compounds with consistent randomised controlled trial evidence in humans, replicated across populations, with effect sizes large enough to matter at the individual level.
- Creatine monohydrate. One of the most studied supplements in existence. Reliably improves strength, power output, and lean mass; recent evidence supports modest cognitive benefits, particularly under sleep deprivation. Cheap, well-tolerated, with no significant safety concerns at standard doses.
- Omega-3 fatty acids (EPA/DHA). Solid evidence for cardiovascular endpoints in higher-risk populations, less clear in healthy populations. Probably worth taking for adults with low fish intake.
- Vitamin D3. Worth supplementing for people with measured deficiency, which is most adults at northern latitudes during winter. Universal supplementation in already-replete populations does not appear to confer benefit.
- Protein powder. Not exotic, but the simplest way for most adults to hit a protein intake (1.6–2.2 g/kg) that supports lean mass and satiety, particularly with age.
That is the list. It is short. It contains nothing that requires a subscription.
Tier 2: mechanistically plausible, mixed human data
These are compounds where the biological mechanism is real, the rodent data is suggestive, and the human data is either preliminary or mixed.
- Magnesium glycinate. Plausibly useful for sleep quality in people with low intake. Effect sizes are modest. Worth a 30-day trial, not a lifetime commitment.
- Berberine. Lowers blood glucose. Probably useful for insulin sensitivity in some populations. Long-term human data is thin.
- Curcumin (high-bioavailability forms). Anti-inflammatory effects are real in vitro. In vivo human evidence is mixed and depends heavily on formulation.
- Ashwagandha. Reasonable short-term evidence for stress markers and sleep. Long-term safety data is incomplete.
The right disposition for Tier 2 is curiosity without commitment. Try one at a time, for a defined period, with a clear outcome in mind, and stop if nothing changes.
Tier 3: interesting in mice
These are compounds where the mechanism is intriguing, the rodent data is compelling, and the human data is thin, contradictory, or commercially compromised.
This tier is where most of the longevity supplement industry lives.
The NMN/NR case study
Nicotinamide mononucleotide (NMN) and nicotinamide riboside (NR) are precursors to nicotinamide adenine dinucleotide (NAD+), a coenzyme central to cellular energy metabolism. NAD+ levels decline with age. Restoring them in mice produces a range of impressive-looking outcomes: improved mitochondrial function, better muscle performance, extended healthspan in some models, modest lifespan effects in others.
The hypothesis is genuinely interesting. The compounds raise NAD+ levels in humans, as measured in blood. The Sinclair lab has been prominent in promoting them, and there is now a substantial supplement market built around the proposition that raising NAD+ in humans will produce mouse-like effects.
The human evidence at present:
- Multiple short-term RCTs confirm that NMN and NR raise blood NAD+ levels. This is not contested.
- Functional endpoints — strength, endurance, cognition, biomarkers of ageing — show small, inconsistent, or null effects in published trials. This is also not contested.
- The leap from "raises a metabolite linked to ageing in mice" to "slows ageing in humans" requires several intermediate claims that have not been demonstrated.
A reasonable summary is that NMN and NR are well-tolerated, biologically active, and unproven for the outcomes that motivate their purchase. The cost — typically $40–80 per month for a meaningful dose — is high relative to that evidence base.
This is the shape of most Tier 3 claims. The mechanism is plausible. The marketing is confident. The human trials, when they arrive, tend to be smaller and less impressive than the prior narrative suggested.
Practical disposition
For someone trying to make sensible decisions:
- Take Tier 1 if the conditions apply. Creatine if training, omega-3 if fish intake is low, vitamin D if deficient, protein if lean mass is a goal. The cost is modest and the evidence is solid.
- Experiment with Tier 2 deliberately. Choose one. Decide what success looks like before starting. Try it for 30 days. If nothing changes, stop.
- Largely ignore Tier 3. The honest expected value, weighted across the field, is approximately zero. There are exceptions. They will look the same as the others until the human trials catch up, which takes a decade.
"When the magnitude of an effect is small, the conditions required to detect it are exactly the conditions where you are most likely to find one whether or not it is there." — Andrew Gelman, paraphrased.
Most of the longevity supplement industry runs on this fact.
