NAD and the Ageing Brain: Part Two: Where It Was Properly Tested

Abstract

Part One established that NAD+ precursors reach their target. The obvious next question is what happens then, and the honest way to answer it is to look at the tissue where the question has been asked most often and most carefully.

That tissue is skeletal muscle. The mechanistic case for NAD+ in ageing muscle — mitochondrial decline, reduced oxidative capacity, sarcopenia — is at least as strong as the case for the brain, and it is far easier to measure.

A meta-analysis published in 2025 pooled the randomised trials. The conclusion is one sentence long and it is not ambiguous.

1.Why Muscle Is the Fair Test

Sarcopenia — the age-related loss of muscle mass and function — is one of the clearest phenotypes of biological ageing, and mitochondrial dysfunction is central to the standard account of it.

NAD+ sits at the centre of mitochondrial energy metabolism. If declining NAD+ availability drives age-related functional loss, muscle is where that should show first and most measurably: grip strength, gait speed, chair-stand time and muscle cross-sectional area are objective, cheap, validated and sensitive to change.

Compared with cognition, where instruments are noisy and effects take years, muscle is the friendly case. A compound that cannot demonstrate an effect here is being asked to demonstrate one somewhere harder.

2.What Was Pooled

Konstantinos Prokopidis, Frank Moriarty, Gülistan Bahat, Harnish Patel and colleagues searched four databases for randomised controlled trials comparing nicotinamide riboside or nicotinamide mononucleotide against placebo, and applied a random-effects meta-analysis to measures of sarcopenia.

Included participants had a mean age ranging from 60.9 to 83 years — the population in which the intervention is marketed and in which it should work if it works at all.

3.The Results

For nicotinamide mononucleotide, every pooled outcome was null.

Skeletal muscle index: mean difference −0.42, confidence interval −0.99 to 0.14, p equal to 0.14. Handgrip strength, analysed separately for each hand: 0.61 with an interval from −0.89 to 2.10, and 0.45 from −1.06 to 1.96, with p-values of 0.42 and 0.56. Gait speed: −0.01, interval −0.08 to 0.06, p equal to 0.79. Five-times chair stand: −0.21, interval −0.70 to 0.29, p equal to 0.41.

The narrative synthesis added that nicotinamide mononucleotide did not improve knee extension strength, the short physical performance battery, or thigh muscle mass.

The authors' conclusion: current evidence does not support nicotinamide mononucleotide and nicotinamide riboside supplementation for preserving muscle mass and function in adults with a mean age of over 60.

4.The Two Findings Inside the Null

Two results in the narrative synthesis run in opposite directions and both deserve reporting.

Nicotinamide riboside was associated with a longer six-minute walk distance in people with peripheral artery disease. That is a positive signal in a population with a specific vascular limitation — and it is consistent with the cardiovascular hypothesis Martens and colleagues flagged in Part One.

And in participants with mild cognitive impairment, nicotinamide riboside was associated with lower scores on the short physical performance battery and slower five-times chair stand. That is worse physical performance, in the population most likely to be buying it for their brain.

We report the second finding with the caveats it deserves: it comes from narrative synthesis rather than a pooled estimate, it is one result among many, and it may be noise. We report it at all because a compound marketed for cognitive ageing produced a decrement in cognitively impaired participants, and that is not a sentence that appears in any marketing.

5.What the Authors Suggest Instead

Their recommendation for future work names three variables: supplementation dosage, baseline NAD+ deficiency, and combined interventions.

The second is the most interesting and the least studied. None of the pooled trials selected participants for low NAD+. If the effect exists only in people who are genuinely depleted, then trials in unselected older adults would return exactly this pattern of nulls, and the field would have spent a decade testing repletion in people who were not deficient.

That is a testable proposition and it has not been tested. It is also, notably, the same structural argument that appears in our taurine series, where a reframing by frailty status suggested the informative subgroup was narrow and specific.

Editorial Comment

MindHeaven® uses no NAD+ precursor supplement and makes no claim about them.

The reason this part sits second in the series rather than last is that it is the strongest human evidence in the whole file, and it is negative. Placing negative evidence early is a discipline rather than a style: an article that reaches the null in its closing paragraph has already spent the reader's attention on the mechanism.

Part Three turns to the brain, where the mechanistic work is genuinely elegant and the species is a mouse.