NAD and the Ageing Brain: Part One: The Molecule Works

Abstract

Most compounds in this section fail somewhere between the bottle and the bloodstream, which gives their defenders a permanent escape route: perhaps it never reached the target. NAD+ precursors do not have that problem.

A crossover trial published in Nature Communications in 2018 established that 1 gram of nicotinamide riboside a day raises NAD+ in human cells by about 60 per cent. That is target engagement, documented, in humans.

This is the first of five parts, one per publication, on what happens after that. It is worth starting here because everything the field claims rests on this trial having worked — and because of what the same trial found when it looked at whether anything followed.

1.The Design

Christopher Martens, Douglas Seals and colleagues at the University of Colorado Boulder ran a two-by-six-week randomised, double-blind, placebo-controlled crossover trial in 30 healthy middle-aged and older adults.

A crossover design means every participant served as their own control, which is the right choice for a small pharmacological question: it removes between-person variability, and NAD+ metabolism varies substantially between people.

The dose was 1,000 mg of nicotinamide riboside daily. The primary objective was explicitly stated as determining whether nicotinamide riboside raises blood cellular NAD+ metabolism in humans — not whether it makes anyone healthier.

One methodological detail deserves attention because it recurs in this series. NAD+ and its related metabolites are measurable in circulating peripheral blood mononuclear cells but undetectable in plasma and urine, so the team assessed the NAD+ metabolome in those cells. Where a molecule is measured determines what can be concluded, and here the compartment was chosen because it was the only one that works.

2.What Rose

NAD+ in peripheral blood mononuclear cells rose by approximately 60 per cent compared with placebo, a mean change of 6.2 picomoles per milligram of protein.

Nicotinic acid adenine dinucleotide — a sensitive and reliable biomarker of increased NAD+ metabolism and a product of nicotinamide riboside utilisation — rose nearly fivefold, a mean change of 1.1 picomoles per milligram.

Several related metabolites moved without reaching significance: NADP+, nicotinamide, and nicotinamide mononucleotide at roughly 1.5-fold. The authors read the nicotinamide increase carefully rather than favourably, noting that it would suggest increased activity of NAD+-consuming enzymes, which break NAD+ down.

The supplement was well tolerated and elicited no serious adverse effects over the study period.

This is a clean pharmacological result. The compound is absorbed, it is metabolised along the expected pathway, and the intended molecule increases substantially in the compartment where it can be measured.

3.What Did Not Follow

The exploratory functional analyses are the part of this paper that rarely gets quoted, and they are in the same results section as the finding that does.

No differences were observed in measures of glucose or insulin regulation. No effect on overall motor function. No effect on maximal exercise capacity, assessed by VO2 max and treadmill time to exhaustion. No effect on markers of submaximal exercise performance.

What the authors did highlight was cardiovascular. Their discussion identifies the ability of nicotinamide riboside to reduce systolic blood pressure and aortic stiffness as the most promising hypotheses to test in a future larger-scale trial, particularly in individuals with above-normal baseline systolic pressure.

Note the framing: hypotheses to test, in a future trial, in a subgroup. That is how an exploratory signal should be described, and the contrast with how such signals are usually reported is the reason we are quoting it.

4.Why This Trial Sets the Terms

Thirty participants and twelve weeks in total cannot establish that nicotinamide riboside does nothing functionally. The trial was not designed to, and the authors do not claim it did.

What it does is remove an argument. In the rest of this series — a null meta-analysis in muscle, a mouse study on cerebral blood flow, a review of circadian coupling, and two ongoing human trials — nobody can attribute a disappointing result to the compound failing to arrive.

That makes NAD+ precursors unusually testable, and it makes null results in this literature more informative than null results elsewhere. When taurine or spermidine trials come back empty, the delivery question stays open. Here it does not.

It also leaves the field with a specific burden. If NAD+ rises by 60 per cent and nothing measurable changes, then either NAD+ availability is not the limiting factor it was proposed to be, or the effects require longer, larger, or a different population than has been studied.

Editorial Comment

MindHeaven® does not use nicotinamide riboside or nicotinamide mononucleotide. Boost contains niacinamide as a nutrient, which is a different proposition and one we take up in Part Five.

We open this series with the pharmacology rather than with the promise because the sequence matters. The usual order — mechanism, mouse lifespan, human trial in a closing sentence — leaves a reader believing the human evidence is stronger than it is.

Reversed, the picture is clearer. The molecule works. Part Two is about the tissue where the question was asked most thoroughly, and answered.