The NAD+ Puzzle: Why Lifestyle Still Wins
It seems that everywhere I look I see headlines about NAD+ the miracle molecule. Nicotinamide adenine dinucleotide, or NAD+, is a molecule at the centre of human biology. It enables mitochondria to generate energy, helps repair DNA, supports circadian rhythm, and fuels enzymes such as sirtuins that regulate stress responses.
When NAD+ becomes depleted, energy falls, damage accumulates, and resilience declines. Blood tests have shown that NAD+ as well some of its constituent building blocks (known as precursors) specifically NMN and NR, can increase NAD+ by 40 to 60 per cent. Clinics offer intravenous NAD+ at premium prices, promising renewed energy and sharper minds. But here is the puzzle: much of that rise is in circulation, not necessarily inside the tissues where ageing unfolds.
For patients and practitioners, the critical question is not whether supplements move a number in the blood, but whether they restore function inside the cell. That is why the NAD+ story is more complex than simply “take a precursor” and why lifestyle interventions continue to show the most reliable impact.
Why NAD+ matters
NAD+ is woven into the fabric of human biology. It fuels mitochondria, drives DNA repair, and helps synchronise the circadian rhythm. When NAD+ runs low, energy wanes, repair falters and resilience fades.
Evidence shows that NAD+ levels often decline with age, though not in every tissue. In the brain, for example, middle aged levels can be half those of youth [1]. This decline is linked to frailty, sluggish metabolism and neurodegeneration [2]. It is no surprise that topping NAD+ back up has become one of longevity’s hottest ideas. The buzz has at times outpaced the evidence, with marketing promising rejuvenation long before the science has caught up.
The promise and the limits of precursors
In animal models, precursors such as NMN and NR boost NAD+ and deliver measurable positive benefits, from improved metabolism to modest lifespan extension [2]. Human trials confirm that both molecules reliably increase circulating NAD+, usually by 40 to 60 per cent after a few weeks [3,4,5]. Some studies report better insulin sensitivity [5], reduced blood pressure [3], and improved aerobic capacity [6]. Others show little effect.
Intravenous infusions can briefly push NAD+ several fold higher, but levels fall back within a day [12]. Oral supplements are steadier, but the bigger question remains, do these rises in blood translate into changes that matter in tissues?
From blood to tissue?
This is where the evidence becomes more uncertain. One trial of NR in older adults showed increased NAD+ in blood but no change in muscle NAD+ on biopsy [4]. By contrast, brain imaging demonstrated that NR could increase NAD+ in the human brain [7], and functional benefits in muscle metabolism and vascular stiffness suggest some tissues do respond [3,5]. Formulation may also matter, with liposomal NMN showing greater uptake in immune cells.
The key point is that raising NAD+ in blood does not automatically mean it is reaching the places where ageing is most relevant. Until this gap is bridged, supplementation should be seen as experimental rather than definitive.
Recycling, the overlooked salvage pathway
Most of the NAD+ in our bodies doesn’t come from new supplements, but from recycling what we already have. Each time NAD+ is used, it breaks down into a smaller part called nicotinamide (NAM). The body can then rebuild NAD+ from NAM through a process known as the salvage pathway, with an enzyme called NAMPT doing most of the work [8]. As we age, this recycling system becomes less efficient: NAMPT slows down [9], an enzyme called CD38 starts burning through more NAD⁺ [10], and chronic inflammation also adds more strain. Simply adding more precursors is like pouring water into a leaky bucket.
Lifestyle as a natural NAD+ strategy
Here lifestyle shines. Exercise increases NAMPT activity by 25 to 100 per cent within weeks [9], and aerobic training can raise muscle NAD+ by around 30 per cent. High intensity intervals acutely boost NAD+ synthesis in immune cells.
Sleep and circadian rhythm are just as important. NAD+ naturally rises and falls across the day, peaking when we are most active [8]. Sleep disruption flattens these cycles, while restoring rhythm can bring them back. In fact, circadian disruption can lower tissue NAD+ by 20 to 40 per cent [8].
Nutritional timing adds another layer. In animals, intermittent fasting can raise liver NAD+ by up to 50 per cent [2]. In humans, early time restricted eating improves markers of NAD+ activity, though direct blood measures remain limited.
These interventions do not just raise NAD+, they improve resilience at multiple levels, from metabolism to brain function, with benefits proven across healthspan.
Beyond precursors
The frontier now is not single molecules but exploring multi-target strategies. These aim to boost NAMPT, reduce CD38 activity, prevent NAD+ waste, and align production with circadian rhythm. Early human data suggest such systems approaches can raise NAD+ by 50 to 60 per cent while also improving markers of immune ageing [11]. This is promising, but still early days.
A balanced view
Taken together, the evidence suggests that NAD+ precursors raise circulating serum levels by about 40 - 60 per cent [3-5], and IV infusions can briefly push them up several fold. The critical uncertainty is whether these increases consistently reach tissues and drive downstream benefits. Biopsy and imaging data so far are mixed, with some tissues showing uptake and others little or none.
By contrast, lifestyle interventions such as training, fasting and sleep can shift recycling efficiency by 20 - 50 per cent [8,9], and these effects are proven to occur directly in muscle, brain and metabolic pathways. No single strategy is definitive, but lifestyle provides the most reliable and sustainable gains. Supplements and new approaches may one day add to this, but their true value depends on showing tissue penetration and functional benefits in humans.
Conclusion
The NAD+ story is not about chasing the latest capsule or infusion, but about understanding a system. Supplements can raise numbers in the blood, but lifestyle restores the rhythms that keep NAD+ flowing where it is needed most. The hype has helped put this molecule in the spotlight, but the science reminds us of a deeper truth. When it comes to sustaining resilience, lifestyle still wins.
By Dr Andrew Crockett
References
Peluso AA, Romani M, Sirtori CR, et al. Does NAD+ decline with age? Re-evaluation of the evidence across human tissues. Antioxid Redox Signal. 2021;35(5):337-349.
McReynolds MR, Chellappa K, Baur JA. Age-related NAD+ decline. Exp Gerontol. 2020;134:110888.
Martens CR, Denman BA, Mazzo MR, et al. Chronic nicotinamide riboside supplementation is well-tolerated and elevates NAD+ in healthy middle-aged and older adults. Nat Commun. 2018;9:1286.
Elhassan YS, Kluckova K, Fletcher RS, et al. Nicotinamide riboside augments the aged human skeletal muscle NAD+ metabolome and induces transcriptomic and anti-inflammatory signatures. Cell Rep. 2019;28(7):1717-1728.e6.
Yoshino M, Yoshino J, Kayser BD, et al. Nicotinamide mononucleotide increases muscle insulin sensitivity in prediabetic women. Science. 2021;372(6547):1224-1229.
Zhou CC, Yang X, Hua X, et al. Nicotinamide mononucleotide supplementation improves aerobic capacity in amateur runners: a randomized trial. Front Nutr. 2022;9:959376.
Valko PO, Beverley C, Taylor A, et al. Nicotinamide riboside supplementation increases brain NAD+ in humans. Cell Rep Med. 2023;4(2):100981.
Ramsey KM, Yoshino J, Brace CS, et al. Circadian clock feedback cycle through NAMPT-mediated NAD+ biosynthesis. Science. 2009;324(5927):651-654.
de Guia RM, Agerholm M, Nielsen TS, et al. Aerobic and resistance training reverses age-dependent decline in NAD+ salvage capacity in human skeletal muscle. Physiol Rep. 2019;7(12):e14139.
Camacho-Pereira J, Tarragó MG, Chini CC, et al. CD38 dictates age-related NAD decline and mitochondrial dysfunction through an SIRT3-dependent mechanism. Cell Metab. 2016;23(6):1127-1139.
Das A, Torrens-Moloney B, Morton C, et al. A novel multi-target NAD+ restoration therapy improves biomarkers of ageing in humans: a randomized placebo-controlled crossover trial. GeroScience. 2024;46:129-146.
Airhart SE, Shireman LM, Risler LJ, Anderson GD, Nagana Gowda GA, Raftery D, Tian R, Shen DD, O'Brien KD, Schwartz SM. An open-label, non-randomized study of the pharmacokinetics of β-nicotinamide mononucleotide and nicotinamide adenine dinucleotide in humans. PLoS One. 2017;12(12):e0186459.
