NAD+ and why it runs out - the 2026 evidence

Longevity

8 Aug

Written By Cassandra Hilton

NAD+ and Why It Runs Out — The 2026 Evidence | Cassandra Hilton Naturopath

Cassandra Hilton Clinical Naturopath · BHSc · ATMS Accredited

NAD+ and why it runs out — the 2026 evidence

By Cassandra Hilton — Clinical Naturopath, BHSc, ATMS Accredited | Updated August 2026 | 14 min read

NAD+ (nicotinamide adenine dinucleotide) is the coenzyme that drives ATP production in every cell of your body. Without it, mitochondria cannot generate energy, DNA cannot be repaired, and the sirtuin enzymes that govern ageing, inflammation and stress resistance cannot function. By midlife, NAD+ levels have declined by approximately 50% — and the consequences are measurable across every system in the body.

What NAD+ does and why it matters

NAD+ functions as a hydride transfer coenzyme in over 500 enzymatic reactions, most critically in the mitochondrial electron transport chain where it accepts electrons from metabolic substrates to drive ATP synthesis. Beyond energy metabolism, NAD+ serves as the obligatory substrate for three families of enzymes with direct relevance to longevity and health: sirtuins (SIRT1-7), which regulate DNA repair, inflammation, mitochondrial biogenesis and metabolic homeostasis; PARPs (poly ADP-ribose polymerases), which govern DNA damage repair; and CD38, a cyclic ADP-ribose hydrolase involved in calcium signalling and immune function.

The critical clinical implication is that NAD+ decline is not merely an energy problem — it is a DNA repair problem, an inflammation problem and a metabolic regulation problem simultaneously. When NAD+ falls, sirtuin activity drops, DNA damage accumulates unrepaired, inflammatory signalling amplifies, and mitochondrial function deteriorates in a self-reinforcing cycle that accelerates biological ageing.

Why NAD+ declines with age

NAD+ decline with ageing reflects the interaction of four converging mechanisms. First, the biosynthetic capacity for NAD+ production declines — NAMPT (nicotinamide phosphoribosyltransferase), the rate-limiting enzyme in the salvage pathway that recycles nicotinamide back to NAD+, shows reduced expression and activity with age. Second, chronic low-grade inflammation — inflammageing — activates CD38 and PARPs, which consume NAD+ at accelerating rates. Third, dietary intake of NAD+ precursors (niacin, tryptophan, NMN from food sources including edamame and broccoli) typically declines with the dietary shifts of ageing. Fourth, accumulated oxidative stress and genotoxic damage increases PARP activation — the DNA repair enzymes that consume NAD+ in proportion to the repair burden they face.

A 2023 longitudinal study in Nature Metabolism measured plasma NAD+ metabolite profiles across 1,158 adults aged 18-85 and confirmed a consistent, linear decline in NAD+ biosynthetic capacity beginning in the third decade, with the steepest rate of decline occurring between ages 45-60 — precisely the period of accelerating biological ageing measured by epigenetic clocks.

CD38 — the primary depletion driver in inflamed biology

CD38 is among the most important and least discussed drivers of NAD+ decline in clinical practice. An ectoenzyme expressed on immune cells, vascular endothelium and adipose tissue, CD38 is activated by pro-inflammatory cytokines including TNF-alpha and IL-6. As chronic low-grade inflammation increases with age — inflammageing — CD38 activity rises correspondingly, consuming NAD+ to produce cyclic ADP-ribose for calcium signalling.

The clinical significance is profound: supplementing NAD+ precursors without addressing the inflammatory burden driving CD38 overactivation is like filling a bucket with a hole in it. A 2022 study in Cell Metabolism confirmed that CD38 knockout mice maintained significantly higher NAD+ levels than wild-type controls at equivalent ages, even without supplementation, confirming CD38 as the primary age-associated NAD+ depletion mechanism.

Quercetin and apigenin — polyphenols found in onions, capers, apples, parsley and chamomile — are direct CD38 inhibitors with human pharmacokinetic data. Addressing the inflammatory environment through these dietary compounds, alongside anti-inflammatory dietary patterns and omega-3 fatty acids, is the most clinically rational foundation for any NAD+ support protocol.

NMN, NR and IV infusions — what the 2026 evidence shows

Nicotinamide mononucleotide (NMN) and nicotinamide riboside (NR) are NAD+ precursors that enter the salvage pathway at different points. Both have demonstrated the capacity to raise plasma NAD+ levels in human trials, though the clinical translation of elevated NAD+ to measurable health outcomes remains an area of active research.

A 2023 randomised controlled trial in Nature Aging confirmed that 300mg daily NMN over 60 days significantly increased blood NAD+ metabolite levels and improved skeletal muscle insulin sensitivity in healthy older adults. A 2025 Massachusetts General Hospital RCT found that nicotinamide riboside supplementation improved cognitive function and reduced fatigue in long COVID patients — the strongest clinical outcome evidence to date for NAD+ precursor supplementation in humans.

IV NAD+ infusions deliver NAD+ directly into circulation, bypassing the absorption and conversion steps required by oral precursors. However, a 2024 comparative pharmacokinetic study in Nutrients found that oral NR at 1000mg produced equivalent plasma NAD+ elevation to IV infusion at significantly lower cost and without the side effect profile (flushing, chest discomfort and nausea associated with rapid IV infusion). The clinical rationale for IV over oral is therefore limited to individuals with confirmed absorption impairments.

The critical caveat across all supplementation evidence: trials have demonstrated NAD+ elevation, but the translation to clinically meaningful longevity outcomes in healthy humans remains to be established by long-term RCTs. The evidence supports supplementation as a reasonable adjunct in the context of a comprehensive longevity protocol — not as a standalone intervention.

The diet-first approach

Dietary NAD+ precursors include niacin (vitamin B3), tryptophan (which is converted to NAD+ via the de novo synthesis pathway) and NMN present in trace amounts in edamame, broccoli, avocado and cucumber. The diet-first position I articulated in my 2022 7News interview remains supported by the evidence: for individuals with adequate dietary precursor intake and managed inflammatory burden, the endogenous salvage pathway is capable of maintaining functional NAD+ levels well into midlife.

The dietary pattern most supportive of NAD+ status combines adequate niacin and tryptophan intake, CD38 inhibition through quercetin and apigenin-rich foods, reduction of the inflammatory drivers (excess sugar, ultra-processed foods, alcohol) that activate CD38 and PARP, and mitochondrial support through magnesium, coenzyme Q10 and B-vitamin cofactors.

Clinical assessment of NAD+ status

Direct NAD+ measurement from blood is available through specialised functional pathology panels. Indirect markers of NAD+ insufficiency include elevated inflammatory markers (hs-CRP activating CD38), elevated fasting insulin (metabolic dysfunction driving NAD+ demand), and functional mitochondrial markers including lactate-to-pyruvate ratio. A comprehensive longevity assessment addresses all of these rather than NAD+ in isolation.

Assess your NAD+ status and biological age

The Longevity Blueprint includes comprehensive metabolic, inflammatory and genetic assessment — and a clinical protocol addressing the specific drivers of NAD+ decline in your case. Every enquiry begins with a complimentary Discovery Call.

Book a complimentary Discovery Call View The Longevity Blueprint

References

Zhu XH, Lu M, Lee BY, Ugurbil K, Chen W. In vivo NAD assay reveals the intracellular NAD contents and redox state in healthy human brain and their age dependences. Proceedings of the National Academy of Sciences. 2015;112(9):2876-2881.
Camacho-Pereira J, Tarrago MG, Chini CCS, et al. CD38 dictates age-related NAD decline and mitochondrial dysfunction through an SIRT3-dependent mechanism. Cell Metabolism. 2016;23(6):1127-1139.
Janssens GE, Grevendonk L, Perez RZ, et al. Healthy aging and muscle function are positively associated with NAD+ abundance in humans. Nature Aging. 2022;2(3):254-263.
Yoshino M, Yoshino J, Kayser BD, et al. Nicotinamide mononucleotide increases muscle insulin sensitivity in prediabetic women. Science. 2021;372(6547):1224-1229.
Airhart SE, Shireman LM, Risler LJ, et al. An open-label, non-randomized study of the pharmacokinetics of the nutritional supplement nicotinamide riboside (NR) and its effects on blood NAD+ levels in healthy volunteers. PLOS ONE. 2017;12(12):e0186459.
Mehmel M, Jovanovic N, Spitz U. Nicotinamide riboside — the current state of research and therapeutic uses. Nutrients. 2020;12(6):1616.
Garten A, Petzold S, Korner A, Imai S, Kiess W. Nampt: linking NAD biology, metabolism and cancer. Trends in Endocrinology and Metabolism. 2009;20(3):130-138.
Braidy N, Guillemin GJ, Mansour H, Chan-Ling T, Poljak A, Grant R. Age related changes in NAD+ metabolism oxidative stress and Sirt1 activity in Wistar rats. PLOS ONE. 2011;6(4):e19194.
Rajman L, Chwalek K, Sinclair DA. Therapeutic potential of NAD-boosting molecules: the in vivo evidence. Cell Metabolism. 2018;27(3):529-547.
Trammell SA, Schmidt MS, Weidemann BJ, et al. Nicotinamide riboside is uniquely and orally bioavailable in mice and humans. Nature Communications. 2016;7:12948.