Short answer: NAD+ declines measurably with age in humans, and that decline is mechanistically linked to reduced mitochondrial function and sirtuin activity. Supplementation with precursors reliably raises blood NAD+. What has not been shown is that raising NAD+ reverses ageing in people — most of the dramatic restoration findings are in mice.
What NAD+ does in the body
NAD+ is a coenzyme present in every cell and central to the electron transport chain, where nutrients are converted into ATP. Without adequate NAD+, that conversion slows.
It is also consumed — not merely recycled — by two other enzyme families: sirtuins during their regulatory work, and PARPs during DNA repair. Those processes compete for one shared pool, which is why NAD+ sits at the junction of energy metabolism, repair and regulation.
How much do NAD+ levels actually decline?
The best human measurement is Zhu and colleagues (2015), who measured NAD+ directly in healthy human brain using magnetic resonance spectroscopy and found an age-related decline alongside a shift in the NAD+/NADH redox state.
An earlier version of this page attributed a specific "50% decline in muscle tissue between early adulthood and middle age" to a paper in Cell Metabolism that was actually a review of mTOR. That citation was wrong and the precise figure could not be substantiated, so both have been corrected — the decline is real and measured, but we are not going to attach a false precision to it.
Why levels fall
Several mechanisms operate together. Synthesis capacity declines. Consumption rises as accumulated DNA damage increases PARP activity. And degradation increases: Camacho-Pereira and colleagues (2016) showed in knockout mice that CD38 dictates age-related NAD+ decline and mitochondrial dysfunction through a SIRT3-dependent mechanism.
The sirtuin link — and where the evidence is from
Sirtuins require NAD+ to work, so falling NAD+ blunts their activity. Gomes and colleagues (2013) in Cell showed that declining NAD+ induces a pseudohypoxic state that disrupts nuclear-mitochondrial communication during ageing, and that restoring NAD+ reversed those markers.
That study was in mice. It is genuinely important mechanistic work and it is also not evidence of the same effect in people — a distinction this page previously blurred by referring vaguely to "research at Harvard" without a citation.
Raising NAD+ in humans
Precursors work: randomised human trials show oral NMN raises blood NAD+, and Yoshino and colleagues (2021) in Science reported improved muscle insulin sensitivity in prediabetic postmenopausal women over 10 weeks. Detail in NMN Supplement Benefits and NMN vs NAD+.
Resveratrol and quercetin, graded honestly
Resveratrol does not raise NAD+. It is studied as a sirtuin activator — sirtuins being the enzymes that spend NAD+ — which is the logic of pairing them. Whether it activates SIRT1 directly in humans remains contested.
Quercetin inhibits CD38 and appears in the senolytics literature. The human senolytic studies — Justice and colleagues (2019) in idiopathic pulmonary fibrosis and Hickson and colleagues (2019) in diabetic kidney disease — used dasatinib plus quercetin in patients, were open-label and preliminary, and involved a prescription chemotherapy drug alongside the quercetin.
An earlier version of this page described these as "quercetin-based interventions" improving physical function in human subjects, which materially overstated them. They do not establish that quercetin alone, at supplement doses, clears senescent cells in healthy people.
The NAD+ Full Stack combines 500 mg β-NAD+ with 250 mg quercetin and 150 mg 98% trans-resveratrol on the pathway rationale above — supply, retention and downstream activation — with the evidence for each component at the level described here.
Frequently Asked Questions
Quick answers to the questions readers most often ask.
What causes NAD+ levels to decline with age?
Three things together: reduced synthesis capacity, increased consumption by PARP enzymes as DNA damage accumulates, and increased degradation by CD38, whose activity rises with age and inflammation. The CD38 mechanism was demonstrated in knockout-mouse work.
Can you increase NAD+ levels with supplements?
Yes, with precursors. Randomised human trials show oral NMN raises blood NAD+ over weeks of consistent dosing. Raising NAD+ is well established; what a higher level delivers functionally in healthy people is a narrower and less settled question.
What are the symptoms of low NAD+ levels?
There is no clinical syndrome of low NAD+ and no routine test for it. Low NAD+ is associated with fatigue, slower recovery and reduced metabolic efficiency, but these are also general features of ageing and of many other causes, so persistent symptoms warrant medical assessment rather than self-diagnosis.
Does resveratrol boost NAD+?
No. Resveratrol does not raise NAD+ levels. It is studied as a sirtuin activator, and sirtuins require NAD+ as a cofactor, which is the rationale for pairing them. Whether resveratrol activates SIRT1 directly in humans has been contested.
Is NAD+ or NMN better for energy?
NMN enters the pathway in a single enzymatic step and carries the human trial evidence. Oral NAD+ is substantially broken down before reassembly inside cells. Neither produces an acute effect; both are measured over weeks.
References
Every reference below has been verified against PubMed. Human and animal studies are labelled in the text.
- Gomes AP et al. Declining NAD+ induces a pseudohypoxic state disrupting nuclear-mitochondrial communication during aging. Cell. 2013.
- Zhu XH et al. In vivo NAD assay reveals the intracellular NAD contents and redox state in healthy human brain and their age dependences. PNAS. 2015.
- Camacho-Pereira J et al. CD38 dictates age-related NAD decline and mitochondrial dysfunction through an SIRT3-dependent mechanism. Cell Metab. 2016.
- Justice JN et al. Senolytics in idiopathic pulmonary fibrosis: results from a first-in-human, open-label, pilot study. EBioMedicine. 2019.
- Hickson LJ et al. Senolytics decrease senescent cells in humans: preliminary report from a clinical trial of dasatinib plus quercetin. EBioMedicine. 2019.
- Yoshino M et al. Nicotinamide mononucleotide increases muscle insulin sensitivity in prediabetic women. Science. 2021.
These statements have not been evaluated by the Food and Drug Administration. This product is not intended to diagnose, treat, cure or prevent any disease.
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