NAD+ and cellular energy

Of NAD+, and of the Quiet Currency by Which Cells Spend Energy, Repair the Genome, and Mark the Years

A scholarly essay from academic literature and from the published research of Elysium Health on precursors that raise NAD+ in the body

It is not unfitting to consider a dinucleotide that is older than the kingdoms of life and yet newly fashionable in the marketplace of aging. Nicotinamide adenine dinucleotide, written NAD+, is not a vitamin in the popular sense, nor a hormone. It is a coenzyme and a consumed substrate: the cell’s redox currency in energy metabolism, and the coin that sirtuins, poly(ADP-ribose) polymerases, and NAD glycohydrolases spend when they regulate chromatin, mend DNA, and signal. Academic reviews in Endocrine Reviews, Nature Reviews Molecular Cell Biology, and Aging Cell now treat the age-related fall in NAD+ as a plausible contributor to metabolic, vascular, muscular, and cognitive decline. Whether raising it in humans restores youth is a narrower, unfinished question. This essay sets out the mechanisms, the problems that attend the decline, and the evidence—including Elysium Health’s peer-reviewed trials—for supplements that generate NAD+ from precursors.

Of cellular energy, which is the first and oldest office

In glycolysis, the tricarboxylic-acid cycle, and oxidative phosphorylation, NAD+ accepts hydride to become NADH; NADH returns its electrons to the respiratory chain so that ATP may be made. The phosphorylated pair NADP+/NADPH serves anabolic work and the glutathione defence against oxidants. Without a sufficient NAD+/NADH ratio, mitochondria falter, fatty-acid oxidation slows, and the cell cannot keep the books of catabolism and biosynthesis. This redox office does not destroy the dinucleotide; it merely shuttles it between oxidised and reduced forms. The pool itself is finite, and it is drained by a second class of reactions.

Those consuming reactions are the ones that link energy status to aging biology. Sirtuins (SIRT1–SIRT7) are NAD+-dependent deacylases. They remove acetyl and related groups from histones and from metabolic proteins, using one NAD+ per reaction and releasing nicotinamide and O-acetyl-ADP-ribose. PARP1 and PARP2, summoned by DNA strand breaks, polymerise ADP-ribose at the cost of many NAD+ molecules per repair event. CD38, CD157, and SARM1 hydrolyse NAD+ in immune and axonal signalling. These families compete for the same pool. When DNA damage or chronic inflammation runs high, PARPs and CD38 can starve sirtuins of substrate and, if the drain is severe, impair the redox reactions that make ATP. Energy generation and genetic housekeeping are therefore not separate ledgers; they draw on one treasury.

Of genetic regulation, which is how the currency speaks to chromatin

SIRT1 in the nucleus deacetylates histones and regulators such as PGC-1α, FOXO, and p53, coupling nutrient state to mitochondrial biogenesis, stress resistance, and inflammatory tone. SIRT6 participates in DNA repair and in the silencing of repetitive elements. Mitochondrial SIRT3 deacetylates enzymes of the electron-transport chain and of antioxidant defence, so that the organelle’s work and its protection travel together. Because sirtuin catalysis consumes NAD+, a falling NAD+/NADH or NAD+/nicotinamide ratio is itself a signal that the cell is less able to run these programmes.

PARP1’s genetic office is repair. It detects breaks, paints the chromatin with poly(ADP-ribose), and recruits the machinery of base-excision and strand-break repair. That office is indispensable; PARP1-null mice age badly in some respects and are prone to cancer. Yet chronic PARP activity, driven by accumulated damage, can empty the NAD+ pool and thereby suppress SIRT1—an antagonism documented in premature-aging syndromes such as Cockayne syndrome and xeroderma pigmentosum group A, where NAD+ replenishment or PARP restraint has improved laboratory phenotypes. Genetic regulation by NAD+ is thus two-handed: sirtuins tune transcription and mitochondrial quality when the pool is ample; PARPs spend the pool to keep the genome intact when it is not.

Of aging, and of the problems that follow a smaller pool

Tissue NAD+ declines with chronological age in rodents and, in several studies, in human skin, liver, and blood. The causes are plural. Salvage synthesis through nicotinamide phosphoribosyltransferase (NAMPT) may wane in some tissues. CD38 expression rises with “inflammaging,” and CD38-knockout mice keep NAD+ better into late life. Persistent DNA damage keeps PARPs busy. The downstream picture, as Covarrubias, Chini, Imai, Sinclair, Guarente and many university groups have mapped it, is familiar among the hallmarks of aging: less sirtuin activity; poorer mitochondrial quality control and mitophagy; weaker DNA-repair capacity when the pool is spent; deregulated nutrient sensing; epigenetic drift; sarcopenia and metabolic inflexibility in animal models. Restoring NAD+ with precursors has, in worms, flies, and mice, improved glucose handling, endothelial function, ischemic tolerance, and aspects of healthspan. Those preclinical gains are the warrant for human trials. They are not themselves human proof.

Of precursors, and of how the body remakes what it has spent

Humans rebuild NAD+ by de novo synthesis from tryptophan, by the Preiss–Handler pathway from nicotinic acid, and chiefly by salvage from nicotinamide. Two supplements now dominate the clinical literature because they enter salvage efficiently and raise circulating NAD+ more durably than nicotinamide itself: nicotinamide riboside (NR), which is phosphorylated to nicotinamide mononucleotide (NMN) and then adenylated to NAD+; and NMN, the immediate precursor. A 2026 Nature Metabolism comparison found that two weeks of oral NR or NMN at one gram a day approximately doubled circulating NAD+, whereas nicotinamide did not sustain that rise. Oral NR and NMN are generally well tolerated over weeks to months. What they have not yet shown, in adequately powered trials, is a consistent lengthening of human healthspan or a slowing of hard clinical endpoints in the healthy old.

Of Elysium Health, and of three preparations that generate NAD+

Elysium Health, co-founded with the MIT biologist Leonard Guarente, has built its NAD+ programme around two oral products and a proprietary NR used in university trials. The company’s other capsules—Matter for cognition, Format for immune aging—do not themselves generate NAD+ and are set aside here. The three NAD-raising preparations are Basis, Signal, and the proprietary nicotinamide riboside designated NR-E.

Basis is nicotinamide riboside plus pterostilbene, a blueberry-related stilbene intended to support SIRT1. In a randomised, double-blind, placebo-controlled trial of 120 adults aged sixty to eighty, published in 2017 in npj Aging and Mechanisms of Disease (Dellinger, Guarente, and colleagues), the recommended daily dose—250 milligrams of NR and 50 milligrams of pterostilbene—raised whole-blood NAD+ by about 40 percent at four weeks, a rise sustained at eight weeks. A double dose raised NAD+ by about 90 percent at four weeks and 55 percent at eight weeks. Placebo did not raise NAD+. No serious adverse events were attributed to the product. The trial was funded by Elysium and conducted by an independent contract research organisation. It established target engagement: Basis can raise human NAD+. It did not establish that the rise restores youthful physiology.

A later six-month, double-blind trial in 111 adults with non-alcoholic fatty liver disease tested the same combination against placebo (Dellinger et al., Hepatology, 2023). The primary endpoint, hepatic fat fraction, did not change versus placebo. Prespecified secondary markers of liver inflammation—alanine aminotransferase and gamma-glutamyltransferase—fell over time in the recommended-dose arm relative to placebo. An open-label pilot has explored brief Basis use around menopausal symptoms; such work is preliminary. The honest reading of Basis is that it is a documented NR-plus-pterostilbene preparation that elevates blood NAD+ and has a mixed, still thin record on clinical organs.

Signal is Elysium’s NMN product: 250 milligrams of nicotinamide mononucleotide with a SIRT3-activation complex of honokiol and viniferin, aimed at mitochondrial sirtuin rather than at nuclear SIRT1. The company cites human NMN literature showing that 250 milligrams a day can raise blood NAD+ on the order of 40 percent in a month, and broader NMN trials that have reported effects on insulin sensitivity, walking performance, or sleep in selected older cohorts. Those findings belong to the general NMN literature, not all of it Elysium’s. There is not yet a large, independent, outcome-rich trial of the Signal combination itself comparable to the 2017 Basis NAD+ study. The design rationale is coherent—NMN to refill the pool, SIRT3 ligands to favour the mitochondrial deacetylase—but synergy in humans remains a hypothesis.

NR-E is Elysium’s proprietary nicotinamide riboside, used without pterostilbene in trials run with academic partners. Elysium lists collaborations that include a Mayo Clinic study of bone, muscle, and metabolic function in aging; a University of Copenhagen trial in older adults with chronic obstructive pulmonary disease; and Norwegian trials of NAD replenishment in atypical parkinsonism and progressive multiple sclerosis. Those studies test whether raising NAD+ changes function in diseased or aged tissues. Until their peer-reviewed results are complete, they are a programme, not a verdict.

A closing measure

NAD+ is the cell’s redox coin and the spent substrate of sirtuins, PARPs, and CD38. Its decline with age is real in laboratory animals and plausible in human tissues; the problems that follow—strained mitochondria, less nimble DNA repair, quieter sirtuin programmes, inflammaging that itself consumes the pool—are the reasons the molecule has become a target. Precursors work, biochemically: NR and NMN raise circulating NAD+; Elysium’s Basis trial is among the cleaner demonstrations that a marketed combination can do so by about 40 percent at the labelled dose. What the academic literature still withholds is proof that such a rise, in ordinary older adults, prevents the fatal or disabling diseases of late life. Preclinical promise is strong; human physiology is mixed; company science is useful when it is randomised and published, and must be read as company science. Wisdom would keep the biochemistry, credit the trials that measured NAD+ honestly, wait for the organ-level results now in progress, and not mistake a fuller blood dinucleotide for a recovered youth.

Principal sources

Endocrine Reviews, NAD+ in aging biology (2023). Covarrubias, Perrone, Grozio, Verdin, NAD+ metabolism and cellular processes during ageing. Imai and Guarente, NAD+ and sirtuins in aging and longevity. Chini and colleagues, NAD metabolism, senescence, and aging, Aging Cell. Dellinger, Guarente et al., repeat-dose NRPT increases NAD+ in humans, npj Aging and Mechanisms of Disease (2017). Dellinger et al., NR and pterostilbene in NAFLD, Hepatology (2023). Martens et al., NR in midlife and older adults. Lapatto et al., NR twin study, Science Advances. Freeberg et al., dietary NAD+-boosting compounds in humans. Cuenoud et al., Nature Metabolism comparison of NR, NMN, and nicotinamide. Elysium Health publications and trial registry descriptions of Basis, Signal, and NR-E.