Cellular fuel

NAD⁺ — the coenzyme that powers energy metabolism and fuels the sirtuin longevity enzymes; it declines steadily with age.

Fasting response increases it.

Caloric restriction lowers mitochondrial ATP synthesis and drives accumulation of oxidized NAD⁺; the rise in AMP and NAD⁺ is what activates SIRT1 and AMPK, which then activate PGC-1α (PMC8321869). Together they form the caloric-restriction longevity chain on the map: fasting → NAD⁺ → SIRT1 → PGC-1α. Caloric restriction and exercise both stimulate the NAD+ salvage pathway through AMPK, modifying the age-dependent fall in NAD+ — so this edge runs through the AMPK → NAD⁺ link rather than acting directly. The human numbers ARE on the exercise arm and they ARE strong: skeletal-muscle NAMPT correlated negatively with AGE (r-squared 0.297, P<0.001, n=57) and VO2-peak was the best predictor of NAMPT; 12 weeks of aerobic training raised NAMPT 12 percent in young and 28 percent in older people, and resistance training raised it 25 and 30 percent — the older group gained more. Tissue-specific: in the same work, NAMPT in abdominal subcutaneous adipose was unaffected by either age or 6 weeks of HIIT. Muscle responds; fat does not. PMC8321869

Energy sensing increases it.

AMPK-SIRT1 review, Am J Physiol — AMPK activation raises cellular NAD+ and the NAD+/NADH ratio (via nampt in the salvage pathway) as a metabolic-stress response. PMC2853213. Mechanism and its brake are both named: AMPK upregulates NAD+ synthesis and sirtuin activity in a nampt-dependent manner, nampt being the rate-limiting enzyme of the salvage pathway that dominates NAD+ supply in most tissues. The AMPK activators metformin and aicar raise nampt by suppressing miR-146a — they phosphorylate ikk, which attenuates NF-kappa-B, which lowers miR-146a, which otherwise binds the Nampt 3'-utr and cuts nampt protein. AICAR produced an AMPK-driven rise in NAD+, higher sirtuin activity, greater oxidative mitochondrial activity and improved endurance. The brake strengthens with age: miR-146a rises in senescent cells, so the same AMPK signal buys less NAD+ in an old cell than a young one. PMC2853213

Tryptophan balance increases it.

The branch terminates in de novo NAD+ synthesis - which is why one pathway appears in both mood and longevity discussions. Carried by the intermediary-metabolism and clinical reviews (PMC9967593; doi 10.1016/j.molmet.2023.101755; PMC12293478; PMC7005133). Verbatim: “The kynurenine metabolic pathway is the sole de novo NAD(+) biosynthetic pathway, generating NAD(+) from ingested tryptophan”. doi 10.1016/j.molmet.2023.101755 · PMID 31954874 · PMC9967593

Ketone fuel increases it.

The metabolic ratios lactate/pyruvate and β-hydroxybutyrate/acetoacetate are considered valuable tools to evaluate the in vivo redox cellular state by estimating the free NAD+/NADH in cytoplasm and…. PMC8125771

Curbs the main NAD⁺ consumer reduces it.

The enzyme that explains why NAD+ falls with AGE. CD38 is a NAD glycohydrolase (EC 3.2.2.5) and one of the primary enzymes that degrade NAD in mammals; increased CD38 expression is responsible for NAD decline and mitochondrial dysfunction in older mice, acting through an SIRT3-dependent mechanism. The direction is destructive, so the edge is inhibitory: more CD38 activity, less NAD+. Corroborated by inhibition in both directions: the specific inhibitor 78c reverses tissue NAD+ decline and improves glucose tolerance, muscle function, exercise capacity and cardiac function in aged mice, and increases lifespan and healthspan in naturally aged male mice (Peclat 2022, doi 10.1111/acel.13589). Limit, and it binds the whole node: every CD38 finding here is preclinical — cells, mice and one small molecule that has never been given to a human. No CD38 inhibitor has a human trial. Camacho-Pereira 2016, Cell Metab 23(6):1127-1139, PMID 27304511 / PMC4911708 — CD38 dictates age-related NAD decline and mitochondrial dysfunction through an SIRT3-dependent mechanism. doi 10.1111/acel.13589 · PMID 27304511 · PMC4911708

NAD⁺ salvage increases it.

The TAP. NAMPT catalyzes the rate-limiting step of the salvage pathway, converting nicotinamide to NMN, which the NMNATs then convert to NAD+. Most mammalian tissues depend on this route because NAM is itself the product of every NAD-consuming enzyme. The one piece of human evidence in this whole node set: NAMPT abundance in human skeletal muscle correlates negatively with AGE, and 12 weeks of aerobic or resistance exercise training raises it. Measured on muscle biopsies in young and older people. PMC6577427 — Aerobic and resistance exercise training reverses age-dependent decline in NAD+ salvage capacity in human skeletal muscle ; Chini 2024, Aging Cell, doi 10.1111/acel.13920 / PMC10776128 — NAD metabolism: role in senescence regulation and aging. doi 10.1111/acel.13920 · PMC6577427

Spares NAD⁺ during DNA repair reduces it.

Drain two. PARP1 consumes NAD+ to build poly-ADP-ribose chains during DNA repair; its Michaelis constant for NAD+ is 50-97 uM. The honest status, stated by the review itself: "PARP levels/activity have been shown to increase OR decrease depending on the study" — so unlike CD38, PARP1 is not established as a driver of the age-related decline. It is a genuine consumer whose direction of change with age is unresolved. Chini 2024, Aging Cell, doi 10.1111/acel.13920 / PMC10776128 — NAD metabolism: role in senescence regulation and aging ; Cell Metab 2019, S1550413119305029 — NAD+ in brain aging and neurodegenerative disorders. doi 10.1111/acel.13920 · PMC10776128

The Axon's Self-Destruct Switch reduces it.

Drain three, and the most narrowly scoped. In neurons the dimerised SARM1 degrades NAD+ to nicotinamide, ADPR and small amounts of cADPR, much like CD38; its Km is 24 uM. SARM1-mediated degradation is observed during axonal degeneration in vitro and in vivo. Two limits the source states outright: "the role that SARM1 plays in NAD+ depletion in other tissues remains uncertain" and "the role of SARM1 in aging is still unknown." Drawn so the axonal route is visible, not as a claim about aging. Cell Metab 2019, S1550413119305029 — NAD+ in brain aging and neurodegenerative disorders ; Chini 2024, Aging Cell, doi 10.1111/acel.13920 / PMC10776128 — NAD metabolism: role in senescence regulation and aging. doi 10.1111/acel.13920 · PMC10776128

NAD methylation leak reduces it.

The leak, and it is not a consumer at all. NNMT methylates nicotinamide, diverting the salvage pathway’s own substrate toward excretion instead of recycling. Raising NAMPT cannot help if the nicotinamide it needs has already been methylated away. Expression rises in adipose tissue and liver with age. preclinical; no human NNMT intervention exists. Chini 2024, Aging Cell, doi 10.1111/acel.13920 / PMC10776128 — NAD metabolism: role in senescence regulation and aging. doi 10.1111/acel.13920 · PMC10776128

It increases Longevity gene.

Cantó 2009, Nature 458:1056 — NAD+ is the obligate co-substrate that activates the SIRT1 deacetylase. PMID 19262508. Mouse skeletal muscle. SIRT1 is NAD+-dependent by definition; the NAMPT-dependent vs NAMPT-independent route is disputed (PMC2853213). NAD+ is the substrate, not a modulator — sirtuins consume it to deacetylate, so the arrow is stoichiometric: it is described as indispensable for sirtuin activity. Human randomized evidence: in a double-blind, randomized, crossover trial a salvage-pathway-targeting supplement raised whole-blood NAD+, and that rise was accompanied by increased SIRT1 and increased NAMPT in peripheral blood mononuclear cells, alongside lower plasma IL-2, reduced glycated serum protein, and an IgG glycosylation shift toward a younger biological age. measured in blood, not in the tissues where the aging phenotype lives — and Nat Metab 2025 reviews NAD+ precursor trials specifically to flag the crucial knowledge gaps that remain. PMID 19262508 · PMC2853213

It reduces Cellular aging.

A named positive feedback loop, spelled out step by step: age-associated metabolic inflammation can deplete NAD+, leading to age-dependent loss of SIRT activity. Reduced SIRT1 reduces mitochondrial biogenesis, reduced mitochondrial SIRT3 reduces antioxidant and repair systems, and reduced NAD+ may also impair SIRT2, enhancing NLRP3 inflammasome activity. Thus inflammaging can induce a positive feedback loop through altered SIRT function to drive ROS production, mitochondrial dysfunction, and more inflammation. doi 10.1016/j.molmet.2023.101755 · PMC11233824

It increases Hearing.

Mitochondrial antioxidants, modulators of mitochondrial function, calcium channel blockers, and mtDNA mutations that affect mitochondrial activity in the auditory system have emerged as critical factors in hearing protection. The reviewers state their own gap: there is still a lack of information on the underlying mechanisms of redox homeostasis and molecular redox networks in hair cells - so these are protective-target candidates, not demonstrated interventions. The clinical fact that makes protection the only strategy: mammalian cochlear hair cells do not regenerate, which is why SNHL is described as the most common type of permanent hearing impairment. doi 10.1016/j.mito.2025.102063 · PMC10102650

It increases Micronutrient status.

Micronutrient status is assembled from supplement-trial indices; none of the papers cited studied micronutrient status itself. Sources: PMC13074595; doi 10.3390/ijms26146740; doi 10.1139/H07-174. doi 10.3390/ijms26146740 · PMC13074595

It increases Mitochondrial energy.

NAD+ is a central redox factor and enzymatic cofactor; ATP generation through the electron transport chain requires NAD+ as the critical electron acceptor. 2025, npj Metab Health Dis — NAD+ metabolism and its modulation of mitochondria in aging and disease. doi 10.1038/s44324-025-00067-0

It reduces DNA integrity.

The aging-associated loss of NAD+ is related to increased expression of PARPs, caused by increased DNA damage and the need for DNA repair during aging. Covarrubias 2021, Nat Rev Mol Cell Biol — NAD+ metabolism and its roles in cellular processes during aging. PMID 33353981

It increases New mitochondria.

SIRT1 deacetylates and activates PGC-1alpha, which leads to increased mitochondrial biogenesis; NAD+ is required for SIRT1 activity. Covarrubias 2021, Nat Rev Mol Cell Biol — NAD+ metabolism and its roles in cellular processes during aging. PMID 33353981

It increases Cellular cleanup.

Autophagy is regulated downstream of NAD+ levels via sirtuins (mostly SIRT1). Decline of NAD+ levels reduces overall autophagic flux as well as selective removal of mitochondria via mitophagy. Covarrubias 2021, Nat Rev Mol Cell Biol — NAD+ metabolism and its roles in cellular processes during aging. PMID 33353981

It reduces Calms body-wide inflammation.

NAD+ can directly and indirectly influence many key cellular functions, including metabolic pathways, cellular senescence and immune cell function; NAD+ levels gradually decline with age. Covarrubias 2021, Nat Rev Mol Cell Biol — NAD+ metabolism and its roles in cellular processes during aging. PMID 33353981

It increases Memory & focus.

NAD+ augmentation restores mitochondrial function and bioenergetics, leading to enhanced neuronal survival and improved cognitive function. shown in premature-aging animal models, not human outcome trials. Lautrup 2019, Cell Metab — NAD+ in brain aging and neurodegenerative disorders. doi 10.1016/j.cmet.2019.09.001

It increases Muscle.

NMN administration to aged mice increased oxygen consumption and endurance; NAD+ precursors and PARP inhibition raised NAD+ and mitochondrial respiration. rodent. 2025, npj Metab Health Dis — NAD+ metabolism and its modulation of mitochondria in aging and disease. doi 10.1038/s44324-025-00067-0

It reduces Neuronal overexcitation.

Altered energy metabolism is named among the mechanisms that lead to excitotoxic damage; cellular energy status governs how much calcium the mitochondria can absorb before the buffer fails. doi 10.1186/s40035-021-00278-7 · PMC8788129

Thermo (Thermogenic Disposal) →

SIRT1 Activator (Caloric-Restriction Mimetic) →

NAD+ Booster (Cellular Energy Currency) →