Job one: redox cycling
Every step that produces ATP, glycolysis, the Krebs cycle, beta-oxidation, the electron transport chain, relies on NAD+ cycling between its oxidized (NAD+) and reduced (NADH) forms. NAD+ accepts electrons, becomes NADH, delivers them downstream, and returns to NAD+ to do it again.
That cycling is why the cellular pool of NAD+ matters. If pool size falls, mitochondrial ATP production loses throughput. Cells with high metabolic demand, muscle, brain, immune cells, feel it first.
Job two: sirtuin activation
Sirtuins (SIRT1 through SIRT7) are a family of NAD+-dependent deacetylases that remove acetyl groups from proteins, including histones, metabolic enzymes, and transcription factors. Their activity depends on NAD+ availability: low NAD+, low sirtuin activity.
Sirtuins regulate mitochondrial biogenesis, fatty-acid oxidation, circadian rhythm, and DNA repair. Several are implicated in caloric-restriction phenotypes in model organisms, which is where much of the "NAD+ and longevity" narrative originates.
Job three: PARP and DNA repair
Poly(ADP-ribose) polymerases (PARPs) detect damaged DNA and initiate repair by transferring ADP-ribose units from NAD+ onto target proteins. When DNA damage accumulates, PARP activation is high, and NAD+ gets consumed quickly.
That’s part of why NAD+ pool size drops with aging and with chronic cellular stress: damage drives sustained PARP activity, which drains NAD+ faster than biosynthesis can replenish it.
CD38 and the aging drain
CD38 is an immune-cell NAD+ hydrolase that consumes NAD+ at high rates. Its expression rises during aging and chronic inflammation, and its activity is a major driver of the age-related decline in tissue NAD+ levels. Research into CD38 inhibitors is active for exactly this reason.
What this implies for protocol design
Raising systemic NAD+ doesn’t automatically raise NAD+ at the tissue or sub-cellular compartment where it matters most for a given outcome. Protocol design, dose, frequency, adjunctive precursors, and labs, is individualized by clinician review rather than prescribed by blanket rule.
What an honest clinician will tell you: tissue NAD+ drops with age, and supporting it is biologically reasonable. Whether that translates to specific outcomes in you, at your dose, over your timeline, that’s what the check-ins and labs are for.