Rewire Weekly is one science backed protocol every Tuesday, drawn from the latest longevity and neuroscience research. I am a practitioner and researcher. The goal is not wellness content. It is clinical evidence translated into something you can actually use.

By your mid 40s, the molecule that powers your sirtuins, repairs your DNA, and fuels your mitochondria has dropped by roughly half. Not because you are doing anything wrong. NAD+ depletion is one of the few things that happens to every human body with sufficient time, regardless of lifestyle. Exercise slows the decline. It does not stop it.

NAD+ is the shared currency for three enzyme systems that define how fast you age at the cellular level. Sirtuins use it to regulate gene expression, mitochondrial biogenesis, and the inflammatory response. PARP enzymes consume it every time a strand of DNA breaks and needs repair. CD38, an enzyme that rises with chronic inflammation and with age, hydrolyzes it as part of immune signaling. All three systems compete for the same pool. By the time most people are in their 40s and 50s, the pool is no longer sufficient to run all three at full capacity simultaneously.

Nicotinamide mononucleotide (NMN) is the most direct oral precursor for restoring NAD+ levels. It sits one biosynthetic step upstream of NAD+ in the salvage pathway, and unlike longer chain precursors, it bypasses the rate limiting enzyme that declines with age. Four human randomized controlled trials now show measurable increases in blood NAD+ levels, improvements in physical performance, and preserved biological age in middle aged adults. There is also a legitimate debate about whether oral NMN actually does what it is claimed to do in the gut, and about whether blood NAD+ elevations mean anything for the brain specifically. Both of those questions deserve direct answers, not omission.

NAD+ functions as a cofactor for over 500 enzymatic reactions in human cells. Three families matter most for aging.

The sirtuins (SIRT1 through SIRT7) are NAD+ dependent deacylases. SIRT1 regulates the circadian clock, fat oxidation, and neuronal survival. SIRT3 governs mitochondrial protein acetylation and manages reactive oxygen species in the mitochondrial matrix. SIRT6 controls telomere stability and DNA repair. When NAD+ falls below the concentration sirtuins need to function, their activity drops regardless of whether sirtuin protein is present. More sirtuin protein without adequate NAD+ is inert. This is why NAD+ supplementation is the upstream intervention. You are not activating sirtuins directly. You are restoring the substrate they require.

The PARP enzymes (poly ADP ribose polymerases) detect and repair DNA strand breaks. Each repair cycle consumes NAD+. As DNA damage accumulates with age, oxidative stress, and UV exposure, PARP activity increases and NAD+ consumption rises with it. The feedback loop is direct: more damage demands more repair, which depletes more NAD+, which impairs sirtuin function, which reduces the cellular defenses that prevent further damage. PARP activation and NAD+ depletion amplify each other.

CD38 is an NAD+ hydrolase whose expression increases substantially with age and with chronic low grade inflammation. CD38 cleaves NAD+ as part of immune cell signaling. A single inflamed tissue can drive local CD38 activity high enough to significantly reduce NAD+ availability systemwide. This is one mechanism by which chronic inflammation accelerates biological aging at the cellular level, beyond the direct inflammatory damage it causes.

NMN enters the system at the salvage pathway entry point via NAMPT, the rate limiting enzyme that converts nicotinamide to NMN. NAMPT declines with age. NMN supplementation provides the product of that step directly, bypassing NAMPT and delivering substrate to NMNAT enzymes that complete the conversion to NAD+. This is why NMN is considered more direct than tryptophan or niacin based approaches to raising NAD+, both of which require multiple enzymatic steps through pathways that also decline with age.

The landmark trial is Yoshino and colleagues (2021, Science, 341 citations), a 10 week, randomized, double blind, placebo controlled trial in postmenopausal women with prediabetes who were overweight or obese. NMN supplementation significantly improved muscle insulin sensitivity assessed by the hyperinsulinemic euglycemic clamp, which is the gold standard measure of peripheral insulin sensitivity. Skeletal muscle insulin signaling improved via phosphorylation of AKT and mTOR, the key nodes in the insulin signaling cascade. Gene expression analysis of quadriceps muscle showed upregulation of platelet derived growth factor receptor beta and pathways related to muscle remodeling. This is the first controlled human evidence that NMN produces downstream metabolic changes in skeletal muscle beyond simply raising blood NAD+ levels.

Lin Yi and colleagues (2022, GeroScience, 135 citations) ran the most comprehensive dose finding trial available: 80 middle aged healthy adults, 60 days, randomized to placebo, 300mg, 600mg, or 900mg per day. Blood NAD+ increased significantly in all NMN treated groups at both day 30 and day 60 (p≤0.001 versus placebo and versus baseline). Physical performance on the six minute walking test improved at all NMN doses (p<0.01 versus placebo). The most important finding: biological age calculated via the Aging.Ai 3.0 algorithm increased significantly in the placebo group and remained unchanged in all three NMN groups (p<0.05 versus placebo). The largest NAD+ elevations and longest walking distances were in the 600mg and 900mg groups, with 600mg representing the point where blood NAD+ response was maximized without meaningful additional return at 900mg.

Igarashi and colleagues (2022, NPJ Aging, 72 citations) studied 250mg per day in older men over 6 to 12 weeks. Whole blood NAD+ and NAD+ metabolite concentrations increased significantly. There were nominally significant improvements in gait speed and grip strength, which the authors flagged as requiring validation in larger trials. The compound was well tolerated with no significant adverse effects at this dose.

Kim and colleagues (2022, Nutrients, 54 citations) examined 108 older Japanese adults at 250mg per day for 12 weeks, specifically testing morning versus afternoon dosing. The afternoon group showed the largest effect sizes for lower limb function via the five repetition sit to stand test (Cohen's d = 0.72) and for reduced drowsiness (d = 0.64). The afternoon NMN group also showed significant improvement in Pittsburgh Sleep Quality Index scores. This is the only trial examining timing effects, and it suggests that for physical performance and alertness outcomes in older adults, afternoon dosing may outperform morning dosing.

The most clinically significant new piece of evidence is Christen and colleagues (2026, Nature Metabolism, 5 citations), a 14 day randomized, open label, placebo controlled trial in 65 healthy participants, directly comparing NMN, nicotinamide riboside (NR), and nicotinamide (Nam). The finding: both NMN and NR comparably elevated circulatory NAD+ concentrations in healthy adults. Neither worked faster via an acute direct pathway. The mechanism for both turned out to involve the gut microbiome: NMN and NR are converted by gut bacteria to nicotinic acid (NA), which then enters the Preiss-Handler pathway to generate NAD+. Both are effective for sustained systemic NAD+ elevation, and their efficacy appears equivalent at comparable doses.

This is the mechanistic context for Huberman's sublingual protocol. Huberman takes 2g NMN sublingually in the morning. The rationale is to bypass gut conversion and deliver NMN directly into systemic circulation without the microbiome conversion step. If gut bacteria are consuming NMN and converting it to NA before it can reach tissues intact, then placing NMN under the tongue and absorbing it through the sublingual mucosa would theoretically allow more intact NMN to reach circulation and tissues directly. The hypothesis is plausible. However, there is currently no human controlled trial comparing sublingual versus oral NMN on tissue NAD+ concentrations. Whether sublingual delivery achieves meaningfully superior outcomes in practice remains an open question.

Peter Attia's more fundamental concern is worth taking seriously: even when peripheral blood NAD+ rises substantially, there is no reliable evidence in humans that brain NAD+ rises in parallel. The neurovascular data from aged mice (Tarantini et al. 2019, Redox Biology, 256 citations) showed NMN restored neurovascular coupling, improved cerebral blood flow, improved spatial working memory, and reversed mitochondrial fragmentation via the SIRT1/nitric oxide pathway. The mechanistic picture in rodents is compelling. But the question of whether oral or sublingual NMN restores brain NAD+ in aging humans has not been confirmed in controlled trials. The brain sits behind the blood brain barrier and has its own NAD+ regulatory mechanisms. Peripheral blood NAD+ and intracellular brain NAD+ are not the same measurement.

The honest summary: the evidence for systemic NAD+ elevation and peripheral metabolic benefits, specifically insulin sensitivity, physical performance, and preserved biological age, is solid at 600mg per day oral NMN. The brain specific and longevity extension benefits, while mechanistically compelling in animal models, remain less certain in humans. NMN and NR appear to work through the same gut dependent mechanism and produce comparable blood NAD+ elevations at equivalent doses. The sublingual protocol is a rational hypothesis for improving tissue delivery, not yet a confirmed superior approach.

On the NMN versus NR question for practical purposes: if price and availability are comparable, the evidence currently supports either. If you want to stay closest to the specific doses and populations used in the human RCTs showing physical performance and metabolic benefits, NMN at 600mg per day is the evidence matched choice.

NMN (as beta NMN, 600mg per day). Look for beta NMN specifically on the label or certificate of analysis. Third party testing for purity and identity verification matters here because the NMN market includes a significant proportion of underdosed or improperly formulated products. The Lin Yi 2022 trial used a verified NMN formulation. Generic products may not match those specifications.

I have reviewed the available options against the clinical evidence. The most reliably standardized and tested NMN at the evidence backed 600mg dose is available through my Fullscript dispensary at a discount below retail.

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