The molecule that powers every cell in your body is disappearing. By age 50, your NAD+ levels have dropped to roughly half of what they were in your twenties. By 80, you're operating on perhaps 10-20% of your youthful supply. This isn't merely an inconvenient biochemical footnote—it's a fundamental driver of the aging process itself, affecting everything from mitochondrial function to DNA repair to epigenetic stability.

Nicotinamide adenine dinucleotide, or NAD+, functions as the central metabolic currency of cellular energy production. It shuttles electrons in the reactions that convert food into ATP, activates the sirtuin enzymes that regulate longevity pathways, and serves as a substrate for DNA repair mechanisms. When NAD+ declines, these critical processes falter in ways that manifest as the familiar signs of aging: decreased energy, cognitive decline, metabolic dysfunction, and accelerated cellular senescence.

The scientific community has identified NAD+ restoration as one of the most promising intervention points for age reversal. Unlike many anti-aging targets, NAD+ sits upstream of multiple aging hallmarks simultaneously. Restore NAD+ levels, and you potentially address mitochondrial dysfunction, genomic instability, and epigenetic drift in a single intervention. The question isn't whether NAD+ matters—that science is settled. The question is how to most effectively restore it, and that's where the cutting edge of longevity medicine is now focused.

Your body isn't simply using up NAD+ faster as you age—it's actively destroying it through competing enzymatic pathways that become increasingly aggressive over time. Understanding these mechanisms reveals why simple supplementation strategies often fall short and why a systems-level approach to NAD+ restoration is essential for meaningful age intervention.

The primary culprit is CD38, a glycoprotein whose expression increases dramatically with age and chronic inflammation. CD38 functions as an NADase, directly consuming NAD+ and converting it to cyclic ADP-ribose. Research from the Buck Institute has demonstrated that CD38 levels can increase by 250% between ages 30 and 80, creating an ever-widening drain on your NAD+ pool. Senescent cells—the damaged, zombie-like cells that accumulate with age—secrete inflammatory factors that further upregulate CD38 expression, creating a vicious feedback loop.

Simultaneously, the PARP enzymes that repair DNA damage consume NAD+ as their essential substrate. As genomic damage accumulates with age from oxidative stress, environmental toxins, and replication errors, PARP activity increases proportionally. Each DNA repair event consumes one molecule of NAD+, and your aging genome requires exponentially more repairs than your youthful one did.

The salvage pathway, which recycles nicotinamide back into NAD+, also becomes less efficient with age. NAMPT, the rate-limiting enzyme in this pathway, shows decreased expression in aging tissues. This means your body loses the ability to efficiently regenerate NAD+ from its breakdown products, compounding the effects of increased consumption.

The downstream consequences cascade through every major aging hallmark. Declining NAD+ impairs sirtuin activity, reducing their ability to maintain epigenetic marks and coordinate stress responses. Mitochondria lose their capacity for efficient ATP production, creating the energy deficit that underlies age-related fatigue. The NAD+-dependent enzyme PARP1 can no longer adequately repair DNA damage, allowing mutations to accumulate. Understanding that NAD+ decline isn't passive depletion but active destruction by specific enzymatic pathways opens the door to targeted interventions beyond simple precursor supplementation.

Takeaway

NAD+ decline results from active enzymatic consumption by CD38 and PARPs, not just reduced production—effective restoration requires addressing both supply and demand sides of the equation.

The supplement market offers several NAD+ precursors, but their effectiveness varies dramatically based on bioavailability, tissue distribution, and the specific metabolic context of your body. Choosing the optimal precursor—and dosing it correctly—requires understanding the nuanced science behind each compound's journey from ingestion to cellular NAD+ elevation.

Nicotinamide mononucleotide (NMN) has emerged as the frontrunner in recent research, particularly following David Sinclair's advocacy. NMN is one enzymatic step closer to NAD+ than NR, requiring only the enzyme NMNAT for conversion. Human trials have demonstrated that oral NMN at doses of 250-1000mg daily can significantly elevate blood NAD+ levels within weeks. The recent discovery of the Slc12a8 transporter suggests NMN can be absorbed directly into cells in some tissues, though this pathway's significance in humans remains under investigation.

Nicotinamide riboside (NR) benefits from a longer research history and established human safety data. NR requires conversion to NMN before becoming NAD+, adding an enzymatic step. However, NR has demonstrated excellent oral bioavailability and consistent NAD+ elevation in human trials at 300-1000mg daily. Some researchers argue NR's additional metabolic step may actually provide regulatory advantages, preventing excessive NAD+ accumulation in tissues that don't require it.

The humble niacin (nicotinic acid) shouldn't be dismissed despite its prosaic status. Niacin elevates NAD+ through a separate pathway (the Preiss-Handler pathway) that may offer complementary benefits. At doses of 500-2000mg, niacin produces robust NAD+ elevation, though the characteristic flushing response limits tolerability for many users. Extended-release formulations reduce flushing but carry liver concerns at higher doses.

Current evidence suggests optimal dosing for most adults falls between 500-1000mg daily of NMN or NR, ideally taken in the morning to align with circadian NAD+ rhythms. Sublingual delivery may enhance bioavailability by bypassing first-pass liver metabolism. Emerging liposomal formulations show promise for improved cellular uptake. The most sophisticated protocols now combine precursors to address multiple synthetic pathways simultaneously, though head-to-head human comparison data remains limited.

Takeaway

NMN and NR both effectively elevate NAD+ at 500-1000mg daily, with NMN requiring fewer metabolic steps—morning dosing aligns with circadian biology for optimal effect.

Taking an NAD+ precursor without addressing the enzymatic processes that deplete NAD+ is like filling a bathtub with the drain open. The most advanced age-intervention protocols now combine precursor supplementation with compounds that reduce NAD+ consumption, enhance synthetic efficiency, and support the methylation demands created by NAD+ metabolism.

CD38 inhibitors represent perhaps the most impactful synergistic intervention. Compounds like apigenin (found in chamomile and parsley), quercetin, and luteolin have demonstrated significant CD38 inhibition in research models. Apigenin at 50mg daily has shown measurable CD38 suppression in human studies. By reducing CD38's consumption of NAD+, these compounds allow precursor supplementation to more effectively raise and maintain elevated NAD+ levels. The flavonoid combination of apigenin and quercetin (250-500mg each) has become standard in sophisticated longevity protocols.

Methylation support addresses a critical bottleneck in NAD+ metabolism that's often overlooked. When NAD+ is broken down, it releases nicotinamide, which must be methylated to N-methyl-nicotinamide for excretion. This methylation consumes methyl groups from SAMe, potentially depleting methylation capacity. High-dose NAD+ precursor supplementation without adequate methyl donor support can paradoxically impair other methylation-dependent processes including DNA methylation, neurotransmitter synthesis, and detoxification pathways. Trimethylglycine (betaine) at 1-3 grams daily, along with adequate B12 and folate, ensures methylation capacity matches increased NAD+ turnover.

Sirtuin activation compounds like resveratrol and pterostilbene may enhance the functional benefits of elevated NAD+. While NAD+ is the essential substrate for sirtuin enzymes, these polyphenols appear to increase sirtuin activity at any given NAD+ level. Pterostilbene (50-100mg) offers superior bioavailability compared to resveratrol and has shown consistent benefits in human trials when combined with NR.

The most comprehensive protocols also address the upstream causes of NAD+ decline. Reducing chronic inflammation lowers CD38 expression. Senolytics that clear senescent cells eliminate a major source of inflammatory signals. Lifestyle factors including time-restricted eating, exercise, and cold exposure independently elevate NAD+ through NAMPT activation. The future of NAD+ restoration isn't a single pill but an integrated systems approach that addresses synthesis, consumption, and functional utilization simultaneously.

Takeaway

Combine NAD+ precursors with CD38 inhibitors like apigenin and quercetin plus methylation support from TMG—this systems approach addresses both production and consumption for maximum cellular impact.

NAD+ restoration represents one of the most actionable interventions in the current anti-aging arsenal. The science connecting NAD+ decline to multiple aging hallmarks is robust, and the tools for restoration are increasingly sophisticated. We've moved beyond simple precursor supplementation toward integrated protocols that address the complex dynamics of NAD+ metabolism.

The practical framework emerging from current research combines 500-1000mg of NMN or NR taken in the morning, CD38 inhibition through apigenin and quercetin, methylation support via TMG, and lifestyle interventions that support endogenous NAD+ production. This multi-pronged approach addresses both supply and demand in the cellular NAD+ economy.

As direct NAD+ delivery methods and more targeted CD38 inhibitors enter clinical development, the effectiveness of NAD+ restoration will only improve. For those serious about age intervention, establishing a solid NAD+ protocol today creates the metabolic foundation upon which future advances can build.