Longevity Science: NAD+, NMN, and the Biology of Aging

In 2013, López-Otín et al. published a landmark paper identifying 9 hallmarks of aging: genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular communication. Understanding these hallmarks helps explain why interventions like calorie restriction, exercise, and certain supplements can slow aging. Most longevity interventions target multiple hallmarks simultaneously.

NAD+ (nicotinamide adenine dinucleotide) is a coenzyme involved in hundreds of metabolic reactions. It's critical for energy production, DNA repair (via sirtuins and PARP), and cellular signaling. NAD+ levels decline by approximately 50% between ages 40 and 60. This decline is associated with reduced mitochondrial function, impaired DNA repair, and metabolic dysfunction. David Sinclair's research at Harvard has shown that restoring NAD+ levels in mice reverses many aspects of aging. Human trials are ongoing but early results are promising.

NMN (nicotinamide mononucleotide) and NR (nicotinamide riboside) are precursors to NAD+ that can be taken as supplements. Both have shown the ability to raise NAD+ levels in human trials. A 2021 clinical trial showed NMN supplementation (250mg/day) increased blood NAD+ levels by 38% in healthy adults. Another study showed NR supplementation raised NAD+ in muscle tissue. However, the key question — does raising NAD+ actually slow aging or improve health outcomes in humans? — is still being studied. Most evidence comes from animal studies. Peter Attia takes NMN but acknowledges the human evidence is still emerging.

Senescent cells — often called "zombie cells" — are cells that have stopped dividing but refuse to die. They accumulate with age and secrete inflammatory compounds (the SASP) that damage surrounding tissue. Senolytics are compounds that selectively eliminate senescent cells. The most studied are quercetin and dasatinib (a chemotherapy drug). Fisetin, a flavonoid found in strawberries, has also shown senolytic activity in animal studies. Human trials are in early stages, but the concept is compelling. Clearing senescent cells has reversed multiple aging phenotypes in mice.

Based on current evidence, the highest-leverage longevity interventions are: 1. Exercise (especially Zone 2 + strength training) — the single most evidence-backed intervention 2. Sleep (7-9 hours, consistent schedule) 3. Calorie restriction or intermittent fasting 4. Protein adequacy (1.6-2.2g/kg to preserve muscle mass) 5. Stress management (chronic stress accelerates aging via cortisol and inflammation) Supplements with reasonable evidence: Creatine, Omega-3, Vitamin D3/K2, Magnesium, NMN/NR (emerging evidence).