Cellular Health & Longevity

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Each category groups compounds by their primary mechanism of action in cellular aging. Select a topic for a detailed guide covering evidence, dosing, costs, and regulatory status.

The Biology of Cellular Aging

Understanding why cells age is the foundation for evaluating every compound in this chapter. The hallmarks of aging — first systematized by López-Otín et al. (2013) and updated in 2023 — describe interconnected processes that drive age-related decline at the molecular and cellular level.

NAD+ Decline

Nicotinamide adenine dinucleotide (NAD+) is a coenzyme present in every living cell. It is essential for energy metabolism, DNA repair, and the activity of sirtuins — a family of proteins that regulate cellular stress responses and gene expression. NAD+ levels decline progressively with age, falling by approximately 50% between ages 40 and 60 in some tissues (Yoshino et al., 2011). This decline is driven by increased activity of NAD+-consuming enzymes, particularly CD38 and PARP, and by reduced biosynthesis. Restoring NAD+ levels — through precursors such as NMN and NR — is a central strategy in longevity research, championed by David Sinclair at Harvard Medical School.

Cellular Senescence & Senolytics

Senescent cells are cells that have permanently stopped dividing but refuse to die. They accumulate with age and secrete a cocktail of inflammatory molecules known as the senescence-associated secretory phenotype (SASP). This chronic, low-grade inflammation — sometimes called "inflammaging" — contributes to tissue dysfunction, cardiovascular disease, neurodegeneration, and cancer risk. Senolytics are compounds that selectively eliminate senescent cells. The combination of dasatinib and quercetin was the first senolytic regimen demonstrated to clear senescent cells in humans (Justice et al., 2019). Fisetin, a plant flavonoid, is also under investigation.

mTOR, Autophagy & Nutrient Sensing

The mechanistic target of rapamycin (mTOR) is a nutrient-sensing kinase that promotes cell growth when nutrients are abundant. Chronic mTOR activation — driven by modern diets high in protein and sugar — suppresses autophagy, the cell's recycling system for damaged proteins and organelles. Inhibiting mTOR with rapamycin extends lifespan in every organism tested, from yeast to mice. Matt Kaeberlein at the University of Washington has led translational research on rapamycin's longevity effects, including the Dog Aging Project. Autophagy activation through mTOR inhibition, caloric restriction, or compounds like spermidine is one of the most consistently supported interventions in aging biology.

Caloric Restriction Mimetics

Caloric restriction (CR) — reducing caloric intake by 20–40% without malnutrition — extends lifespan across virtually every model organism. However, sustained CR is impractical for most humans. Caloric restriction mimetics are compounds that activate the same molecular pathways as CR without requiring reduced food intake. These include metformin (AMPK activation), rapamycin (mTOR inhibition), resveratrol (SIRT1 activation), and spermidine (autophagy induction). Nir Barzilai at Albert Einstein College of Medicine leads the TAME (Targeting Aging with Metformin) trial — the first FDA-sanctioned clinical trial to test a drug specifically for aging as an indication.

Key Researchers

• David Sinclair (Harvard Medical School) — NAD+ biology, sirtuins, epigenetic reprogramming. Co-discoverer of sirtuin-activating compounds. Co-founder of multiple biotech companies focused on NAD+ and aging reversal. His dual role as researcher and company founder has drawn scrutiny regarding conflicts of interest.
• Matt Kaeberlein (University of Washington) — mTOR, rapamycin, the Dog Aging Project. A leading voice in translational geroscience focused on moving longevity research from model organisms to companion animals and humans.
• Nir Barzilai (Albert Einstein College of Medicine) — Metformin, centenarian genetics, the TAME trial. Principal investigator of the Longevity Genes Project and architect of the case that aging should be recognized as a treatable condition by the FDA.

NAD+ Precursors

Compounds that raise intracellular NAD+ levels to support sirtuin activity, DNA repair, and mitochondrial function.

SIRT1 Activators & Polyphenols

Natural and synthetic compounds studied for sirtuin activation, anti-inflammatory effects, and caloric restriction mimicry.

Senolytics & Senescent Cell Clearance

Compounds that selectively eliminate senescent cells to reduce chronic inflammation and age-related tissue dysfunction.

Autophagy Activators & mTOR Modulators

Compounds that enhance cellular recycling (autophagy) by inhibiting mTOR or activating complementary pathways. mTOR inhibition is among the most consistently replicated lifespan-extending interventions in model organisms.

Metabolic & Caloric Restriction Mimetics

Compounds that activate AMPK and other energy-sensing pathways associated with caloric restriction, without requiring reduced food intake.

Mitochondrial Support

Compounds that support mitochondrial function, biogenesis, and protection against oxidative damage — processes that decline with aging.

Essential Nutrients & Cofactors

Vitamins and cofactors critical for cellular function that are commonly deficient, especially in individuals on medications like metformin or PPIs.

Real Questions, Informed Discussion

Discuss protocols, share experiences, and explore the science behind cellular health and longevity compounds.