The Hallmarks of Aging
Modern longevity science has identified several interconnected "hallmarks" of aging that drive the deterioration we associate with getting older. The most promising anti-aging compounds target one or more of these hallmarks:
- Genomic instability — DNA damage accumulates over time
- Telomere attrition — Protective chromosome caps shorten
- Epigenetic alterations — Gene expression patterns change
- Loss of proteostasis — Protein quality control declines
- Deregulated nutrient sensing — mTOR, AMPK, insulin/IGF-1 pathways become dysregulated
- Mitochondrial dysfunction — Cellular energy production declines
- Cellular senescence — "Zombie cells" accumulate and secrete inflammatory factors
- Stem cell exhaustion — Regenerative capacity diminishes
- Altered intercellular communication — Chronic inflammation increases
The Core Longevity Compounds
Rapamycin (mTOR Inhibition)
The most validated longevity compound. Weekly low-dose rapamycin (3-6 mg) selectively inhibits mTORC1, enhancing autophagy and reducing cellular senescence. It's the only compound proven to extend maximum lifespan in mammals.
Metformin (AMPK Activation)
Activates the cellular energy sensor AMPK, inhibits mTOR, and improves metabolic health. Epidemiological data suggests metformin users live longer than non-diabetic controls. The TAME trial is testing this directly.
NAD+ Precursors (NMN/NR)
Restore declining NAD+ levels, activating sirtuins and supporting DNA repair. NAD+ levels drop ~50% between ages 40-60, and restoration has shown broad anti-aging effects in animal models.
Resveratrol (SIRT1 Activation)
Activates SIRT1 and works synergistically with NAD+ precursors. Take with fat for absorption. Best evidence when combined with NMN.
Epithalon (Telomerase Activation)
A synthetic tetrapeptide that activates telomerase, potentially slowing or reversing telomere shortening. Typically used in cycles.
Building Your Stack
Tier 1 (Strongest Evidence):
- Rapamycin 3-6 mg weekly (requires prescription and physician monitoring)
- Metformin 500-1000 mg daily (extended release, with meals, away from exercise)
Tier 2 (Good Evidence):
- NMN 500-1000 mg daily (morning)
- Resveratrol 500 mg daily (with fat-containing meal)
Tier 3 (Emerging Evidence):
- Epithalon cycles (10-day protocols, 2-3 times per year)
- Senolytics (Dasatinib + Quercetin, periodic courses)
Important Considerations
- Start one compound at a time to assess individual response
- Regular bloodwork monitoring is essential
- Some compounds may interact (e.g., metformin may blunt exercise benefits)
- The field is rapidly evolving — stay updated on new research
- Lifestyle fundamentals (sleep, exercise, nutrition, stress) remain the foundation
The Future
The longevity field is advancing rapidly. Combination therapies, personalized approaches based on biological age testing, and novel compounds targeting specific aging hallmarks are all in development. The goal isn't just to live longer, but to extend healthspan — the years of healthy, vibrant life.