Aging & Longevity

Cells maintain protein quality through chaperones, the proteasome, and autophagy. This system collapses with age, allowing misfolded proteins to accumulate — causing Alzheimer's (amyloid/tau), Parkinson's (alpha-synuclein), and cataracts. ISRIB dramatically improved memory in aged mice but has not yet translated to humans.

The thymus — the organ that trains new immune cells — shrinks dramatically after puberty, losing 90%+ of functional tissue by age 50. Old people cannot mount effective immune responses to new infections or vaccines. Greg Fahy's TRIIM trial (N=9) showed partial thymic regeneration, but no properly powered trial has confirmed this.

Mitochondria accumulate DNA mutations at 10-17x the rate of nuclear DNA due to poor repair mechanisms. Damaged mitochondria can outcompete healthy ones within a cell through 'clonal expansion.' There is no approved therapy to selectively remove or repair mutant mtDNA, leaving cells increasingly energy-starved with age.

Rapamycin is the most consistently life-extending drug ever found in lab animals — working in yeast, worms, flies, and mice (10-25% lifespan extension). But it was designed as an immunosuppressant. The Dog Aging Project TRIAD trial ($7M NIH grant, 580 dogs) won't conclude until 2029, and ARPA-H just funded a $30.8M human trial of a next-gen rapamycin analog.

NAD+ is a critical molecule that declines 40-60% between ages 30 and 70. Supplements like NMN and NR reliably double circulating NAD+ levels in humans within 14 days, but clinical trials have not consistently shown the dramatic health improvements seen in mice.

Scientists can reset old cells to a younger state using Yamanaka factors, but pushing too far turns cells cancerous or makes them forget their identity. The first human trial of epigenetic reprogramming therapy was FDA-cleared in 2025 (Life Biosciences), but nobody has established the precise 'dose' that rejuvenates without causing tumors.

Senescent 'zombie cells' accumulate with age and poison surrounding tissue. Drugs that kill them (senolytics) show dramatic benefits in mice, but current drugs like dasatinib+quercetin are repurposed cancer drugs that also damage healthy cells — particularly platelets and immune cells — leading to inconsistent clinical results.

We lack a reliable, FDA-accepted way to measure biological age. Without this, testing anti-aging interventions requires decades-long trials waiting for disease or death. Epigenetic clocks like GrimAge and DunedinPACE show promise but disagree with each other and have not been validated as regulatory endpoints.