Hypothesis

SGLT2 inhibitors (canagliflozin, dapagliflozin, empagliflozin) are underrated geroprotectors that extend lifespan via AMPK activation, senescence reduction, and telomere preservation — with existing FDA approval and established safety profiles.

Evidence

Mouse data: 13-14% lifespan extension in male mice (NIA Interventions Testing Program) — placing SGLT2i among only 12 validated lifespan-extending compounds.

Human telomere data: Rare reversal of age-related telomere shortening after just 6 months of treatment (Cell Reports Medicine, 2025).

Mortality data: 43% lower all-cause mortality vs non-users in real-world data from 25,000+ patients.

Senescence reduction: 40-50% reduction in senescent cells in aortic tissue after 7-14 days of treatment via AMPK-dependent mechanisms.

Mechanism

AMPK activation → mTORC1 inhibition → reduced cellular senescence + improved mitochondrial function + enhanced autophagy.

Why Underrated

SGLT2 inhibitors are framed as diabetes/heart failure drugs despite: (1) robust geroprotective preclinical data, (2) existing safety data from millions of prescriptions, (3) low translation barrier vs. novel compounds requiring de novo development.

The clinical opportunity: repurposing as longevity interventions at lower doses than currently prescribed for metabolic disease.

Key Citations

• NIA Interventions Testing Program (lifespan data)
• Cell Reports Medicine 2025 (telomere reversal)
• GetHealthSpan longevity research review (2025)
• PMC11812426 (mechanism studies)