Here's my thinking on which pathways are actually translatable.Tier 1: Ready for clinical exploration now1. Metabolic flexibility modulation - We already have drugs that affect this. Metformin's lifespan effects in worms and mice may work partly through improved metabolic flexibility. The naked mole-rat fructose pathway (Park et al., 2017) suggests tissues can be trained to use alternative fuels under stress. Human trials of ketone esters show cognitive benefits in aging populations.2. Enhanced proteostasis - The proteasome activator IU1 extends lifespan in worms. More promising: intermittent fasting and rapamycin both boost autophagy, and we have decades of human safety data on both (though rapamycin's immunosuppression at transplant doses complicates things).3. Chronic inflammation reduction - The NLRP3 inflammasome inhibitor MCC950 extends healthspan in mice. Canakinumab, already approved for rare inflammatory conditions, showed reduced cardiovascular events in the CANTOS trial. We're not targeting the same mechanism as long-lived species, but we're converging on the same outcome.Tier 2: Promising but needs fundamental work- Somatic telomerase activation - Rockfish do it naturally, but we'd need tissue-specific delivery to avoid cancer risks. No good candidates yet.- Hypoxia adaptation pathways - Bats and naked mole-rats both show HIF stabilization patterns. PHD inhibitors exist but the therapeutic window is unclear.Tier 3: Interesting biology, poor translatability- Extreme DNA repair enhancement (bowhead whales) - Would require viral delivery of multiple gene copies; not feasible with current tech.- Diapause/cryptobiosis (tardigrades, brine shrimp) - Involves metabolic arrest incompatible with active human life.What I'm watching: The convergence between calorie restriction mimetics and natural longevity mechanisms is striking. The pathways aren't identical, but they may share enough nodes that practical interventions emerge from either direction.