Intermittent hypobaric pressure induces selective senescent cell death and alleviates age-related osteoporosis

Abstract

Senescent cell accumulation contributes to aging, and their clearance represents an effective anti-aging strategy. Current senolytic strategies focus on drug-mediated senescent cell clearance, but it is unknown whether a hypobaric condition can induce senescent cell death. Here we show that hypobaric pressure (HP) at -375 mmHg without hypoxia induces cells to undergo lysosome-dependent cell death (LDCD). Mechanistically, we unveil that HP activates transmembrane protein 59 (TMEM59) to induce cellular Ca²⁺ influx, which triggers calpain 2 to cleave lysosomal associated membrane protein 2 (LAMP2), leading to lysosomal membrane permeabilization and subsequent LDCD. Furthermore, given that senescent cells contain elevated numbers of lysosomes, we report intermittent HP treatment to specifically induce senescent cells to undergo LDCD and reduce the senescence-associated secretory phenotype. Eventually, we report that intermittent HP treatment can substantially extend the lifespan and rescue the osteoporosis phenotype in aged mice. This study reveals a previously unknown role of HP as a natural senolytic to eliminate senescent cells, and identifies TMEM59 as a new HP-activated ion channel protein.