White adipose atrophy exacerbates cold stress and accelerates aging in male mice.

Adipose tissues are highly dynamic in response to environmental temperature changes. During aging, subcutaneous white adipose tissues (WAT) decreases, yet whether this atrophy exacerbates cold stress and triggers systemic aging remains unclear. Here we show that adipocyte-specific expression of the LmnaG609G mutation in male mice leads to progressive WAT atrophy, accelerates aging, and shortens lifespan, whereas female mice remain unaffected. This lipoatrophy exacerbates cold stress, triggering cyclooxygenase-2 (COX-2) upregulation in WAT, and increased prostaglandin E2 production, which mediates the elevation of core body temperature (CBT). Inhibiting COX-2 by celecoxib or thermotherapy by housing the lipoatrophic mice at 26 °C (normally 22 °C) ameliorates cold stress, restores CBT, reduces aging features, and extends lifespan. Our findings reveal that subcutaneous WAT atrophy and subsequent CBT elevation induced by chronic mild cold stress are drivers of systemic aging in male mice, identifying thermotherapy as a potential regimen for progeria.