MKP ‐2 Genetic Depletion Modulates Adipose Lipid Composition, Cellular Senescence, and Aging in Mice

ABSTRACT

Aging is characterized by a gradual decline in physiological functions, impaired cellular repair mechanisms, and increased disease susceptibility. Mitogen‐activated protein kinase phosphatase‐2 (MKP‐2) regulates diverse biological functions, including regulation of infection, brain activity, nutrient metabolism, and cell‐cycle progression, but its role in senescence and adipose lipid metabolism in vivo remains unclear. Here, we investigated the effects of MKP‐2 deficiency on cellular senescence and adipose lipid composition in aged mice using targeted lipidomics. MKP‐2‐deficient mouse embryonic fibroblasts (MEFs) and epididymal white adipose tissue (EWAT) exhibited reduced premature senescence. Lipidomic analysis revealed increased hexosylceramides (HexCERs) and phosphatidylglycerols (PG), and decreased diacylglycerols (DGs) in adipose tissue. These lipid alterations were accompanied by preserved lamin B1, reduced p53 phosphorylation, p16, and PAI‐1, and increased JNK and Akt phosphorylation in EWAT. MKP‐2 deficiency was also associated with extended lifespan and enhanced insulin responsiveness. Together, these studies identify MKP‐2 as a potential regulator linking adipose lipid metabolism, stress‐responsive signaling, cellular senescence, and aging, with its loss promoting a metabolically resilient adipose state that may contribute to improved systemic health and lifespan.