Adipose mitochondrial functional enhancement via DsbA-L rewires systemic aging through an adipokine-mediated longevity pathway

ABSTRACT: Mitochondrial dysfunction is a hallmark of aging, but whether restoring mitochondrial function in adipose tissue alone can delay systemic aging is unknown. Here we show that adipose-specific upregulation of the mitochondrial chaperone DsbA-L in mice improves metabolic and cognitive function and extends lifespan, linking adipose mitochondrial fitness directly to systemic aging. DsbA-L upregulation reprograms adipose gene expression and raises circulating levels of the adipokine Serpina3m. Fat-body-specific knockdown of Spn42De (CG9460), the Drosophila serpin counterpart of Serpina3m, shortens lifespan, whereas its overexpression extends it. SERPINA3, the human ortholog, is enriched in centenarians. Unlike conventional mitochondrial enhancers, DsbA-L couples metabolic efficiency to endocrine signaling, and berberine increases DsbA-L expression, indicating that this pathway is pharmacologically tractable. These benefits occur in both sexes and identify DsbA-L–Serpina3m signaling as a target for healthy aging.

INSTRUMENT(S):

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Blood Serum

SUBMITTER: did 11  

LAB HEAD: Zixin Cai

PROVIDER: PXD086072 | Pride | 2026-10-27

REPOSITORIES: Pride