Abstract

Mitochondrial unfolded protein response (UPRmt) is crucial in preserving mitochondrial health and, consequently, in prolonging healthspan. Natural bioactive polysaccharides have emerged as a central focus for delaying senescence, although their links to mitochondrial stress responses remain incompletely understood. In this study, a purified fraction ofLycii Fructuspolysaccharide (FSP) significantly extended lifespan, improved healthspan-related phenotypes, and enhanced resistance to heat, oxidative, and ultraviolet stress inC. elegans. FSP also preserved mitochondrial abundance and morphology, increased adenosine triphosphate (ATP) levels and mitochondrial membrane potential, and reduced reactive oxygen species. Transcriptomic and qPCR analyses, together withhsp-60andhsp-6reporter assays, showed an enhanced UPRmt-associated response after FSP treatment. FSP-mediated lifespan extension was not observed in theatfs-1andubl-5mutant strains, supporting pathway involvement of ATFS-1/UBL-5-dependent UPRmtsignaling. FSP reduced senescence-associated β-galactosidase positivity and improved mitochondrial function in human dermal fibroblasts. Our findings provide a vision of regulating UPRmtfor anti-aging interventions with plant polysaccharides and highlight the anti-aging potential of FSP by improving mitochondrial health.