A Purified Lycii Fructus Polysaccharide Fraction Extends Healthspan in <i>Caenorhabditis elegans</i> with an ATFS-1/UBL-5-Associated Mitochondrial Unfolded Protein Response.

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 of Lycii Fructus polysaccharide (FSP) significantly extended lifespan, improved healthspan-related phenotypes, and enhanced resistance to heat, oxidative, and ultraviolet stress in C. 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 with hsp-60 and hsp-6 reporter assays, showed an enhanced UPRmt-associated response after FSP treatment. FSP-mediated lifespan extension was not observed in the atfs-1 and ubl-5 mutant strains, supporting pathway involvement of ATFS-1/UBL-5-dependent UPRmt signaling. FSP reduced senescence-associated β-galactosidase positivity and improved mitochondrial function in human dermal fibroblasts. Our findings provide a vision of regulating UPRmt for anti-aging interventions with plant polysaccharides and highlight the anti-aging potential of FSP by improving mitochondrial health.