3-Ketoacyl thiolase delays aging ofCaenorhabditis elegansand is required for lifespan extension mediated bysir-2.1

Abstract

Studies of long-lived Caenorhabditis elegans mutants have identified several genes that function to limit lifespan, i.e., loss-of-function mutations in these genes promote longevity. By contrast, little is known about genes that normally act to delay aging and that when mutated cause premature aging (progeria). To seek such genes, we performed a genetic screen for C. elegans mutants that age prematurely. We found that loss-of-function mutations of the ketoacyl thiolase gene kat-1 result in an increased accumulation of the lipofuscin-like fluorescent aging pigment, shortened lifespan, early behavioral decline, and other abnormalities characteristic of premature aging. These findings suggest that kat-1 acts to delay C. elegans aging. kat-1 encodes a conserved metabolic enzyme that catalyzes the last step of fatty acid oxidation and was previously shown to regulate fat accumulation in worms. We observed that kat-1 is required for the extension of lifespan and enhanced thermotolerance mediated by extra copies of the deacetylase gene sir-2.1. kat-1 acts independently of other known pathways that affect longevity. Our findings suggest that defects in fatty acid oxidation can limit lifespan and accelerate aging in C. elegans and that kat-1-mediated fatty acid oxidation is crucial for overexpressed sir-2.1 to delay aging.progeria | lipofuscin | fatty acid oxidation | sirtuins | protein deacetylation

Genetic Regulation of Caenorhabditis elegans Lysosome Related Organelle Function

“…kat-1 mutations elevate LRO Nile red in strains that also carry a mutation in the C. elegans homologue of mammalian tubby gene, tub-1 [18]. kat-1 mutations were also identified in a genetic screen for elevated intestinal autofluorescence [29].…”

“…This could be because kat-1 plays a larger role in ketone or amino acid metabolism or that one of its two predicted paralogs T02G5.7 or T02G5.4 serves a functionally redundant role. Loss of function mutations in kat-1 produce hallmarks of premature aging [29] including shortened lifespan, decreased stress resistance, decrease locomotory ability with aging, and evidence of early tissue aging [29]. We postulate that in a kat-1 mutant, disruption of pathways of beta oxidation and possibly in terminal oxidation of branched chain amino acids leads to increased formation of LRO autofluorescent pigment and increased accumulation of Nile red in the LRO.…”

Hormetins, antioxidants and prooxidants: defining quercetin-, caffeic acid- and rosmarinic acid-mediated life extension in C. elegans

“…Lipofuscin consists primarily of lipid peroxidation products and oxidized proteins that resist proteolytic degradation (Berdichevsky et al 2010). The results in Fig.…”

Effect of the tocotrienol-rich fraction on the lifespan and oxidative biomarkers in Caenorhabditis elegans under oxidative stress

“…The aging of C. elegans is characterized by a progressive decline in locomotion, decreased defecation and decreased pharyngeal pumping rate (12–14). In addition, the intestinal cells of C. elegans accumulate an autofluorescent aging pigment called lipofuscin throughout adulthood (14,15). Protein carbonyl has also been reported to accumulate during the aging of C. elegans (16), but changes in the levels of 8-OHdG, which is a DNA damage marker, have not been extensively studied (17–19).…”