Saturated very long chain fatty acid configures glycosphingolipid for lysosome homeostasis in long-lived C. elegans

The contents of numerous membrane lipids change upon ageing. However, it is unknown whether and how any of these changes are causally linked to lifespan regulation. Acyl chains contribute to the functional specificity of membrane lipids. In this study, working with C. elegans, we identified an acyl chain-specific sphingolipid, C22 glucosylceramide, as a longevity metabolite. Germline deficiency, a conserved lifespan-extending paradigm, induces somatic expression of the fatty acid elongase ELO-3, and behenic acid (22:0) generated by ELO-3 is incorporated into glucosylceramide for lifespan regulation. Mechanistically, C22 glucosylceramide is required for the membrane localization of clathrin, a protein that regulates membrane budding. The reduction in C22 glucosylceramide impairs the clathrin-dependent autophagic lysosome reformation, which subsequently leads to TOR activation and longevity suppression. These findings reveal a mechanistic link between membrane lipids and ageing and suggest a model of lifespan regulation by fatty acid-mediated membrane configuration.

Degrading intestinal DAF-2 nearly doubles Caenorhabditis elegans lifespan without affecting development or reproduction

Twenty-eight years following the breakthrough discovery that a single-gene mutation of daf-2 can double the lifespan of Caenorhabditis elegans, it remains unclear where this gene, which encodes an insulin/IGF-1 receptor, is expressed and where it acts to regulate aging. Here, by inserting DNA sequences of fluorescent tags into the genomic locus of daf-2 and that of its downstream transcription factor daf-16, we determined that both genes are expressed in most or all tissues from embryos through adulthood, in line with their diverse functions. Using tissue-specific auxin-induced protein degradation, we determined that both DAF-2 and DAF-16 act in the intestine to regulate organismal aging. Strikingly, loss of DAF-2 in the intestine nearly doubled C. elegans lifespan but did not produce the adverse developmental or reproductive phenotypes associated with genetic daf-2 mutants. These findings unify the mechanism of lifespan regulation by genes and that by dietary restriction, and begin to focus anti-aging research on nutrient supply.

17-a-estradiol has sex-specific effects on neuroinflammation that are partly reversed by gonadectomy

17-α-estradiol (17aE2) treatment from 4-months of age extends lifespan in male mice and can reduce neuroinflammatory responses in the hypothalamus of 12-month-old males. Although 17aE2 improves longevity in males, female mice are unaffected, suggesting a sexually dimorphic pattern of lifespan regulation. We tested whether the sex-specific effects of 17aE2 on neuroinflammatory responses are affected by gonadal removal and whether hypothalamic changes extend to other brain regions in old age. We show that sex-specific effects of 17aE2 on age-associated gliosis are brain region-specific and are partially dependent on gonadectomy. 17aE2 treatment started at 4 months of age protected 25-month-old males from hypothalamic inflammation. Castration before 17aE2 exposure reduced the effect of 17aE2 on hypothalamic astrogliosis in males. By contrast, sex-specific inhibition of microgliosis generated by 17aE2 was not significantly affected by castration. In the hippocampus, gonadectomy influenced the severity of gliosis and the responsiveness to 17aE2 in a region-dependent manner. The male-specific effects of 17aE2 correlate with increases in hypothalamic ERα expression, specifically in gonadally intact males, consistent with the idea that 17aE2 might act through this receptor. Our results indicate that neuroinflammatory responses to 17aE2 are partially controlled by the presence of sex-specific gonads. Loss of gonadal function and age-associated neuroinflammation could, therefore, influence late-life health and disease onset, leading to sexual dimorphism in both aging and in response to drugs that modify the pace of aging.

Long-lived termite kings and queens activate telomerase in somatic organs

Kings and queens of termites, like queens of other advanced eusocial insects, are endowed with admirable longevity, which dramatically exceeds the life expectancies of their non-reproducing nest-mates and related solitary insects. In the quest to find the mechanisms underlying the longevity of termite reproductives, we focused on somatic maintenance mediated by telomerase. This ribonucleoprotein is well established for pro-longevity functions in vertebrates, thanks primarily to its ability of telomere extension. However, its participation in lifespan regulation of insects, including the eusocial taxa, remains understudied. Here, we report a conspicuous increase of telomerase abundance and catalytic activity in the somatic organs of primary and secondary reproductives of the termite Prorhinotermes simplex and confirm a similar pattern in two other termite species. These observations stand in contrast with the telomerase downregulation characteristic for most adult somatic tissues in vertebrates and also in solitary insects and non-reproducing castes of termites. At the same time, we did not observe caste-specific differences in telomere lengths that might explain the differential longevity of termite castes. We conclude that although the telomerase activation in termite reproductives is in line with the broadly assumed association between telomerase and longevity, its direct phenotypic impact remains to be elucidated.

A cell non-autonomous mechanism of yeast chronological aging regulated by caloric restriction and one-carbon metabolism

Caloric restriction (CR) improves healthspan and lifespan of organisms ranging from yeast to mammals. Understanding the mechanisms involved will uncover future interventions for aging associated diseases. In budding yeast, Saccharomyces cerevisiae, CR is commonly defined by reduced glucose in the growth medium, which extends both replicative and chronological lifespan (CLS). We found that conditioned media collected from stationary phase CR cultures extended CLS when supplemented into non-restricted (NR) cultures, suggesting a potential cell non-autonomous mechanism of CR-induced lifespan regulation. Chromatography and untargeted metabolomics of the conditioned media, as well as transcriptional responses associated with the longevity effect, pointed to specific amino acids enriched in the CR conditioned media (CRCM) as functional molecules, with L-serine being a particularly strong candidate. Indeed, supplementing L-serine into NR cultures extended CLS through a mechanism dependent on the one-carbon metabolism pathway, thus implicating this conserved and central metabolic hub in lifespan regulation.

Oleic acid protects Caenorhabditis mothers from mating-induced death

Reproduction comes at a cost, including death. Previous studies of the interconnections between reproduction, lifespan, and fat metabolism in C. elegans were predominantly performed in low-reproduction conditions. To understand how increased reproduction affects lifespan and fat metabolism, we examined mated worms; we find that a Δ9 desaturase, FAT-7, is significantly up-regulated. Dietary supplementation of oleic acid (OA), the immediate downstream product of FAT-7 activity, restores fat storage and completely rescues mating-induced death, while other fatty acids cannot. OA-mediated lifespan restoration is also observed in C. elegans mutants suffering increased death from short-term mating, and in mated C. remanei females, indicating a conserved role of oleic acid in post-mating lifespan regulation. Because OA supplementation does not further increase the reproductive span or the brood size of mated C. elegans mothers, our results suggest that altering specific fat metabolism uncouples reproduction and somatic lifespan regulation, providing potent targets to ameliorate the cost of reproduction.

A cell non-autonomous mechanism of yeast chronological aging regulated by caloric restriction and one-carbon metabolism

Caloric restriction (CR) improves healthspan and lifespan of organisms ranging from yeast to mammals. Understanding the mechanisms involved will uncover future interventions for aging associated diseases. In budding yeast, Saccharomyces cerevisiae, CR is commonly defined by reduced glucose in the growth medium, which extends both replicative and chronological lifespan (CLS). We found that conditioned media collected from stationary phase CR cultures extended CLS when supplemented into non-restricted (NR) cultures, suggesting a potential cell non-autonomous mechanism of CR-induced lifespan regulation. Chromatography and untargeted metabolomics of the conditioned media, as well as transcriptional responses associated with the longevity effect, pointed to specific amino acids enriched in the CR conditioned media (CRCM) as functional molecules, with L-serine being a particularly strong candidate. Indeed, supplementing L-serine into NR cultures extended CLS through a mechanism dependent on the one-carbon metabolism pathway, thus implicating this conserved and central metabolic hub in lifespan regulation.

Lysosome activity is modulated by multiple longevity pathways and is important for lifespan extension in C. elegans

Lysosomes play important roles in cellular degradation to maintain cell homeostasis. In order to understand whether and how lysosomes alter with age and contribute to lifespan regulation, we characterized multiple properties of lysosomes during the aging process in C. elegans. We uncovered age-dependent alterations in lysosomal morphology, motility, acidity and degradation activity, all of which indicate a decline in lysosome function with age. The age-associated lysosomal changes are suppressed in the long-lived mutants daf-2, eat-2 and isp-1, which extend lifespan by inhibiting insulin/IGF-1 signaling, reducing food intake and impairing mitochondrial function, respectively. We found that 43 lysosome genes exhibit reduced expression with age, including genes encoding subunits of the proton pump V-ATPase and cathepsin proteases. The expression of lysosome genes is upregulated in the long-lived mutants, and this upregulation requires the functions of DAF-16/FOXO and SKN-1/NRF2 transcription factors. Impairing lysosome function affects clearance of aggregate-prone proteins and disrupts lifespan extension in daf-2, eat-2 and isp-1 worms. Our data indicate that lysosome function is modulated by multiple longevity pathways and is important for lifespan extension.