Abstract
The metabolic and endocrine functions of adipose tissue and the ability of organisms to cope with cellular stress have a direct impact on physiological ageing and the aetiology of various diseases such as obesity-related pathologies and cancer. The endocrine effects of adipose tissue are mediated by secreted adipokines, which modulate metabolic processes and influence related maladies. Although a plethora of molecules and signaling pathways associate ageing with proteotoxic stress and cellular metabolism, our understanding of how these pathways interconnect to coordinate organismal physiology remains limited. We dissected the mechanisms linking adiponectin signalling pathways and endoplasmic reticulum (ER) proteotoxic stress responses that individually or synergistically affect longevity in C. elegans. Animals deficient for the adiponectin receptor PAQR-1 respond to ER stress, by rapidly activating the canonical ER unfolded protein response (UPRER) pathway, which is primed in these animals under physiological conditions by specific stress defence transcription factors. PAQR-1 loss enhances survival and promotes longevity under ER stress and reduced insulin/IGF-1 signalling. PAQR-1 engages UPRER, autophagy and lipase activity to modulate lipid metabolism during ageing. Our findings demonstrate that moderating adiponectin receptor -1 activity extends lifespan under stress, and directly implicate adiponectin signalling as a coupler between proteostasis and lipid metabolism during ageing.
Highlights
Ageing is characterized by deterioration of physiological regulatory functions, and progresses towards frailty and age-associated pathology
We observed that the small percentage of paqr-1 mutants that developed into adults during the endoplasmic reticulum (ER) stress test remained viable more than 8 days after hatching on plates containing tunicamycin, whereas WT animals, paqr-2 or paqr-3 mutants that reached adulthood under the same conditions perished in less than 3 days
We find that paqr-1(tm3262) mutants subjected to daf-2 RNAi display enhanced survival compared to WT animals (Fig. 3A). daf-2 silencing increases ER stress resistance in both WT animals and paqr-1(tm3262) mutants (Fig. 3B). paqr-1 expression is not altered during ageing or under animals containing xbp-1(tm2457), pek-1(ok275) or atf-6(ok551) mutations were laid on plates in the presence of 5 μg/ml tunicamycin
Summary
Ageing is characterized by deterioration of physiological regulatory functions, and progresses towards frailty and age-associated pathology. Organelle-specific response pathways are regulated by the endoplasmic reticulum (ER) unfolded protein response (UPRER), the less well characterized mitochondrial unfolded protein response (UPRmt), the peroxisomal quality control system and autophagy[2, 7, 8]. Deterioration of these homeostatic mechanisms is a general feature of ageing and occurs in several age-associated diseases. It is recognized that adipose tissue is a highly active metabolic and endocrine organ, and that secreted adipose-derived hormones (adipokines) are important for metabolic homeostasis[11, 12]. Adiponectin, together with cognate adiponectin receptors which mediate its anti-diabetic and anti-atherogenic metabolic actions, are potential versatile therapeutic targets for obesity-related diseases and the metabolic syndrome
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