The MicroRNA mir-83 Disrupts Autophagy in Aging Nematode Worms

Researchers here find a proximate cause of age-related impairments in autophagy in nematode worms. The cellular maintenance processes of autophagy, responsible for recycling unwanted and damaged molecules and structures, are well known to decline with age. This dysfunction contributes to numerous age-related conditions, particularly in tissues containing significant populations of very long-lived cells, in which the build up of damaged components becomes disruptive to function. Upregulation of autophagy, on the other hand, is a feature of many interventions shown to slow aging in laboratory species. In some cases, as for calorie restriction, autophagy is required for the beneficial effects on life span.

Macroautophagy, a key player in protein quality control, is proposed to be systematically impaired in distinct tissues and causes coordinated disruption of protein homeostasis and ageing throughout the body. Although tissue-specific changes in autophagy and ageing have been extensively explored, the mechanism underlying the inter-tissue regulation of autophagy with ageing is poorly understood. Here, we show that a secreted microRNA, mir-83, homologous to mammalian miR-29, controls the age-related decrease in macroautophagy across tissues in Caenorhabditis elegans.

Upregulated in the intestine by hsf-1 with age, mir-83 is transported across tissues potentially via extracellular vesicles and disrupts macroautophagy by suppressing CUP-5, a vital autophagy regulator, autonomously in the intestine as well as non-autonomously in body wall muscle. Mutating mir-83 thereby enhances macroautophagy in different tissues, promoting protein homeostasis and longevity.

Our results not only show that a secreted microRNA is an inter-tissue messenger controlling autophagy for protein homeostasis but also indicate that tissues other than the nervous system (e.g., the intestine) broadcast signals for protein homeostasis throughout the body. Similarly, transcellular chaperone signaling from muscle to intestine and neurons is important in the response against proteotoxic stress.


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