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Exploiting superlongevous model mammals to explore new links between protein and organelle homeostasis and lifespan extension

Project description

Bats may hold a secret to longer healthier lives via protein homeostasis

Proteostasis is the protein equivalent of homeostasis, precisely controlling the synthesis, folding, conformational maintenance and degradation of the entire proteome of a cell. Orchestrating this very large symphony does not rely on a single conductor but on a complex and adaptive proteostasis network. Dysfunction of this network can lead to increased levels of misfolded proteins or aggregation, which are linked to ageing and some neurodegenerative diseases. The EU-funded ComBATageing project is studying the potential role of intracellular proteostasis, particularly the role of autophagy, in the unusual longevity of bats. Autophagy is the proteolytic process by which cells remove potentially toxic protein aggregates and damaged organelles. Combined with phylogenomic studies of adaptive selection in proteostasis-associated genes in bats and other mammals, the outcomes could shed light on the role of proteostasis in normal ageing and disease.

Objective

Despite being one of the most familiar biological process affecting our lives, little is known about the molecular mechanics of ageing. A better understanding of ageing and related diseases is today crucial to face its deleterious effects on our growing older population. Among mammals bigger species typically live longer than smaller ones. When corrected for body size, almost all mammals have the same longevity quotients, exception made for the chiroptera. Bats are capable of living up to 10 times longer than expected despite their characteristic high metabolic rates. During my doctorate, I discovered the presence of a distinctive behaviour in bats' autophagic pathway, suggesting that these animals may rely on an improved system for intracellular proteostasis accounting for the flight-associated high metabolic stress. The same evolutive adaptation could ultimately have played a role in allowing bats to achieve exceptional longevity. Here I propose to carry out an in-depth analysis of the proteostatic system, and in particular of the autophagic pathway, in bats. Samples from wild populations of bats will be used to derive primary cell lines allowing to characterise bats’ intracellular phenotype and proteostatic activity. Thanks to the expert personnel and cutting-edge facilities of the hosting institute, I will exploit imaging and proteomics tools to isolate bat-specific molecular features of adaptation in proteostasis and unveil their role in determining their unique ageing pattern. A complementary phylogenomic analysis will be performed to detect traces of adaptive selection in proteostasis-associated genes in bats and other mammals. For the first time, the complexity of interactions behind proteostasis and ageing will be examined from a privileged, integrative perspective. This innovative project holds huge potential as it could lead to a greater understanding of the role of protein homeostasis in mammalian ageing contributing to dampen its effects on our society.

Coordinator

OSPEDALE SAN RAFFAELE SRL
Net EU contribution
€ 183 473,28
Address
VIA OLGETTINA 60
20132 Milano
Italy

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Region
Nord-Ovest Lombardia Milano
Activity type
Private for-profit entities (excluding Higher or Secondary Education Establishments)
Links
Total cost
€ 183 473,28