Post-reproductive inhibition of the autophagic vesicle nucleation complex extends C. elegans lifespan through the neurons
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Abstract
Autophagy represents an ubiquitous intracellular catabolic process that
delivers cytoplasmatic components to the lysosome for degradation. This
study shows that key autophagy genes are detrimental in late life and shorten
lifespan. This is in stark contrast to previous reports, which linked autophagy
almost exclusively to cytoprotective and longevity-promoting effects. While
autophagy is still positive in young worms, negative effects were only observed
with advanced age. This finding is in accordance with the antagonistic
pleiotropy hypothesis of aging, which predicts that some genes mediate
beneficial effects early in life when natural selection is strong, but are
detrimental late in life when natural selection is weak.
Specifically, post-reproductive inactivation of genes governing the early
autophagic step of vesicle nucleation such as bec-1, unc-51 and epg-8 strongly
extend C.elegans lifespan. In contrast, no longevity was observed upon postreproductive
inactivation of autophagy flux genes past the step of vesicle
nucleation. The here presented data supports an age-related impairment of
autophagy, which is likely at the root of its harmful effects in late life.
This study further uncovers that post-reproductive inhibition of
autophagosome nucleation extends lifespan primarily through neurons.
Notably, this neuronal mediated lifespan extension is accompanied by
improved neuronal health, reduced sarcopenia and improved mobility.
The obtained results collectively hold the potential to become
paradigm defining in regards to how autophagy modulates health as well as
lifespan across aging. Moreover, targeting the process of vesicle nucleation
may prove to be a potential therapeutic avenue in treating humans with agerelated
neurodegenerative diseases.