As in the case of the daf-2 mutants, inactivation of TOR signaling in C. elegans also resulted in increased levels of autophagy, and suppression of autophagy resulted in the reversal of these lifespan-increasing effects
Autophagic activity has been shown to decline with age in various animal models
They demonstrated that RNAi-mediated knockdown of the autophagy gene bec-1 significantly reduced the lifespan of the daf-2 mutants, clearly identifying autophagy as a process that is required for the increased longevity of this mutant (
Neuron-specific overexpression of the Atg8a gene resulted both in an increase in lifespan and a reduction in the accumulation of toxic protein aggregates in neurons
nine hallmarks of aging—genomic instability, telomere shortening, epigenetic alterations, loss of proteostasis, dysregulated nutrient sensing, mitochondrial dysfunction, cell senescence, stem cell loss, and altered intercellular communication
Remarkably, autophagy has been shown to be intimately involved in nearly all of these processes.
telomere dysfunction directly stimulates autophagy to promote the death of precancerous cells
In summary, autophagy has been shown to counter the effects of the majority of the presented hallmarks of aging.
possibly indicating that insulin signaling is more relevant to longevity than IGF-1 signaling. Alternatively, perhaps these differences between C. elegans and mice can be attributed to the fact that daf-2 encodes for a receptor that shows significant homology to both the IGF-1 receptor and the insulin receptor
suggesting that dual knockout (or knockdown) of these receptors is necessary to achieve enhanced lifespan extension.
indicating that the IIS pathway suppresses autophagy
activation of the IIS pathway is known to inhibit autophagy via the activation of mTORC1 and inhibition of FoxO signaling
Under conditions of nutrient deprivation (and suppressed IIS), FoxO3 upregulates autophagy by promoting the expression of autophagy-related genes,
general increase in the expression of genes in the autophagy-lysosomal pathway in centenarians
Aging is associated with hyperinsulinemia and insulin resistance that are caused by greater secretion of insulin in response to the same stimulus compared to younger individuals
In summary, aging is associated with decreasing levels of autophagic activity that are partially the result of dysregulated IIS
display both enhanced autophagy and better-preserved and regulated IIS
extensive evidence that indicates that exercise effectively suppresses insulin resistance and hyperinsulinemia
Mechanistically, one of the ways in which exercise is thought to increase insulin sensitivity is via contraction-stimulated glucose uptake, which involves the activation of AMPK