Maximizing Longevity and Healthspan: Multiple Approaches All Converging on Autophagy

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• 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

• Healthy centenarians

• 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