Maximizing Longevity and Healthspan: Multiple Approaches All Converging on Autophagy

Abstract

Our understanding of the molecular basis of aging has greatly increased over the past few decades. In this review, we provide an overview of the key signaling pathways associated with aging, and whose modulation has been shown to extend lifespan in a range of model organisms. We also describe how these pathways converge onto autophagy, a catabolic process that functions to recycle dysfunctional cellular material and maintains energy homeostasis. Finally, we consider various approaches of therapeutically modulating these longevity pathways, highlighting exercise as a potent geroprotector.

KSHV dysregulates bulk macroautophagy, mitophagy and UPR to promote endothelial to mesenchymal transition and CCL2 release, key events in viral‐driven sarcomagenesis

“…29,30 Then, we explored the possibility of interfering with EndMT reprogramming induced by KSHV by restoring macroautophagy with Metformin, a protein kinase AMP-activated catalytic subunit alpha 2 (AMPK) activator able to induce macroautophagy without interfering with the expression of KSHV latent proteins. 31 As shown in Figure 4B, Metformin restored macroautophagy, as indicated by the reduction of SQSTM1, and counteracted SNAI1 upregulation induced by KSHV, further suggesting the interconnection between macroautophagy reduction and EndMT reprogramming in infected cells. To assess whether macroautophagy restoration by Metformin could reduce ER stress/UPR activation, we assessed the phosphorylation status of eIF2α in KSHV-infected cells.…”

“…These results suggest that the reduction of macroautophagy contributed to the activation of UPR and promoted EndMT similarly to EMT 29,30 . Then, we explored the possibility of interfering with EndMT reprogramming induced by KSHV by restoring macroautophagy with Metformin, a protein kinase AMP‐activated catalytic subunit alpha 2 (AMPK) activator able to induce macroautophagy without interfering with the expression of KSHV latent proteins 31 …”

Irisin and Autophagy: First Update

“…A great amount of data suggested that SkM can regulate both systemic physiology and aging via the release of myokines. Exercise has been shown to promote the muscle secretion of the myokines such as IL-4, IL-6, IL-7, IL-15, decorin, irisin, LIF, metrnl, myonectin, and myostatin, all of which could induce or inhibit autophagy throughout muscle and possibly nonmuscle tissue [ 102 ]. In general, the role of myokines in regulating autophagy has not been extensively studied.…”

The Mitochondrial Permeability Transition: Nexus of Aging, Disease and Longevity

“…Because autophagy can remove damaged cell components that are associated with aging, this process, and particularly macrophagy, plays an important role in retarding aging and aging-related disease [ 128 , 129 , 130 , 131 , 132 , 133 , 134 ]. A selective form of macroauthophagy is mitophagy, which specifically removes damaged mitochondria and thus protects the cell from the deleterious effects of dysfunctional mitochondria, and specifically mitochondria with activated mPTP (see below).…”

“…In model animals, as well as humans, the expression and activity of autophagy genes is reduced with age in various tissues, resulting in the accumulation of intermediates of the process, indicating defective autophagy. The overexpression of specific autophagy genes leads to life extension, while the loss of function of autophagy genes is often associated with age-dependent degenerative diseases [ 131 , 137 , 138 , 139 ].…”