Autophagy and aging: Maintaining the proteome through exercise and caloric restriction

Kurt A Escobar,Trisha A Vandusseldorp,Christine M Mermier,Nathan H Cole

doi:10.1111/acel.12876

Abstract

Accumulation of dysfunctional and damaged cellular proteins and organelles occurs during aging, resulting in a disruption of cellular homeostasis and progressive degeneration and increases the risk of cell death. Moderating the accrual of these defunct components is likely a key in the promotion of longevity. While exercise is known to promote healthy aging and mitigate age‐related pathologies, the molecular underpinnings of this phenomenon remain largely unclear. However, recent evidences suggest that exercise modulates the proteome. Similarly, caloric restriction (CR), a known promoter of lifespan, is understood to augment intracellular protein quality. Autophagy is an evolutionary conserved recycling pathway responsible for the degradation, then turnover of cellular proteins and organelles. This housekeeping system has been reliably linked to the aging process. Moreover, autophagic activity declines during aging. The target of rapamycin complex 1 (TORC1), a central kinase involved in protein translation, is a negative regulator of autophagy, and inhibition of TORC1 enhances lifespan. Inhibition of TORC1 may reduce the production of cellular proteins which may otherwise contribute to the deleterious accumulation observed in aging. TORC1 may also exert its effects in an autophagy‐dependent manner. Exercise and CR result in a concomitant downregulation of TORC1 activity and upregulation of autophagy in a number of tissues. Moreover, exercise‐induced TORC1 and autophagy signaling share common pathways with that of CR. Therefore, the longevity effects of exercise and CR may stem from the maintenance of the proteome by balancing the synthesis and recycling of intracellular proteins and thus may represent practical means to promote longevity.

Highlights

Aging is a biological phenomenon characterized at the cellular level by a progressive accumulation of dysfunctional proteins and damaged organelles
Investigation into the mechanisms underpinning lifespan and longevity shows that the appropriate maintenance of the proteome and organelle population is key in the augmentation of lifespan and/or mitigation of many pathologies associated with the aging process (Balch, Morimoto, Dillin, & Kelly, 2008; Xu et al, 2014)
Autophagic function declines during aging (Cuervo & Macian, 2014; Mejias‐Pena et al, 2016; Salminen & Kaarniranta, 2012) and current investigation offers strong empirical support for the important influence exerted by autophagy over organismal lifespan (Jung et al, 2010; Madeo et al, 2015; Martinez‐Lopez et al, 2015)

Summary

| INTRODUCTION

Aging is a biological phenomenon characterized at the cellular level by a progressive accumulation of dysfunctional proteins and damaged organelles. Reduced cytosolic protein synthesis has been shown to suppress age‐associated mitochondrial degeneration in yeast (Wang, Zuo, Kucejova, & Chen, 2008) This evidence suggests that normal levels of autophagy may be sufficient to maintain cytosolic proteostasis if the rate of protein and organelle synthesis is reduced; it may be possible that the reduced levels of autophagy observed in older cells may not be linked to aging, but offer an indirect reflection of excess TORC1 activity (Pani, 2011). AMPK is a highly conserved kinase that becomes activated during periods of energetic stress, when reductions of ATP

Elegans

Findings

| CONCLUSIONS