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

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.

Keywords: aging; autophagy; caloric restriction; exercise; mTOR; physical activity.

Figure 1

Influence of caloric restriction on life span and age‐related pathologies in various model organisms and potential underlying pathways (represented by dashed lines). Caloric restriction activates 5′ adenosine monophosphate kinase (AMPK) and Sirtuin‐1 and downregulates target of rapamycin complex 1 (TORC1). AMPK and SIRT1 in turn stimulate autophagy and further inhibit TORC1. Blue arrow head and red capped head represent activation and inhibition, respectively

Figure 2

Effects of acute and chronic exercise on autophagy in multiple tissues

Figure 3

Common autophagy signaling pathways shared between skeletal muscle contraction (i.e., acute exercise) and caloric restriction. Perturbations in calcium (Ca⁺⁺), adenosine monophosphate (AMP), and nicotinamide adenine dinucleotide (NAD⁺) activate calcineurin, 5′ adenosine monophosphate kinase (AMPK), and sirtuin‐1 (SIRT1), respectively. AMPK induces autophagosome formation through ULK1 while AMPK and SIRT1 act to upregulate expression of Atgs by increasing forkhead box transcription factors (FOXOs) and peroxisome proliferator‐activated receptor gamma coactivator 1‐alpha (PGC1α) and downregulate mammalian target of rapamycin complex 1 (mTORC1). Calcineurin activation and mTORC1 inhibition activate transcription factor EB (TFEB) which activates the CLEAR (coordinated lysosomal expression and regulation) gene network and the transcription of Atgs