Mitochondrial metabolic reprogramming induced by calorie restriction

Abstract

Significance: Calorie restriction (CR) is a known intervention that delays most aging processes. Most of the beneficial effects of CR are mediated by improved maintenance of mitochondrial performance in aged individuals. The control of mitochondrial biogenesis, apoptosis, and protein turnover is required for healthy aging. CR is able to induce molecular mechanisms that preserve oxidative capacity and decrease oxidative damage.

Recent advances and critical issues: Published data indicate that peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α) is activated in old animals under CR conditions compared to ad libitum counterparts, enhancing mitochondrial biogenesis. Molecular regulation of PGC-1α has recently attracted significant research interest. We discuss the master regulators of energy metabolism such as AMP-activated protein kinase and sirtuin 1 among others that have been demonstrated to activate mitochondrial biogenesis through increased PGC-1α activity at transcriptional and post-translational levels. Additionally, we describe the latest findings that explain how CR promotes mitochondrial efficiency and decreases mitochondrial-derived oxidative damage.

Future directions: Understanding the beneficial mitochondrial changes conferred by CR will aid design of therapies for age-related diseases and help slow the aging process. Given the difficulty for humans to adhere to CR, we also explore new molecules that have been proposed during the last years to mimic the CR phenotype and their potential as future therapeutics.

FIG. 1.

Calorie restriction (CR) benefits. CR affects many processes in organisms that promote benefits to age-related diseases and delays aging. ROS, reactive oxygen species. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars

FIG. 2.

Mitochondrial dysfunction promotes diseases. Impaired mitochondrial metabolism has been correlated to many diseases. The organs with higher energetic requirements have been found to be most altered by mitochondrial dysfunction. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars

FIG. 3.

Mitochondrial changes induced by CR. Besides the increase in mitochondrial content observed in CR conditions, mitochondrial components and dynamics are also modulated by CR. These changes have been proposed to play a role in the benefits of CR to mitochondrial function. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars

FIG. 4.

Diagram of enhanced mitochondrial function under CR and mimetics. CR and mimetics modulate stress and bioenergetic sensors, leading to the activation of master integrators, such as AMP-activated protein kinase (AMPK) and sirtuin 1 (SIRT1) among others. These proteins activate mitochondrial biogenesis and antioxidant response through the transcriptional coactivator peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α) and nuclear respiratory factor 2 (NRF2), leading to an improvement in mitochondrial function. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars

FIG. 5.

Regulation of PGC-1α activity. Mitochondrial biogenesis is regulated through PGC-1α to control the amount of mitochondria depending on the environmental conditions. Under CR, mitochondrial biogenesis is activated by deacetylation of PGC-1α, while inactivation of this protein is achieved by negative regulatory domains present in its amino acid sequence. eNOS, endothelial nitric oxide synthase; TORC, transducer of regulated CREB; MAPK, mitogen-activated protein kinase; NRIP1, nuclear receptor-interacting protein 1. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars