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-1a) is activated in old animals under CR conditions compared to ad libitum counterparts, enhancing mitochondrial biogenesis. Molecular regulation of PGC-1a 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-1a 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. Antioxid. Redox Signal. 19, 310-320.

Mitochondrial activity and dynamics changes regarding metabolism in ageing and obesity

“…Importantly, AMPK and SIRT1, two major metabolic sensors in cells, modulate directly PGC1α activity through phosphorylation and deacetylation respectively (Jager et al, 2007;Nemoto et al, 2005). Thus, SIRT1 and AMPK modulate PGC1α activity at the transcriptional and post-translational level (Martin-Montalvo and de Cabo, 2013) (Fig. 1).…”

Role of mitochondrial dysfunction and altered autophagy in cardiovascular aging and disease: from mechanisms to therapeutics

“…Studies also suggest that CR improves mitochondrial biogenesis (113,116,138), although this point remains controversial (75). The cellular pathways involved in mitochondrial protection induced by CR appear to converge on the expression/activity of the dyad AMPK/Sirt1 (27,116,172) and activation of downstream effectors, including PGC-1␣ (113,114). Sirt1 confers vasoprotection by reducing endothelial ROS production, inhibiting NF-B signaling, and attenuating vascular inflammation (174).…”

Resveratrol and SRT1720 Elicit Differential Effects in Metabolic Organs and Modulate Systemic Parameters Independently of Skeletal Muscle Peroxisome Proliferator-activated Receptor γ Co-activator 1α (PGC-1α)

“…SRT treatment can furthermore ameliorate metabolic defects in both HFD-fed (11) and aged mice (12), but as for RSV, it is controversial whether SRT directly activates SIRT1 to mediate these metabolic changes (13). However, for both compounds, peroxisome proliferator-activated receptor ␥ co-activator 1␣ (PGC-1␣) has been proposed as the common downstream effector to modulate transcription of metabolic gene programs (5,11,14). This is regardless of the putative direct target of these compounds, because PGC-1␣ is activated by AMPK-mediated phosphorylation, SIRT1-induced deacetylation, and increased cAMP levels (15)(16)(17).…”

“…In metabolic organs, PGC-1␣ is an important transcriptional co-activator that controls several integrated metabolic programs, such as mitochondrial biogenesis, oxidative phosphorylation (OXPHOS), and ␤-oxidation (18). These processes are furthermore postulated to be induced by CR (14) and upon administration of RSV and SRT in mice (5,11). Accordingly, RSV and SRT treatment have been reported to activate PGC-1␣ and lead to metabolic remodeling in several organs, especially in skeletal muscle (5,11).…”