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    • br Mechanistic Insights and Effector Proteins in Caloric Res

    2018-11-07


    Mechanistic Insights and Effector Proteins in Caloric Restriction CR impinges on multiple signaling pathways that regulate growth, metabolism, oxidative stress response, damage repair, inflammation, autophagy, and proteostasis, to modulate the aging process (Lopez-Lluch and Navas, 2016). The relationship between calorie intake and longevity follows a U-shaped curve, dietary excess and malnutrition both negatively impact survival. Between the extremities there is an inverse linear relationship between lifespan and calorie/energy intake, suggesting that adaptive metabolism is a key component in the response to CR. We recently reported a conserved tissue-type independent transcriptional signature of CR in mice involving mitochondrial oxidative phosphorylation and redox metabolism pathways (Barger et al., 2015). This metabolic reprogramming is detected in other species on CR and is recapitulated in genetic models of enhanced longevity, supporting the concept that the CR-induced changes in energetics may indeed underlie the ability of the regimen to delay aging. Mitochondrial function has been linked to key age-sensitive processes including tissue rejuvenation and tumor suppression. Specifically, mitochondrial integrity is important for maintenance of pluripotency of stem cell populations (Xu et al., 2013) and multiple aspects of mitochondrial function have been implicated in cellular senescence (Correia-Melo et al., 2016; Korolchuk et al., 2017). Studies in short-lived organisms from yeast to mice have given insight into the identity of potential “effectors” in the mechanism of delayed aging by CR. Many of the factors implicated in CR\'s mechanisms are involved in vitamin d receptor and nutrient sensing (Fig. 2) These include kinases and deacetylase enzymes involved in post translational modification, nutrient sensing mechanisms to direct cellular signaling, and transcription factors and co-activators that are required to launch a new program of metabolic balance. Several recent reviews have touched on longevity regulation and expand on evidence from rodent, fly, nematode, and yeast studies (Fontana and Partridge, 2015; Lopez-Lluch and Navas, 2016). Here will provide only a brief introduction to some of the most promising candidates in the mechanisms of CR and the next section describes interventions that have been proposed to target these regulatory nodes. AMP-activated protein kinase (AMPK) is a key intracellular signaling factor involved in the adaptive response to energy deficit or changes in energetic demand. AMPK senses energy availability and subsequently regulates other pathways including some of those implicated in aging such as mTOR (negative regulator) and SIRT1 (positive regulator) as outlined below. Aging is associated with a decline in AMPK inducibility (Reznick et al., 2007) whereas CR has been shown to activate the AMPK pathway in multiple tissue in animals (Canto and Auwerx, 2011). PGC-1a (peroxisome proliferator activated receptor gamma coactivator 1 alpha), is a transcriptional coactivator of nuclear receptor transcription factors such as PPARa and PPARg (Martinez-Redondo et al., 2015). This family of nuclear receptor transcription factors regulate genes involved in a wide spectrum of physiological functions including lipid metabolism and have been implicated in diabetes and metabolic syndrome (Semple et al., 2006). AMPK directly phosphorylates PGC-1a resulting in activation, thereby promoting the utilization of lipids as fuel. The mechanistic Target of Rapamycin (mTOR) is a nutrient sensing protein kinase that coordinates cellular growth and metabolism from nutrient and amino acid inputs (Laplante and Sabatini, 2012). mTOR exists in two complexes: mTORC1 and mTORC2 that impinge on protein synthesis, autophagy, and lipid metabolism (Kennedy and Lamming, 2016). Evidence suggests that the beneficial effects of CR on lifespan are at least in part dependent on mTORC1 signaling. Interestingly, AMPK is a negative regulator of mTOR, suggesting that there is a convergence of signaling under CR conditions to simultaneously lower growth signaling, through mTOR and related factors, and enhance lipid metabolism, through PGC-1a and PPARa. Sirtuins are a family of evolutionary conserved enzymes that influence a range of cellular activities including regulation of metabolism, cell fate determination, and chromatin remodeling (Bonkowski and Sinclair, 2016; Imai and Guarente, 2014). Most of the members of the sirtuin family remove acetyl groups to enhance activity of target proteins, although ADP-ribosylation activity has also been reported for some family members. Enzymatic activity of sirtuins requires nicotinamide adenine dinucleotide (NAD) as a co-substrate. This requirement intimately connects the sirtuin family to metabolism, as they are responsive to changes in NAD availability such as pathways of NAD regeneration and recycling and flux in redox metabolism. Taken together, these studies identify roles for nutrient sensitive metabolic regulators in the response to CR and point to the central importance of metabolic integrity in health and longevity.