SIRT1 and caloric restriction: an insight into possible trade-offs between robustness and frailty

Abstract

Purpose of review: This review aims to summarize the importance of the mammalian nicotinamide adenine dinucleotide (NAD)-dependent deacetylase SIRT1 as a critical mediator that coordinates metabolic responses to caloric restriction and the recent progress in the development of SIRT1-targeted caloric restriction mimetics. It also discusses possible trade-offs between robustness and frailty in caloric restriction and the applicability of caloric restriction or SIRT1-targeted caloric restriction mimetics to humans.

Recent findings: Loss-of-function and gain-of-function mouse studies have provided genetic evidence that SIRT1 is a key mediator that orchestrates the physiological response to caloric restriction. SIRT1-activating compounds function as potential caloric restriction mimetics, at least in part, through the activation of SIRT1 in vivo.

Summary: Increasing SIRT1 dosage/activity is effective to provide significant protection from high-fat diet-induced metabolic complications, suggesting that SIRT1 activation likely promotes robustness in the regulation of metabolism. However, caloric restriction itself and caloric restriction mimicry through systemic SIRT1 activation might also generate frailty in response to unexpected environmental stimuli, such as bacterial and viral infections. It will be of great importance to understand the principles of systemic robustness and its spatial and temporal dynamics for the regulation of aging and longevity in mammals in order to achieve an optimal balance between robustness and frailty in our complex physiological system.

Figure 1

Genetic linkage between caloric restriction (CR) and SIRT1. CR enhances mitochondrial biogenesis by up-regulating the expression of the endothelial nitric oxide synthase (eNOS), promoting the production of NO, and increasing SIRT1 expression (left). The activation of PGC-1α by SIRT1 likely mediates the effect of CR on mitochondria. CR also enhances physical activity likely by increasing NAD content (right) and up-regulating SIRT1 protein levels (middle) in the brain. SIRT1 is also required for the metabolic adaptation to CR, although the underlying mechanism is unknown.

Figure 2

The CR-mimetic effects of gain-of-function or chemical activation of SIRT1 in mice. The phenotypes that have not been confirmed by either genetic or pharmacological studies are shown with question marks. Details are described in text.

Figure 3

Possible trade-offs between robustness in metabolism and frailty in infection in CR. Trade-offs between robustness and frailty are an inherent, unavoidable feature of complex systems, such as biological systems. Whereas CR promotes metabolic robustness, it appears to increase frailty to infections pathogens. Given that sirtuin (SIRT1 in particular) activating compounds (STACs) function as a potential CR mimetics, STACs might also convey similar trade-offs. Therefore, it will be critical to seek an optimal balance between robustness in metabolism and frailty in infection in our complex physiological system.