Caloric restriction, SIRT1 and longevity

Abstract

More than 70 years after its initial report, caloric restriction stands strong as the most consistent non-pharmacological intervention increasing lifespan and protecting against metabolic disease. Among the different mechanisms by which caloric restriction might act, Sir2/SIRT1 (Silent information regulator 2/Silent information regulator T1) has been the focus of much attention because of its ability to integrate sensing of the metabolic status with adaptive transcriptional outputs. This review focuses on gathered evidence suggesting that Sir2/SIRT1 is a key mediator of the beneficial effects of caloric restriction and addresses the main questions that still need to be answered to consolidate this hypothesis.

Figure 1. How does caloric restriction (CR) impact on SIRT1 activity?

SIRT1 deacetylates proteic substrates in a reaction that cleaves NAD+ to render NAM. NAD+ acts as a positive modulator (green arrows) of SIRT1 activity, while the accumulation of NAM and NADH (the reduced form of NAD+) lead to inhibition (red arrows) of SIRT1. During CR there is a decline in glycolytic rates in favour of respiratory metabolism as the main energy source. This changes displaces the equilibrium of the reduced/oxidized forms of NAD towards NAD+, thus increasing SIRT1 activity. Similarly, CR leads to an increase in PNC1/Nampt expression, which favors the resynthesis of NAD⁺ from NAM, potentially acting as a major mechanism to drop the leash of SIRT1 inhibition. (SIRT1: Silent Information Regulator T1; NAD: Nicotinamide dinucleotide; NAM: Nicotinamide; CR: Caloric restriction; PNC1: Pyrazinamidase and nicotinamidase 1; Nampt: nicotinamide phosphorybosyl transferase)

Figure 2. Integrative view of mammalian signalling pathways involved in regulating the effects of caloric restriction (CR)

Despite the evidence linking SIRT1 to the effects of CR on mammals, these effects might be accomplished by acting in consensus with other factors. For example, CR might be not only sensed by SIRT1 as a change in the NAD⁺/NADH ratio, but also by AMPK as a change in the AMP/ATP ratio. AMPK can regulate mitochondrial respiration, which in turn, can also positively regulate SIRT1. Both AMPK and SIRT1 can impact the activity of FOXO transcription factors, which also have been extensively linked to the regulation of metabolism and longevity. Additionally, CR promotes the downregulation of insulin-derived signals, which also interacts with FOXO transcription factors. Hence, the metabolic and longevity responses to CR, rather than defined by single elements, may be a consequence of the balance of these signalling networks. (CR: caloric restriction; SIRT1: Silent Information Regulator T1; AMPK: AMP-activated protein kinase; FOXO: Forkhead Box O1)