Boosting Sirtuins: The Promising Path to Healthy Aging

Introduction

Sirtuins, a family of NAD+-dependent deacetylases, are emerging as key players in regulating aging and age-related diseases (1). Sirtuins regulate a range of cellular processes, including DNA repair, metabolism, and stress response, by modulating the acetylation state of their target proteins (2). Recent research has demonstrated that boosting sirtuin activity can promote longevity and prevent age-related pathologies. In this review, we will discuss the mechanisms by which sirtuins promote healthy aging and explore various strategies to boost sirtuin activity, including dietary interventions, exercise, and pharmacological agents.

Aging is a complex, multifactorial process that involves a gradual decline in physiological functions and an increased susceptibility to disease. The mechanisms underlying aging still need to be fully understood. Still, recent research has suggested that epigenetic changes, including alterations in protein acetylation, play a vital role in regulating aging and age-related diseases (3). Sirtuins are a family of seven NAD+-dependent deacetylases (SIRT1-7) that regulate a variety of cellular processes, including metabolism, stress response, and DNA repair, by modulating the acetylation state of their target proteins (2). Sirtuins have emerged as crucial regulators of aging and age-related diseases, and boosting sirtuin activity has been shown to promote longevity and prevent age-related pathologies.

Sirtuins and Aging

Sirtuins regulate several cellular processes that are known to play a critical role in the aging process. For example, SIRT1, the best-studied sirtuin, regulates cellular metabolism and stress response by deacetylating key metabolic regulators and transcription factors, including PGC-1α, FOXO, and NF-κB (4). SIRT1 has also been shown to promote DNA repair by deacetylating the DNA repair protein Ku70 and to regulate circadian rhythms by deacetylating the clock protein PER2 (5). Similarly, other sirtuins have been shown to regulate aging-related processes, such as cell survival, inflammation, and mitochondrial function.

Boosting Sirtuin Activity

Given the critical role of sirtuins in regulating aging and age-related diseases, there has been considerable interest in developing strategies to boost sirtuin activity. Several approaches have been proposed, including dietary interventions, exercise, and pharmacological agents.

Dietary Interventions

Caloric restriction (CR) is the most well-known dietary intervention that has been shown to extend lifespan and improve healthspan in various model organisms, including yeast, worms, flies, and mice (6). CR is thought to activate sirtuins by increasing the cellular NAD+/NADH ratio, which is required for sirtuin activity (7). Resveratrol, a natural polyphenol found in red wine, has also been shown to activate sirtuins by increasing the cellular NAD+/NADH ratio and directly activating SIRT1 (8). Other dietary interventions, such as intermittent fasting, have also been shown to increase sirtuin activity (9).

Exercise

Exercise has been shown to promote longevity and improve healthspan in various model organisms and humans. Exercise has also been shown to activate sirtuins, possibly through the induction of oxidative stress and the subsequent activation of the NAD+-dependent enzyme, AMP-activated protein kinase (AMPK) (10).

Pharmacological Agents

Several pharmacological agents have been developed to activate sirtuins, including resveratrol analogs (e.g., SRT1720, SRT2104), nicotinamide riboside (NR), nicotinamide mononucleotide (NMN), and activators of SIRT6 and SIRT7 (11). These agents have shown promising results in preclinical studies, and some have entered clinical trials to treat age-related diseases. However, the safety and efficacy of these agents in humans still need to be thoroughly evaluated.

Conclusion

Sirtuins have emerged as critical regulators of aging and age-related diseases, and boosting sirtuin activity has shown promising results in extending lifespan and improving healthspan. Dietary interventions, exercise, and pharmacological agents are potential strategies to increase sirtuin activity (12). While much research is still needed to fully understand the mechanisms underlying sirtuin regulation and to develop safe and effective interventions for boosting sirtuin activity, the promising results obtained so far suggest that targeting sirtuins may be a fruitful path toward healthy aging.

References:

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