The Role of Sirtuins in Longevity

Despite strenuous controversies, the field of sirtuin research is growing with an increasing number of recent studies revealing their promising connection to longevity. After many years of investigation, understanding of the activity of the silent information regulator 2 (Sir2) family (‘sirtuins’) has greatly expanded, proving its significant involvement in the regulation of many fundamental biological processes. Dr. Leonard Guarente, co-founder of Elysium Health and director of MIT’s Glenn Center for Biology of Aging, stands at the forefront of sirtuin research efforts.

Aiming to uncover the complexities of the human biological aging process, Dr. Guarente identified a family of proteins called sirtuins, which control longevity, and demonstrated their dependency on the nicotinamide adenine dinucleotide coenzyme NAD+ – a compound at the heart of metabolic activity in all living cells. On the basis of his research, Dr. Guarente founded the health company Elysium in 2014, focusing on the development of products that improve human health.

The functional connection between NAD+ and sirtuins plays a significant role in controlling aging and longevity in diverse organisms, according to Dr. Guerente’s research. Recent studies have revealed that NAD availability declines with age, in turn reducing sirtuin activity and affecting inter-cellular communication. Preclinical data suggests the benefit of NAD+ supplements and their positive effects on human health and longevity although, further research is necessary to determine the true efficacy of sirtuins in elongating the life span of different organisms.

Sirtuins and the Connection Between Aging and Metabolism

Acting predominantly as nicotinamide adenine dinucleotide-dependent deactylases, sirtuins are a family of proteins linked to life-span regulation in lower organisms and a host of diverse functions in higher organisms. Seven sirtuin proteins exist in humans, including three (Sirt3, Sirt4, Sirt5) that concentrate within the mitochondria. While each sirtuin shows different functions, they all share similar enzymatic activity, helping to regulate cellular health, DNA expression, and other vital aspects of aging.

However, sirtuins are only able to function in the presence of NAD+ coenzymes, which are critical to metabolism and other biological processes. Using NAD+ and other intercellular metabolites, sirtuins have the potential to act as metabolic sensors and modulate mitochondrial function to match nutrient supply, emerging research reveals.

Dr. Guerente’s lab has identified the connection between sirtuins and longevity control to be a result of their effect on metabolism function. Insulin secretion, lipid mobilization, the regulation of glucose tolerance and many other metabolic phenotypes have been associated with sirtuins, implicating their beneficial impact on mitochondrial metabolism and the cellular aging process.   

Sirtuins and NAD+ in Aging and Disease  

The strong connection between sirtuins and NAD+ allows for the coordination of metabolic and aging control on a cellular and systemic level. Declining levels of both molecules contribute to the development of age-associated functional decline and the pathogenesis of diseases however, researchers continue to investigate methods of remedying this problem. NAD+ supplementation has drawn significant attention in recent years due to its strong potential to mitigate age-associated decline.

NAD+ Supplementation for Longevity 

Nicotinamide adenine dinucleotide, or NAD+, was first discovered in a 1906 study of yeast and glucose fermentation and has since been identified as a vital coenzyme in metabolism function. The presence of NAD+ is necessary to provide a foundation for sirtuin activity responsible for the regulation of energy metabolism as well as aging and longevity control. Although levels of NAD+ decline with age and thuslimit sirtuin function, anti-aging supplements comprised of the coenzyme are becoming increasingly available.

Although human-based clinical data is still lacking, preclinical data is suggestive of a wide-range of benefits associated with NAD+ supplementation. Earlier studies found NAD+ precursors could raise NAD+ levels in mice, making them less susceptible to diabetes. NAD+ supplementation showed metabolic benefits and mitochondrial improvement in animal-based research. More recent studies have shown NAD+ supplementation to decrease tissue decline associated with the deterioration of adult stem cell function and assist in the maintenance of gut health during aging.

While controversy surrounding the role of sirtuins in the aging process and the benefits of NAD+ supplementation continues to affect the medical community, forthcoming studies hope to prove the positive effects of NAD+ supplementation on human life span. Future research may provide in-depth insight into the correlation between energy metabolism and aging, as well as its effects on the pathogenesis of age-related decline and disease.