Basic Research

Sirtuins, NAD⁺, Lifespan Extension, and Aging

Sirtuins are a family of seven enzymes found in every cell that participate in several critical biological processes known to counter aging, like cellular energy optimization and DNA repair.

By Dylan G. Arrazati

Key Points: 

  • Sirtuins extend the lifespan of multiple model organisms and have a central role in cellular survival processes, ranging from DNA repair, mitochondrial maintenance, and cellular stress responses. 
  • Sirtuins can be activated with NAD+ precursors and several polyphenols – natural compounds found in various plants, fruits, nuts, and vegetables. 

The human body is multifaceted and complex, housing a myriad of unique molecules that regulate homeostasis and promote survival. From our diverse pool of cellular health regulators, a family of seven enzymes called sirtuins has emerged as key proteins intricately linked to biological processes that affect metabolism, aging, and longevity. Namely, evidence indicates that sirtuins serve as regulators of aging, as they are linked to cellular rejuvenation and stimulate vital processes like DNA repair, circadian rhythms, and cellular stress responses. Furthermore, given their ability to increase lifespan in multiple model organisms, scientists have established sirtuins as promising targets to extend human lifespan and deter the development of age-associated diseases. 

What Are Sirtuins, and What Do They Do? 

Sirtuins, DNA, NAD+, and Senescence

Sirtuins are guardian proteins that belong to a group of molecules called histone deacetylases (HDACs). HDACs remove cellular tags called acetyl groups from lysine residues on histones, proteins that help package DNA into compact structures called chromatin. Removing these acetyl groups helps determine which genes are turned on or off, and studies show that abnormal HDAC activity is tied to numerous diseases, including cancer, neurodegenerative disorders, and cardiovascular diseases. 

In addition to regulating gene activity, sirtuins play a vital role in repairing damaged DNA that accumulates with age. Particularly, Sirt1 and Sirt7 are the sirtuins responsible for governing genomic stability and DNA repair. To facilitate this critical process, sirtuins require a sufficient pool of nicotinamide adenine dinucleotide (NAD+) – a life-preserving enzyme that governs multiple cellular survival pathways and mitigates hallmarks of aging, such as oxidative stress and inflammation. However, cellular NAD+ levels drastically decline with age, ultimately quenching sirtuin activity and increasing susceptibility to secondary consequences of DNA damage, such as cellular senescence – a stagnant cellular state believed to be a pillar of aging.  

Overwhelming DNA damage triggers cellular stress that leads to senescent cells sprouting across multiple tissues, which drives inflammation, promotes organ deterioration, and compromises the healthy, youthful state of surrounding cells. Although diminished sirtuin activity can exacerbate these consequences, studies show that increasing sirtuin activity reverts cellular senescence and enhances DNA repair, potentially delaying multiple aging features.  

Sirtuins, Mitochondria, and Metabolism 

Another essential function of sirtuins is boosting mitochondrial health. Studies indicate that Sirt3, Sirt4, and Sirt5 are the mitochondrial sirtuins that improve energy metabolism and limit mitochondrial dysfunction. Impaired mitochondria hinder the synthesis of ATP – our cell’s energy currency – and drive the production of reactive oxygen species – harmful compounds that induce oxidative stress – both of which accelerate aging. Uniquely, increasing Sirt3 activity has been shown to increase ATP production and reduce oxidative stress, demonstrating that sirtuins exert anti-aging effects via mitochondrial maintenance. 

Sirtuins are also potent metabolic regulators, with studies suggesting that they can potentially mitigate age-related metabolic ailments like type 2 diabetes and obesity. Research shows that sirtuins are heavily involved in the processing of fat, ranging from synthesis, storage, and usage by cells. Accordingly, these actions help prevent excess fat accumulation across tissues like muscle and the liver. Notably, studies have shown that increasing the activity of Sirt6 improves insulin sensitivity in the muscle and liver of mice and protects against diet-induced obesity. 

Boosting sirtuins further improves metabolism by stimulating glucose production (gluconeogenesis) from amino acids, which is essential for providing our seat of intelligence (brain) with the necessary energy to govern critical processes like memory formation, organ function, and motor function. Overall, it appears that sirtuins play a central role in regulating the metabolic machinery critical for survival. 

(Zhao et al., 2020 | Aging and Disease) The role of sirtuins 1-7 in mammalian aging. Table modified from original source.

The Effects of Sirtuins on Lifespan and Aging

Animal Studies

The dynamic relationship between sirtuins and longevity was first established nearly two decades ago in yeast, with research showing that stimulating Sirt2 increases yeast lifespan by 70%. However, sirtuins gained tremendous attention when studies showed that sirtuins mimicked the life-extending effects of caloric restriction, a dietary regimen shown to exert longevity-promoting effects in multiple model organisms, including worms, flies, and mice. Interestingly, inhibiting sirtuin activity negates the life-extending effects of calorie-restricted mice, highlighting the potential intimate interplay between caloric restriction and sirtuin activation. 

The two sirtuins with the strongest ties to lifespan extension are Sirt1 and Sirt6. Although whole-body overactivation of Sirt1 fails to extend mouse lifespan, one mouse study found that the overactivation of Sirt1 in the hypothalamus – the brain region that regulates homeostasis – of aging mice leads to an ~11% increase in median lifespan. Another study showed that transgenic mice with increased Sirt6 activity live nearly 20% longer than non-modified mice. Furthermore, these transgenic mice exhibited greater running abilities and less fatigue, indicating that enhancing sirtuin activity also extends healthspan and reduces frailty. 

sirt6 extends lifespan
(Roichman et al., 2021 | Nature Communications) Elevated SIRT6 protein levels extend lifespan by about 20% in mice. Transgenic mice with increased SIRT6 (green) live longer than non-modified mice (WT) and transgenic mice with increased SIRT1 (red). Transgenic mice with increased SIRT1 and SIRT6 have similar lifespans to SIRT1 transgenic mice.

Human Studies

While there is still much to learn about the therapeutic and pharmacological potential of sirtuins on humans and lifespan extension, the available data strongly suggests that sirtuins hold promise for improving overall health. In addition to longitudinal human studies finding an association between sirtuins and longevity, other research has shown that sirtuins may play a role in mitigating tumor development and neurodegenerative disorders like Alzheimer’s disease, two diseases strongly linked to aging. That being said, more research is needed to determine the complete role of sirtuins in human longevity, but it’s evident that finding ways to activate sirtuins manually could catapult longevity interventions to a new level.  

Sirtuin Activators  

Although researchers have been able to boost sirtuin activity through genetic modifications, this method may not be feasible for the general public. With this in mind, scientists have turned to natural molecules that can potentially serve as sirtuin-activating compounds (STACs). Namely, scientists have pinpointed a group of compounds called polyphenols as potent sirtuin activators. 

One of the most well-studied polyphenols is resveratrol, the natural compound found in red wine, grapes, and other plants. In addition to increasing sirtuin activity, studies show that resveratrol exerts life-extending effects in worms and flies as well as enhances cognition in postmenopausal women. Research also suggests that resveratrol is a potent activator of AMPK, an enzyme that, upon activation, promotes lifespan extension, energy production, recycling of cellular waste (autophagy), and antioxidant defense systems. 

Two other plant-based polyphenols (flavonoids) with similar structures that have been shown to amplify Sirt1 activity are fisetin and quercetin. Fisetin is one of the few natural compounds shown to extend the lifespan of mice and improve both frailty and inflammation in older adults. Moreover, quercetin has demonstrated effectiveness at driving muscle regeneration in mice and restoring a longevity-linked protein called a-klotho, which, when overactivated, prolongs the lifespan of mice. 

 Beyond polyphenols, evidence suggests that NAD+ precursors, specifically nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN), activate sirtuins in multiple model organisms. Chiefly, the most compelling evidence supporting the role of NAD+ precursors in revitalizing sirtuins is that these compounds significantly replenish the fuel (NAD+) required for sirtuin activation. Without NAD+, the protective effects of sirtuins become obsolete. 

Overall, these compounds represent promising avenues for the development of sirtuin-activating drugs and supplements. Although further studies are required to fully elucidate the connection between sirtuins and aging, this represents an exciting area of study with the potential to improve human health and extend lifespan. 

effects of polyphenols | sirtuin activators
(Kumar et al., 2017 | Nutrients) Overview of the protective effects of polyphenols – potent sirtuin activators. 

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