Is Sirtuin-6 the Fountain of Youth? New Study Finds This “Longevity Gene” Extends Lifespan, Boosts Metabolism, and Fights Frailty in Aged Mice

The aging process comes with many detrimental changes to the body, both internal and external. One such disruption is with our metabolism, leading to stifled metabolic flexibility and reduced overall energy production. Yet, we haven’t nailed down the details of why we lose our energy balance with age — and how to fix it.

Many researchers have zeroed in on a family of genes called sirtuins for the vital role they play in cellular health, aging, and longevity. However, it has been previously unknown how exactly the sirtuins impact metabolic processes in aging humans and animals and whether we can manipulate them to increase longevity and improve healthspan. 

In a May 2021 study published in Nature Communications, a research team out of Bar-Ilan University in Israel looked at the effects of increasing the activity of two of these “longevity genes” — sirtuin-1 (SIRT1) or sirtuin-6 (SIRT6) — on metabolism and lifespan in a group of aged mice. Although SIRT1 typically gets more attention in health and longevity research, this study shows that SIRT6 may be the more potent lifespan extender, providing almost a 30% boost in longevity when mice overexpress the protein — meaning, they have increased activity and levels of it.

How Sirtuin-6 Leads to Lengthened Lifespan 

The seven sirtuin family members (SIRT1-SIRT7) are highly involved with DNA repair, the function of energy-producing centers in cells (mitochondria), controlling inflammation, and generating cellular energy (ATP), among other functions. Notably, sirtuins are dependent on NAD+ (nicotinamide adenine dinucleotide), the essential coenzyme needed by every cell in our bodies. However, NAD+ levels tend to decline with age, leading to a subsequent decline in sirtuin functioning.  

While some studies have focused on SIRT1 activity as an important regulator of lifespan in worms, flies, and yeast, these results haven’t always been replicated in larger species. Previous research has found that increasing SIRT1 activity in mice extends healthspan — the amount of life lived disease-free — but not lifespan, leading scientists to look into the potential longevity-boosting effects of other sirtuins, like SIRT6.

In this study, Roichman and colleagues show that increasing SIRT6 activity extends the lifespan of both male and female mice. However, male mice benefited more from SIRT6, exhibiting a 27% extension in median lifespan, while female mice saw a 15% boost. The researchers also measured maximal lifespan, which was lengthened by 11% and 15% in the SIRT6-boosted male and female mice, respectively. Conversely, the mice with increased SIRT1 activity did not have the same lifespan-extending benefits, while mice with both SIRT1 and SIRT6 upregulated did have longer lives, albeit to a lesser extent than SIRT6 alone.

While the researchers aren’t entirely sure why there are sex-specific differences in lifespan extension, one reason could be that only the SIRT6-boosted male mice had significant inhibitions of inflammatory pathways, which play a role in aging.  

Fighting Frailty and Fixing Physical Fitness

The overexpression of SIRT6 also improved various aspects of healthspan in the aging mice, including reducing the prevalence of some cancers and mitigating degenerative processes. With increasing age, older adults (and mice) tend to experience abnormalities in blood markers, including higher cholesterol and poor iron status or anemia. In these older mice, which were the equivalent of 70 human years, the SIRT6 boost significantly reversed these abnormal markers, as well as preserved the females’ body weights. In older age, we often find that a significant loss of body weight is associated with worse survival.

These mice also had improved functionality and physical status, as SIRT6 repressed the typical age-related decline in exercise abilities, like treadmill running and locomotor activity — the motion and movement needed to get from one place to another that relies on learning and motivation. The 70-year-old-equivalent mice with a boosted activity of SIRT6 also ran significantly longer distances and spent more voluntary time running than the mice who resembled 45-year-old humans. Adding SIRT1 to the mix further improved physical status, as these aged mice had higher treadmill running speeds than the mice with either sirtuin increased alone. 

Taken together, these results show that overexpressing of SIRT6 — or both SIRT1 and SIRT6 — significantly improves healthspan, promotes physical activity and function, and reduces the typical frailty seen with age.

Modeling Metabolic Mastery

SIRT6 mice also showed greater metabolic flexibility. This was seen by an increased ability to create energy from food and maintain normal blood glucose levels during reduced energy availability, like during fasting or advanced age. In addition, aged mice with overexpressed SIRT6 were able to keep their blood sugar levels stable, similar to that of the young mice. As abnormal blood sugar is a leading cause of metabolic disorders, these results suggest that increasing SIRT6 may help reduce the risk of type 2 diabetes, which is increasingly prevalent in older adults. 

Lastly, the SIRT6 mice had increased autophagy — the internal recycling program that removes damaged and dysfunctional cells and cell parts — and maintained their NAD+ levels, which were markedly reduced in the control mice of the same age. This NAD+ boost likely occurred because SIRT6 increased nicotinamide levels, which induces NAD+ biosynthesis pathways — when enzymes like sirtuins use NAD+, they only take some parts of it and the remaining parts, like nicotinamide, get reused to create more NAD+.

Sirtuin-6’s Future as a Fountain of Youth

This study provides evidence that SIRT6 may be a more potent regulator of lifespan than SIRT1, although SIRT1 benefits several markers of healthspan and physical status. As metabolic dysfunction and a reduced ability to create energy are significant drivers of frailty and age-related decline, SIRT6 appears to be a likely contender for mitigating these destructive processes.  

"This discovery, combined with our previous findings, shows that SIRT6 controls the rate of healthy aging," says senior author Professor Haim Cohen. "If we can determine how to activate it in humans, we will be able to prolong life, and this could have enormous health and economic implications.”

References:

Herranz D, Muñoz-Martin M, Cañamero M, et al. Sirt1 improves healthy ageing and protects from metabolic syndrome-associated cancer. Nat Commun. 2010;1:3. Published 2010 Apr 12. doi:10.1038/ncomms1001

Roichman A, Elhanati S, Aon MA, et al. Restoration of energy homeostasis by SIRT6 extends healthy lifespan. Nat Commun. 2021;12(1):3208. Published 2021 May 28. doi:10.1038/s41467-021-23545-7