The French author Jules Renard said, “It is not how old you are but how you are old.” Indeed, despite aging’s inevitability, many researchers explore the biological process in order to combat the accompanying decline in health, increased frailty, and increase in chronic health issues that are associated with the process. Increasing our understanding of the mechanisms underlying the aging process is a key component to facilitate the development of interventions that will lead to the preservation of health and improvements in survival and lifespan.

The highly conserved family of sirtuin proteins—nicotinamide adenine dinucleotide (NAD+)-dependent protein deacylases and mono-ADP-ribosyl transferases—have been at the center of aging research for years. In particular, SIRT6 deacylase is known to regulate aging and metabolism. However, the mechanisms remain largely unknown. Now, new work shows that SIRT6 overexpression leads to a reduction in frailty and lifespan extension in both male and female B6 mice.

The work is published in Nature Communications in the paper, “Restoration of energy homeostasis by SIRT6 extends healthy lifespan.

The international team led by Haim Cohen, PhD, director of the Sagol Healthy Human Longevity Center at Bar-Ilan University, developed transgenic mice that express high levels of the SIRT6 gene and presented data suggesting that their life expectancy can be increased by an average of 30% in both males and females.

In both wild-type and the SIRT6 overexpressing mice, the researchers used a combination of physiological assays, including in vivo multi-omics analyses and 13C lactate tracing. These assays identified an age-dependent decline in glucose homeostasis and hepatic glucose output in wild-type mice. In contrast, the authors noted, “Aged SIRT6-transgenic mice preserve hepatic glucose output and glucose homeostasis through an improvement in the utilization of two major gluconeogenic precursors, lactate and glycerol.”

The team then determined that SIRT6 acts to facilitate healthy aging by increasing hepatic gluconeogenic gene expression, de novo NAD+ synthesis, and systemically enhances glycerol release from adipose tissue. They showed that older animals lose the ability to generate energy in the absence of external energy sources, such as a short fast. On the other hand, the engineered mice maintained an enhanced energy generation capacity from other storage, such as the breakdown of fats and lactic acid. By doing so, they created sugar utilized for energy in muscle and specifically in the brain. In fact, SIRT6 activates a physical response that is identical to diets that increase longevity.

Furthermore, the mice exhibited significant improvement in overcoming a variety of age-related diseases, such as cancer and blood disorders. Beyond this, they were able to conduct the same level of vigorous activity as young mice, and didn’t become frail.

“This discovery, combined with our previous findings, shows that SIRT6 controls the rate of healthy aging,” said 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.” Today, Cohen’s lab is developing methods for extending healthy life based on these findings.