Researchers increase life expectancy of mice 30%, uncover key aging mechanism

Aging is associated with reductions in general health and increased frailty, as well as being a key risk factor for a variety of chronic illnesses. To promote the development of therapies that will lead to the preservation of health and increases in survival and lifespan, we must first increase our understanding of the processes underlying the aging process.

A mounting body of research suggests that diet and metabolism appear to be important targetable regulators of a long and healthy life. Prof. Haim Cohen, Director of Bar-Ilan University’s Sagol Healthy Human Longevity Center, concentrates most of his research on the SIRT6 protein, which regulates a variety of biological processes including aging, obesity, and insulin resistance.

An international team lead by Cohen and his Ph.D. student Asael Roichman ——in collaboration with Prof. Manuel Serrani of the Institute for Research in Biomedicine in Barcelona, Prof. Rafael de Cabo of the National Institute on Aging, and Prof. Eyal Gottlieb of the Technion——reveal that transgenic mice expressing high levels of the SIRT6 protein had a life expectancy that was improved by an average of 30% in both men and females.

The researchers increased the production of SIRT6, a protein that typically diminishes with age, in 250 mice. In a peer-reviewed study published in the journal, Nature Communication, they reported a significant improvement in life expectancy in the protein-rich mice— as well as the fact that the mice were more youthful and less prone to cancer.

The SIRT6 gene, the gene at the center of the study, encodes a stress response protein deacetylase and mono-ADP ribosyltransferase enzyme. SIRT6 is widely-known to be involved in a number of aging-related biological processes, including DNA repair, telomere maintenance, glycolysis, and inflammation. The researchers concentrated on the processes that underpin the aging process, which is critical for creating therapies to enhance health and extend life.

Along with the improved life expectancy, the mice showed considerable progress in overcoming a range of age-related ailments, including cancer and blood issues. Furthermore, they were able to maintain the same degree of strenuous activity as young mice without becoming feeble.

Using a range of biochemical approaches and metabolic investigations, the research group was able to uncover the mechanism by which SIRT6 operates as a type of “fountain of youth,” aiding healthy aging. They discovered that in the absence of external energy sources, such as a brief fast, elderly animals lose their capacity to create energy.

The authors state in the paper, “mechanistically, SIRT6 increases hepatic gluconeogenic gene expression, de novo NAD⁺ synthesis, and systemically enhances glycerol release from adipose tissue. These findings show that SIRT6 optimizes energy homeostasis in old age to delay frailty and preserve healthy aging.”

The genetically-modified mice, on the other hand, were able to generate more energy from other sources, such as the breakdown of lipids and lactic acid. Through this, they synthesized sugar, which is used for energy in muscle and, more importantly, in the brain. The authors report that their findings show that SIRT6 triggers a physiologic response that is similar to that of longevity diets.

“The change in life expectancy is significant, when you consider that an equivalent jump in human life expectancy would have us living on average until almost 120,” said Prof. Haim Cohen of Bar-Ilan.

“This discovery, combined with our previous findings, shows that SIRT6 controls the rate of healthy aging,” says Prof. Cohen, of Bar-Ilan University’s Mina and Everard Goodman Faculty of Life Sciences. “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,” he concluded. 

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