One foot on the gas and one on the brake: How a key protein helps drive healthy longevity

Researchers at Bar-Ilan University have discovered how the longevity-associated protein Sirt6 orchestrates a delicate molecular balancing act that protects the body from age-related decline and disease. The new findings, just published in Proceedings of the National Academy of Sciences (PNAS), reveal how Sirt6 preserves health during aging and may pave the way for therapies that promote a longer, healthier life.

Sirt6, often described as a master regulator of aging, is known for its powerful protective effects against age-related diseases such as cancer, diabetes, inflammation, and frailty. Its impact closely resembles that of calorie restriction, a dietary regimen proven in animals to extend lifespan and enhance the body’s natural repair and healing mechanisms.

Calorie restriction—eating fewer calories without malnutrition—has long been known to improve health and extend lifespan. One of its key effects is to increase the body’s production of hydrogen sulfide (H₂S), a tiny gas molecule that supports wound healing, heart health, and brain function. This new study found that as we age, H₂S levels naturally decline, weakening these protective benefits.

The study also revealed that Sirt6 mimics the effects of calorie restriction, keeping the body’s repair systems running smoothly by fine-tuning H₂S production. However, unlike calorie restriction, which broadly raises H₂S levels, Sirt6 does so with remarkable precision—boosting production when needed but also preventing dangerous overproduction.

“This protein acts like the body’s internal version of calorie restriction,” said Prof. Haim Cohen, Director of the Sagol Healthy Human Longevity Center at Bar-Ilan University’s Goodman Faculty of Life Sciences, who led the study, performed by PhD student Noga Touitou. “Sirt6 protects against age-related diseases such as cancer, diabetes, frailty, and inflammation, and helps maintain the body’s natural balance as we grow older. It has one foot on the gas and the other on the brake—promoting hydrogen sulfide production when it’s beneficial but keeping it under control to prevent harm.”

This discovery underscores the importance of metabolic balance in healthy aging. While previous research primarily focused on increasing H₂S levels to promote longevity, the Bar-Ilan team found that Sirt6 ensures just the right amount of this molecule—enough to protect cells and tissues without causing toxicity.

“Our findings uncover one of the body’s natural strategies for preserving health during aging,” said Prof. Cohen. “By revealing how Sirt6 maintains a precise balance in H₂S production, we provide new insights into the molecular mechanisms of healthy aging and identify promising targets for interventions that slow age-related decline.”

The study builds on Prof. Cohen’s earlier work demonstrating that Sirt6 extends mammalian lifespan and protects the body from multiple age-related diseases. This new research takes a critical step further—showing how Sirt6 achieves these effects by tightly regulating hydrogen sulfide, a key molecule in the biology of longevity.

This study was supported by grants from the Sagol Healthy Human Longevity Center, the Binational Science Foundation (BSF), the Israel Science Foundation (ISF), and the Ministry of Innovation, Science and Technology, and was conducted in collaboration with the laboratory of Prof. Rafael de Cabo at the National Institute on Aging (NIA) in Baltimore, Maryland.