Metabolic dysfunction escalates with age and increases the risk of frailty and chronic disease. Many investigational antiaging drugs target enzymes involved in energy metabolism, such as mammalian target of rapamycin (mTOR) and insulin-like growth factor (IGF)-1. Findings of a new study in mice detail the role of sirtuins in energy metabolism and healthy aging.

Sirtuins are enzymes that play key roles in healthspan and longevity in multiple organisms. They are linked to the regulation of a variety of metabolic processes, including the release of insulin, mobilization of lipids, response to stress, and modulation of lifespan. Sirtuins respond to physiological changes in energy levels, thereby regulating energy homeostasis and health.

When fasting or exercising, the liver helps maintain blood sugar levels using the alternating processes of glycogenolysis (the breakdown of glycogen) and gluconeogenesis (the creation of new glucose). In glycogenolysis, single glucose molecules are released from larger glucose chains, called glycogen, for use as energy. Because the body stores a limited amount of glycogen, the liver uses gluconeogenesis to create glucose from non-carbohydrate precursors, such as lactate and glycerol. The role of gluconeogenesis in aging is unclear, with one study reporting an increase in gluconeogenesis with age in rats and other studies in rats reporting decreased gluconeogenic ability.

Using breeding techniques, the investigators produced a line of mice with livers that over-express the sirtuin enzyme SIRT6, which increases during fasting and regulates glucose metabolism. The researchers bred these mice with normal mice to produce litters with a mix of genotypes. Using this technique, the researchers were able to compare aging processes among littermates, which reduced confounding factors in their analyses.

Compared to their normal siblings, male SIRT6 mice exhibited a 27 percent increase in average lifespan and an 11 percent increase in maximal lifespan. Female SIRT6 mice showed a 15 percent increase in both average and maximal lifespan. Normal mice experienced greater metabolic dysfunction, performed less physical activity, and developed more inflammatory and degenerative diseases with age compared to SIRT6 mice. A series of metabolic tests revealed that SIRT6 mice had increased gluconeogenic gene expression in the liver and enhanced glycerol release from adipose tissue, which provided extra fuel for gluconeogenesis.

The authors concluded that SIRT6 controls healthspan and lifespan through regulating energy metabolism. This mechanistically complicated study will provide the groundwork for future aging research in humans.

• Link to full report.
• Watch aging expert Dr. David Sinclair discuss how metabolism regulates the circadian clock and sirtuin expression.
• Learn more about sirtuins in our overview article.