·       Mice genetically modified to overproduce SIRT6 protein see drastic increases in lifespan and physical performance.
·       SIRT6 improves liver cell energy and glucose sugar production for improved physical activity, healthspan, and survival.

The rising aging global population, referred to as the “Silver Wave,” presents health-related challenges that include age-related diseases and frailty – a condition characterized by fatigue and weakness. Research shows that diet and metabolism are key regulators of lifespan, representing targetable intervention strategies to promote healthy aging. Scientists have uncovered that a protein called SIRT6 regulates aging, obesity, and insulin sensitivity, but how it does so needs further clarification to  improve our attempts to maintain and preserve health during aging.

Cohen and colleagues from Bar-Ilan University in Israel published a study in Nature Communications showing that driving SIRT6 protein production extends mouse lifespan by about 20%. They also show that enhancing SIRT6 production through genetic manipulation in older ages optimizes the energy production balance (homeostasis) of liver and fat tissues to delay frailty and extend life without disease (healthspan).

“This discovery, combined with our previous findings, shows that SIRT6 controls the rate of healthy aging,” said Professor Cohen in a press release. “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.” 

What Are Sirtuins?

Sirtuins are proteins that require the essential, life-sustaining molecule called nicotinamide adenine dinucleotide (NAD+) to perform their function. When sirtuins have enough NAD+ to work properly, they play crucial roles in maintaining DNA health and cell metabolism. Two of the seven sirtuins, SIRT1 and SIRT6, have been suspected of regulating metabolism and aging processes, leading Cohen and colleagues to tease out which of these two sirtuins is most important during aging or whether they act synergistically.

Elevated SIRT6 Levels Dramatically Extend Lifespan

To explore the interaction between SIRT1 and SIRT6 in aging and lifespan, the Israel-based research team genetically modified mice to produce more SIRT1 (SIRT1 transgenic mice), more SIRT6 (SIRT6 transgenic mice), or both (SIRT1 + SIRT6 transgenic mice). They followed the groups of mice for up to 40 months to compare their lifespans. They found that the male and female SIRT6 transgenic mice lived, on average, about 27% and 15% longer than non-modified mice and SIRT1 transgenic mice, respectively. There was no significant difference in lifespan between SIRT6 transgenic and SIRT1 + SIRT6 transgenic mice, so Cohen and colleagues concluded the two proteins don’t synergistically extend lifespan but that SIRT 6 overproduction does so on its own.

(Roichman et al., 2021 | Nature Communications) Elevated SIRT6 protein levels extend lifespan by about 20% in mice. These plots show how overproduction of SIRT1 (red), SIRT6 (green), and the combination of the two (purple) affected the lifespan of male (left) and female mice (right). Male (left graph) and female (middle graph) mice with genetic modifications that increase SIRT6 protein levels only show markedly extended lifespan. Changes in SIRT1 levels only provided no average significant lifespan extension (number of days in parentheses next to the graphs) compared to non-genetically modified mice (WT; blue). The pooled results between the sexes (right) show that SIRT6 extends the average lifespan by about 21.4%. The median lifespan is shown in parenthesis.

Increasing SIRT6 Levels Reduces Age-Related Frailty

To see if the increased SIRT6 protein levels provide healthspan benefits, Cohen and colleagues compared the distances that the three groups of older transgenic mice ran on a spinning wheel, which is indicative of physical performance. Greater distances run indicate reduced frailty since fatigued and tired older mice prefer to remain stationary. The research group found that older, 15-month-old SIRT6 and SIRT1 + SIRT6 but not SIRT1 transgenic mice ran greater distances during nighttime hours, when mice are most active. Because increased SIRT6 protein levels were present in the mouse groups running longer distances but elevated SIRT1 levels alone didn’t yield these results, Cohen and colleagues determined higher SIRT6 levels drive the reduced frailty in older-aged mice.

(Roichman et al., 2021 | Nature Communications) Aged, genetically modified mice with increased SIRT6 protein levels run about as much as young mice, indicating that SIRT6 extends healthspan and reduces frailty. The colored lines show the average distances that mice run on their running wheels throughout the day over the course of two days. The different colors represent genetically modified mice with SIRT1, SIRT6, or SIRT1 and SIRT6 (SIRT1+6) elevated protein levels. The graph on the left shows the results for young mice, and the graph on the right shows them for older mice. Increasing SIRT6 protein levels substantially improves running distance in older mice, similar to levels seen in young mice.

SIRT6 Stimulates Energy Production in the Liver

After determining that increasing SIRT6 protein levels substantially extends mouse health and lifespan, Cohen and colleagues wanted to figure out what physiological mechanisms explain these benefits. By measuring the activity of genes and protein levels involved in energy production, Cohen and colleagues found that SIRT6 preserves metabolism pathways that use NAD+ in old age. Their research indicates that metabolic pathways in the liver producing energy (ATP) along with the sugar glucose deteriorate during aging, leading to perturbed energy homeostasis. Increasing SIRT6 levels in the liver as mice get older enhances energy production and preserves ATP levels along with glucose for brain function.

(Roichman et al., 2021 | Nature Communications) Stimulating SIRT6 protein production improves longevity and healthspan by preserving glucose sugar and cell energy-generating pathways that require NAD+. The schematic shows that SIRT6 protein production preserves NAD+ levels and stimulates the tricarboxylic acid cycle (TCA) to promote the production of cell energy in the form of ATP in the liver. It also stimulates the release of glucose sugar precursors glycerol and lactate from fat tissue and muscle, respectively, to drive glucose generation (gluconeogenesis) that the brain uses for energy. This SIRT6-stimulated cascade leads to preserved liver glucose and energy production in old age.

How Can We Apply Increased SIRT6 to Human Aging?

Through significantly increasing cell energy and glucose production, SIRT6 stimulates the physiological response that is identical to intermittent fasting, a reduced-calorie diet that increases longevity. Cohen’s laboratory is currently trying to devise ways to extend healthy life based on these findings.