Aging is associated with an overall decline in health, increased frailty and is a major risk factor for multiple chronic diseases. Therefore, increasing our understanding of the mechanisms underlying aging processes is a top priority to enable the development of interventions that will lead to the preservation of health and improvements on survival/lifespan.
A growing body of evidence indicates that diet and metabolism are key targetable regulators of healthy lifespan2. Dietary restriction (DR), a reduced calorie intake without malnutrition (calorie restriction, CR), as well as some fasting regimens, provide profound health benefits and lead to lifespan extension3,4,5. Similarly, pharmacological or genetic inhibition of the major nutrient-abundance-sensing signaling pathways, mammalian target of rapamycin (mTOR) and insulin/IGF-1, were shown to improve lifespan in organisms ranging from yeast to mammals6. Likewise, activation of pathways which sense a low-energy state, such as AMP kinase (AMPK) and sirtuins lead to increased longevity in a wide range of organisms6.
Previous studies have shown a loss of metabolic homeostasis with aging. At the level of the whole organism, aged mice and humans show changes in energy expenditure and metabolic flexibility7,8. At the cellular level, aging affects various metabolic pathways, many of which are associated with a decline in mitochondrial function8,9. Notably, the levels of key metabolites that are consumed by cells for energy production, such as glucose, amino acids (AAs), and lipids, are altered with age in the circulation and in tissues7,10. Yet, despite such extensive studies, a comprehensive description of age-related metabolic alterations is lacking. Moreover, it is still unclear why the ability to maintain energy homeostasis is lost with age. The age-dependent changes in metabolite abundance together with the decline in mitochondrial function9, suggest a global decrease in energy production with age. Interestingly, many of the aforementioned interventions that promote longevity also activate mitochondrial function and energy metabolism11, suggesting that enhancing energy production may be beneficial for extending healthy lifespan.
An essential metabolic process for providing energy to the body is gluconeogenesis (GNG). GNG, the de novo synthesis of the body’s primary source of fuel, glucose, from non-carbohydrate precursors, occurs mainly in the liver, and to a lesser extent in the kidney and gastrointestinal tract. This process is necessary for maintaining blood glucose during fasting and physical activity, and contributes ~64% of total glucose production even during the first 22 h of fasting in humans12. GNG is regulated through complex pathways, which include extra- and intra-hepatic mechanisms13. Given the major role of GNG in energy production, one would expect GNG to play a major role in aging and frailty. Yet, the effect of age on GNG capacity in mammals is unclear, and reported studies were mostly performed in cell culture. While some studies showed an increase in GNG capacity with age14, others reported a decrease15,16,17. These contradictory findings can stem from different experimental systems or gluconeogenic precursors used. Thus, an extensive examination of the effect of aging on energy production and GNG, and its potential connection to age-associated frailty, is required.
Sirtuins are nicotinamide adenine dinucleotide (NAD+)-dependent protein deacylases and mono-ADP-ribosyl transferases, which are highly conserved from yeast to mammals. Sirtuins were implicated in many cellular pathways, including DNA repair, metabolism, inflammation, cancer, and aging18. Of the seven mammalian sirtuins, SIRT1-7, SIRT1, and SIRT6 protein levels increase upon dietary restriction and fasting in various mouse tissues and human cell lines19,20,21. While most SIRT1 knockout (KO) mice die perinatally, in a few weeks age22,23, 129svJ background SIRT6 KO mice exhibit severe developmental defects but survive to about 4 weeks of age24. Similarly, in humans and primates, mutations resulting in SIRT6 inactivation result in prenatal or perinatal lethality accompanied by severe developmental brain defects25. Interestingly, whole-body SIRT1 overexpression in mice leads to improvement in parameters reflecting healthspan, but not lifespan26. Whereas whole-brain-specific SIRT1 overexpression did not affect lifespan and brain plasticity, hypothalamic SIRT1 overexpression delays aging27,28. However, whole-body SIRT6 overexpression in the mixed-CB6 mouse background leads to a significant extension of male lifespan and healthspan, associated with inhibition of IGF-1 signaling29,30.
A significant amount of data demonstrate the major role of SIRT6 in metabolism31. SIRT6 represses glycolysis in an HIF1α-dependent manner32, thereby acting as a tumor suppressor by inhibiting the Warburg effect33. Liver-specific deletion of SIRT6 results in increased glycolysis, triglyceride synthesis, reduced β-oxidation, and fatty liver formation34. Similarly, SIRT6 heterozygotic mice show significantly reduced PPARα-induced β-oxidation35. Liver-specific SIRT6 induction showed that SIRT6 negatively regulates GNG by regulating PGC1α and FOXO1 activities36,37. However, Deng and his colleagues34 showed no effect of liver-specific SIRT6 KO on GNG. Importantly, these metabolic roles of SIRT6 were determined in young mice. Thus, given SIRT6’s major role in aging, the broader metabolic role of SIRT6 under fasting as well as the effect of SIRT6 overexpression on metabolism in the context of aging should be described.
Here, we show that overexpression of SIRT6, but not SIRT1, extends lifespan in C57BL/6JOlaHsd mice in both sexes. Overexpression of SIRT6 reduced the age-related metabolic decline in energy metabolism pathways and inhibited frailty by preserving hepatic NAD+ levels, GNG capacity, and maintenance of normoglycemia, key markers of healthy aging. These results emphasize the potential of targeting SIRT6 for maintaining energy metabolism and reducing age-related frailty.
Sherry
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