Sirt1 study helps demystify the role of diet in health and aging

A link between low-calorie diet and longevity was first suggested as early as the 18th century by the Japanese philosopher and scientist Ekiken Kaibara. Since then, several seminal studies demonstrated the association of low-calorie diet with delayed aging and increased longevity. The involvement in these two processes of Sirtuins, a family of proteins with ribosyltransferase or deacetylase activity, has been hotly discussed, and research in this field has led to contradictory results. While Sirt1 is known to play an important role in enhancing longevity through the regulation of metabolism, the precise mechanism is unknown. In their publication in Cell Metabolism, Dr. Satoh and colleagues from the Washington University School of Medicine have shed some light on this phenomenon. Brain-specific Sirt1-overexpressing (BRASTO) transgenic mice displayed significantly increased life span and exhibited phenotypes consistent with delayed aging, as was previously observed with control mice under dietary restrictions. Furthermore, mitochondrial morphology and function in skeletal muscle presented youthful traits in aged BRASTO mice. Looking further into the mechanisms behind these observations, they determined that Sirt1 expression in the brain correlated with enhancement of neural activity in specific areas of the hypothalamus and that this enhancement was due to the deacetylation of the thyroid transcription factor Nkx2-1 by Sirt1 to promote the expression of the orexin type 2 receptor (Ox2r). This pathway was shown to be critical for the maintenance of physical activity, body temperature, mitochondrial function in skeletal muscle, and quality of sleep. Altogether, these results proved that activation of these specific regions of the hypothalamus was directly associated with longevity in mice and suggested that Sirt1-prompted brain activation could be envisaged in other mammals to maintain youthful physiology and extend life expectancy.

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