Sirt4 is a mitochondrial regulator of metabolism and lifespan in <i>Drosophila melanogaster</i>

Significance Sirtuins are a class of proteins known to regulate aspects of genomic stability, metabolism, and lifespan in many organisms. In this study, we show that the mitochondrial sirtuin Sirt4 plays an important role in regulating the organismal response to fasting as well as ensuring normal lifespan in Drosophila . Flies lacking Sirt4 are short-lived, while flies overexpressing Sirt4 are long-lived. Flies lacking Sirt4 display a number of metabolic defects, including sensitivity to starvation; decreased fertility and activity; and an inability to utilize energy stores, particularly long-chain fatty acids, suggesting Sirt4 is important for maintaining metabolic homeostasis. Our results suggest that boosting mitochondrial sirtuin activity may be an important avenue for treating age-related metabolic decline and preserving healthy lifespan.