Maintaining metabolic homeostasis is essential for cellular and organismal health throughout life. Of the multiple signaling pathways that regulate metabolism, such as PI3K/AKT, mTOR, AMPK, and sirtuins, mammalian sirtuins also play unique roles in aging. By understanding how sirtuins regulate metabolic processes, we can start to understand how they slow down or accelerate biological aging. Here, we review the biology of SIRT3, SIRT4, and SIRT5, known as the mitochondrial sirtuins due to their localization in the mitochondrial matrix. First, we will focus on canonical pathways that regulate metabolism more broadly and how these are integrated with aging regulation. Then, we will summarize the current knowledge about functional differences between SIRT3, SIRT4, and SIRT5 in metabolic control and integration in signaling networks. Finally, we will discuss how mitochondrial sirtuins regulate processes associated with aging and oxidative stress, calorie restriction and disease.Copyright © 2021. Published by Elsevier Ltd.