Sirtuins in atherosclerosis: guardians of healthspan and therapeutic targets

Sirtuins are NAD+-dependent deacetylase and deacylase enzymes that control important cellular processes, including DNA damage repair, cellular metabolism, mitochondrial function and inflammation. Consequently, mammalian sirtuins are regarded as crucial regulators of cellular function and organism healthspan. Sirtuin activity and NAD+ levels decrease with age in many tissues, and reduced sirtuin expression is associated with several cardiovascular diseases. By contrast, increased sirtuin expression and activity slows disease progression and improves cardiovascular function in preclinical models and delays various features of cellular ageing. The potential cardiometabolic benefits of sirtuins have resulted in clinical trials with sirtuin-modulating agents; although expectations are high, these drugs have not yet been proven to improve healthspan. In this Review, we examine the role of sirtuins in atherosclerosis, summarize advances in the development of compounds that activate or inhibit sirtuin activity and critically evaluate the therapeutic potential of these agents.