Sirtuins: guardians of mammalian healthspan

Abstract

The first link between sirtuins and longevity was made 15 years ago in yeast. These initial studies sparked efforts by many laboratories working in diverse model organisms to elucidate the relationships between sirtuins, lifespan, and age-associated dysfunction. Here we discuss the current understanding of how sirtuins relate to aging. We focus primarily on mammalian sirtuins SIRT1, SIRT3, and SIRT6, the three sirtuins for which the most relevant data are available. Strikingly, a large body of evidence now indicates that these and other mammalian sirtuins suppress a variety of age-related pathologies and promote healthspan. Moreover, increased expression of SIRT1 or SIRT6 extends mouse lifespan. Overall, these data point to important roles for sirtuins in promoting mammalian health, and perhaps in modulating the aging process.

Mitochondrial Sirtuins and Their Relationships with Metabolic Disease and Cancer

“…Moreover, NAMPT expression is linked to the circadian clock, thereby regulating NAD + levels and sirtuin activity (120). Sirtuins are widely expressed in normal tissues (99) and play diverse biological roles such as regulating oxidative stress, DNA repair, genomic stability, cell survival, apoptosis, metabolism, aging, and longevity (47).…”

“…1), subcellular localization ( Fig. 2), protein targets, and biological functions (42,47). SIRT6 and SIRT7 are found predominantly in the nucleus, whereas both SIRT1 and SIRT2 can be nuclear and cytosolic.…”

“…SIRT6 and SIRT7 are found predominantly in the nucleus, whereas both SIRT1 and SIRT2 can be nuclear and cytosolic. SIRT3, SIRT4, and SIRT5 primarily reside in the mitochondrial matrix (25,47). Here, we focus on SIRT3, SIRT4, and SIRT5: their catalytic activities, protein substrates, major target pathways, and roles in disease, particularly cancer.…”

Sirt7 promotes adipogenesis in the mouse by inhibiting autocatalytic activation of Sirt1

“…Sirt1 deacetylates histones H3K9, H3K56, H4K16, and H1K26 as well as many nonhistone targets thereby contributing to the maintenance of metabolic homeostasis and genomic integrity (3,4). Sirt1 was also identified as a critical component of lifespan extension in response to calorie restriction in several model organisms, although its exact contribution is still under debate (5). The functions of Sirt7 have attracted less attention compared with Sirt1.…”

Proteomic and Biochemical Studies of Lysine Malonylation Suggest Its Malonic Aciduria-associated Regulatory Role in Mitochondrial Function and Fatty Acid Oxidation

“…This modification is now known to have important regulatory roles in diverse cellular processes and physiological conditions, such as transcription, metabolism, and aging (3)(4)(5). Dysregulation of the lysine acetylation pathway is associated with various diseases, such as cardiovascular disease and cancer (6,7).…”