The sirtuins: Markers of metabolic health

Abstract

The sirtuins represent a class of proteins first discovered orthologus to the yeast silent information regulator 2 protein that have been retained in mammalian species. Currently, seven sirtuins have been identified in humans, and their functions currently surpass their originally identified role as histone deacetylase and chromatin silencers to encompass nutrient sensing and metabolic function. All seven sirtuins require NAD(+) in order to carry out their enzymatic activity, and thus become activated in conditions of nutrient depletion, starvation, and cellular stress. Caloric restriction and increased physical activity have been postulated, though perhaps controversially, to mediate sirtuin function. Here, we review the current literature surrounding the functions of the seven human sirtuins, mediators of their function, and the roles they play in metabolic health related to dietary and physical activity interventions. Despite the controversy surrounding sirtuin function with regard to longevity, we have aimed to show that regardless of its effects on aging, sirtuin function is pivotal to pathways involving metabolic health, and should therefore be investigated with regard to improving metabolic diseases such as obesity and type 2 diabetes.

Sirtuins and Their Roles in Brain Aging and Neurodegenerative Disorders

“…Sirtuins are class III HDACs and differ from other classes in that they require NAD + for their activity. This feature couples sirtuin activity to the cellular metabolic status [3], in turn allowing these enzymes to modulate the crucial proteins of the electron transport chain (ETC), stress response, and life/death signaling. Some sirtuins also possess additional enzymatic activities such as mono(ADP-ribosyl)ation (SIRT3, SIRT4, SIRT6), the ability to remove a wide array of other lysine modifications (e.g.…”

Adherence to the Mediterranean Diet and Circulating Levels of Sirtuin 4 in Obese Patients: A Novel Association

“…Sirt4 regulates the pyruvate dehydrogenase complex via enzymatic hydrolysis of the lipoamide cofactor, thus modulating acetyl coenzyme A production, Krebs cycle activity, and ROS generation [12]. Afterwards, it became apparent that Sirt4 is involved in the regulation of fatty acid oxidation in the liver [13–15]. In line with this finding, we have reported that circulating levels of Sirt4 were reduced in obese patients with HS, although the possible contribution of the diet and the adipocyte dysfunction on this association was not investigated [16].…”

Prolonged Growth Hormone/Insulin/Insulin-like Growth Factor Nutrient Response Signaling Pathway as a Silent Killer of Stem Cells and a Culprit in Aging

“…Specifically, it may deacetylate p53 and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α) and thus inhibit apoptosis and enhance mitochondrial function and biogenesis, respectively. Moreover, the SIRT-1-regulated acetylation state of FOXO transcription factors is thought to selectively direct these factors to certain targets in the cell and to regulate cell metabolism and stress responses [74, 75]. Other newly identified novel functions of SIRT-1 include i) neuroprotection, ii) liver regeneration, and iii) delayed replicative senescence of fibroblasts [74].…”

“…These epigenetic changes may be additionally enhanced by caloric restriction and regular physical activity [85–89] as well as by administration of certain drugs, including metformin, berberine, or rapamycin [68–71]. This quiescent state of VSELs is also most likely promoted by other activators of AMPK as well as of SIRT-1 [74, 75]. …”