SIRT1 and the sirtuin protein family

The Sirtuin family is a group of NAD + -dependent deacetylases in mammals, including SIRT1 through SIRT7, which are involved in various biological processes such as cell proliferation, cellular senescence, apoptosis, cellular metabolism, gene transcription, and DNA repair [54]. The Sirtuin family is a regulatory factor associated with aging, and it plays a protective role in age-related diseases such as CVDs, neurodegenerative disease, diabetes, and metabolic disease [55]. Members of the Sirtuin family located in the mitochondria include SIRT3, SIRT4, and SIRT5 [53]. SIRT3 can regulate various cellular processes, including growth arrest, apoptosis, aging, and metabolism, and its expression in VECs can regulate the metabolic transition between glycolysis and mitochondrial respiration [56]. SIRT4 has been studied less extensively, and it is more highly expressed in adult leukocytes and the embryonic thymus. It can maintain genomic stability, regulate mitochondrial function, and play an important antioxidant and anti-inflammatory role [57]. SIRT5, which has depropionylation and weak deacetylation activities, participates in the regulation of various physiological processes, including the tricarboxylic acid cycle, urea cycle, glycolysis, gluconeogenesis, and redox homeostasis [58].

Current studies have shown that SIRT6 and SIRT7 are expressed in the nucleus [43]. As an important member of the Sirtuin family, SIRT6 possesses both deacetylase activity and ADP-nucleic acid transferase activity and is highly similar to SIRT1 in function [59]. SIRT6 acts on multiple transcription factors during aging, helps repair and maintain telomeric DNA chromatin structure, and plays an important protective role in maintaining genomic stability [60]. SIRT7, the least-studied sirtuin protein to date, exists only in eukaryotes; and it has important functions in promoting ribosomal RNA expression, repairing DNA damage, and regulating chromatin compression [61].

SIRT2 is the only sirtuin protein predominantly expressed in the cytoplasm, although it is also present in small amounts in the nucleus and mitochondria [53]. SIRT2 is closely involved in a variety of biological processes, including apoptosis, autophagy, and immune responses. It regulates the expression of its target genes during processes such as replication, transcription, and translation. By reducing oxidative stress and inflammatory responses associated with metabolic disorders, SIRT2 plays a protective role in CVDs, neurodegenerative diseases, tumors, diabetes, and other diseases related to metabolic dysfunction [62], 63].

The SIRT1 gene (Figure 2) is located on human chromosome 10 and spans a total length of approximately 33 kb, containing nine exons, eight introns, and untranslated regions [64]. The conserved catalytic structure of SIRT1 consists of both C-terminal and N-terminal domains. The C-terminal domain complements the β-fold of the NAD + binding domain, while the N-terminal domain is essential for SIRT1 activity [65]. As a longevity-associated protein, SIRT1 is primarily located in the nucleus but is also expressed to a lesser extent in the cytoplasm, where it exhibits NAD + -dependent deacetylase activity. It plays a crucial role in the development of diseases such as cardiovascular, neurodegenerative, and metabolic disorders, linking the aging process to vascular health and metabolic damage [66], 67]. The diversity of SIRT1’s functions depends on the variety of its C-terminal domains, which are involved in regulating biological processes such as oxidative stress, inflammatory response, energy homeostasis, mitochondrial dysfunction, apoptosis, and autophagy [68]. SIRT1 is highly sensitive to the cellular redox state and supports cardioprotection and the maintenance of vascular function by deacetylating a variety of effector molecules and attenuating the effects of ROS [69]. Research on how key members of the sirtuin family regulate CVDs provides effective new approaches for the treatment and prevention of these diseases and is currently one of the main areas of study.

Figure 2:: Structures of SIRT1-SIRT7. SIRT1: Primarily located in the nucleus and capable of shuttling between the nucleus and cytoplasm; SIRT2: Mainly distributed in the cytoplasm and translocates to chromosomes during mitosis; SIRT3/4/5: Exclusively present in mitochondria, serving as mitochondria-specific deacetylases; SIRT6/7: Specifically localized in the nucleus, with SIRT6 predominantly binding to chromatin and SIRT7 enriched in the nucleolus.