Views: 1000 Author: Lin LIU Publish Time: 2025-09-17 Origin: Site
As a family of highly conserved deacetylases (later expanded to deacylases), the Sirtuins family has gradually revealed its core roles in cellular metabolism, DNA repair, oxidative stress regulation, and aging processes since its first discovery in yeast in 1979. This article systematically reviews the discovery history, molecular characteristics, and functional differences among members of the Sirtuins family, with a focus on elucidating its mechanisms of association with aging and potential activation strategies, providing references for research in related fields.
In 1979, a research team at the University of California, Berkeley, discovered a protein in yeast that mediates gene locus silencing (initially named MAR1). Later that year, three other proteins with similar functions were identified, and they were collectively named the Sir (Silent Information Regulator) family, with MAR1 renamed Sir2. With the successive discovery of Sir2 homologs in bacteria, Caenorhabditis elegans, Drosophila melanogaster, and humans, these proteins were formally classified as "Sir2-related enzymes," i.e., the Sirtuins family. Their cross-species conservation suggests a fundamental regulatory role of this family in life activities.
The core catalytic function of Sirtuins is lysine residue deacylation, a two-step reaction that relies on NAD+ as a coenzyme:
① Sirtuins cleave NAD+ into nicotinamide (NAM);
② The acyl group (e.g., acetyl, palmitoyl) on the lysine residue of the substrate protein is transferred to the ADP-ribose moiety of NAD+, forming 2’-O-acyl-ADP-ribose while deacylating the substrate protein.
Classified as Class III histone deacetylases (HDACs), Sirtuins exhibit strict dependence of their activity on NAD+ concentration and dynamic changes in the NAD+/NADH ratio—this characteristic makes them "sensors" of cellular energy status and redox balance, enabling real-time response to cellular metabolic fluctuations and regulation of downstream pathways.
Seven members of the Sirtuins family (SIRT1–SIRT7) have been identified in humans, all containing a conserved catalytic domain composed of 275 amino acids. However, significant differences exist in their subcellular localization, substrate preference, and function (data synthesized from studies by Wioleta Grabowska et al.):
Family Member | Primary Subcellular Localization | Core Substrates/Functions | Special Functional Expansions |
SIRT1 | Nucleus (small amount in cytoplasm) | Histones, p53, FOXO transcription factors | Regulates cell cycle and energy metabolism |
SIRT2 | Cytoplasm (translocates to nucleus under stress) | α-tubulin | Participates in cell cycle regulation |
SIRT3 | Mitochondrial matrix (full-length form in nucleus) | Mitochondrial Complexes I/III, antioxidant enzymes | Enhances electron transport efficiency and inhibits ROS production |
SIRT4 | Mitochondria | No definite deacetylase activity | Mainly exerts ADP-ribosylation; function to be further explored |
SIRT5 | Mitochondria | Aconitase, superoxide dismutase | Regulates mitochondrial metabolism and antioxidant defense |
SIRT6 | Nucleus | Histones, DNA repair-related proteins | Prefers long-chain acyl groups (palmitoyl, myristoyl) for deacylation; participates in DNA repair |
SIRT7 | Nucleolus | Histone H3K18 | Binds to RNA polymerase I and positively regulates ribosomal DNA (rDNA) transcription |
It is important to note that with in-depth research, the function of Sirtuins has exceeded the scope of "deacetylation": for example, SIRT6’s preference for long-chain acyl groups and SIRT4’s unique ADP-ribosylation activity suggest that "deacylase" is a more accurate functional definition for this family.
In 1999, studies found that overexpression of Sir2 in yeast could extend lifespan by up to 70%, and similar phenomena were later observed in Drosophila and C. elegans. The association between Sirtuins and aging thus became a research hotspot. Currently, its mechanisms of regulating aging have been clarified as follows:
Irreparable DNA damage is a core driver of cellular aging, and DNA repair capacity declines with age. SIRT1 and SIRT6 can activate DNA repair-related proteins (e.g., PARP1, Ku70) through deacetylation to promote double-strand break repair; SIRT4 reduces oxidative stress-related DNA damage by regulating mitochondrial metabolism. Together, these three proteins maintain genomic stability and reduce the rate of aging caused by damage accumulation.
Oxidative stress imbalance (excessive accumulation of ROS) is an important hallmark of aging. As a key Sirtuins member in mitochondria, SIRT3 can deacetylate mitochondrial Complexes I/III to improve electron transport efficiency and reduce ROS production; it also regulates the activity of antioxidant enzymes such as superoxide dismutase (SOD) and glutathione peroxidase to enhance cellular antioxidant defense. In addition, SIRT1 and SIRT5 can indirectly inhibit oxidative stress by regulating the activity of metabolic enzymes, collectively maintaining mitochondrial homeostasis.
Sirtuins regulate lifespan by activating anti-aging pathways and inhibiting pro-aging pathways:
• Activating anti-aging pathways: SIRT1 and SIRT3 can activate AMPK (energy-sensing pathway) and FOXO (antioxidant and DNA repair pathway) to promote cellular metabolic reprogramming and stress resistance;
• Inhibiting pro-aging pathways: SIRT1 and SIRT6 can suppress the mTOR pathway (regulating cell proliferation and nutrient sensing) to reduce the senescence-associated secretory phenotype (SASP) caused by abnormal proliferation.
Only the function of SIRT4 remains incompletely understood; it has not been found to participate in the above classical pathways and is temporarily regarded as a "functionally unique member" of the family.
Caloric restriction is currently the only strategy that can extend the lifespan of various species without genetic or pharmaceutical intervention, and its core mechanism is closely related to Sirtuins: except for SIRT4, the expression and activity of other Sirtuins members (especially SIRT1 and SIRT3) are significantly increased under caloric restriction. This further mediates physiological changes such as weight loss, reduced blood glucose/triglycerides, and improved exercise capacity, ultimately achieving lifespan extension and healthspan improvement.
Based on the core role of Sirtuins in aging regulation, the development of its activators has become an important direction for delaying aging and preventing age-related diseases. Current research focuses on the following fields:
• Natural polyphenols: Resveratrol (found in grapes, peanuts) is the most widely studied SIRT1 activator. It can activate SIRT1 by mimicking caloric restriction, extend lifespan in yeast and C. elegans, and reduce aging markers in human diploid fibroblasts; in addition, quercetin, curcumin, fisetin, and other polyphenols can also prevent neurodegenerative diseases, cardiovascular diseases, and metabolic disorders by enhancing SIRT1 activity (currently recommended only for prevention; clinical therapeutic potential remains to be verified).
• Repurposing of clinical drugs: Metformin (an oral hypoglycemic drug for type 2 diabetes) can indirectly increase SIRT1 activity by activating AMPK (the upstream pathway of SIRT1) while upregulating FOXO1 levels, synergistically enhancing anti-aging effects; statins, cilostazol, and other drugs have also been confirmed to activate Sirtuins in vitro, with specific mechanisms to be further studied.
• Synthetic activators (STACs): Compared with natural compounds, synthetic Sirtuins-activating compounds (STACs) have higher water solubility and bioavailability. In preclinical models, STACs have shown therapeutic potential for age-related diseases and aging-associated complications, including cancer, type 2 diabetes, inflammation, cardiovascular diseases, stroke, and hepatic steatosis, making them an important direction for future drug development.
Regular moderate exercise can delay aging by improving metabolism and enhancing antioxidant capacity, and its mechanism is closely related to Sirtuins activation:
• Animal experiments show that long-term (36 weeks) moderate exercise can increase SIRT1 levels in skeletal muscle, liver, and heart of adult rats, while enhancing the activity of SIRT1, AMPK, and FOXO3a in the muscle tissue of aged rats;
• Human studies confirm that the expression of SIRT1 and AMPK genes in skeletal muscle increases after exercise in both young and elderly subjects, and a single bout of exercise can induce SIRT1 expression in young people (this effect is not observed in the elderly), suggesting that the activating effect of exercise on Sirtuins varies with age, and "early intervention" may be more advantageous.
As key molecules linking cellular metabolism and aging regulation, the Sirtuins family, with its NAD+-dependent deacylase activity, functional specificity of family members, and regulatory roles in DNA repair, oxidative stress, and lifespan pathways, has become a core research target in the field of aging biology. Currently, the activating effects of natural compounds, synthetic drugs, and moderate exercise on Sirtuins have been verified in basic research, but many unresolved issues remain: such as the specific function of SIRT4, the synergistic mechanism between different Sirtuins members, and the clinical safety of activators. In the future, more precise molecular mechanism studies and large-scale clinical verification are needed to promote the application of Sirtuins-related intervention strategies in the prevention and treatment of age-related diseases.
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