Sirtuins are a family of NAD⁺-dependent deacylases comprising SIRT1–7 and are involved in metabolism, DNA repair, mitochondrial homeostasis, and inflammatory regulation. Animal studies suggest that certain members may improve healthspan, but there is currently no direct evidence that they can extend the maximum human lifespan.

Keywords: Sirtuins; SIRT1; SIRT2; SIRT3; SIRT6; NAD⁺; aging; mitochondria; DNA repair; healthspan

1 Overview of the Sirtuin Protein Family

1.1 From Yeast Sir2 to Mammalian SIRT1–7

Research on Sirtuins originated from the silent information regulator protein Sir2 in Saccharomyces cerevisiae, rather than mammalian SIRT2. Sir2 participates in chromatin silencing, ribosomal DNA stability, and regulation of replicative lifespan, and its homologs were subsequently identified in multiple organisms. Mammals possess seven members, SIRT1–SIRT7, which retain the NAD⁺-dependent catalytic core but differ markedly in subcellular localization, substrate selectivity, and physiological function.

1.2 NAD⁺-Dependent Deacylation Reactions

Sirtuins use NAD⁺ to remove acetyl groups or other acyl groups from protein lysine residues. The reaction products include the deacylated protein, nicotinamide, and O-acyl-ADP-ribose. Nicotinamide can exert feedback inhibition on Sirtuins, whereas intracellular NAD⁺ abundance, the NAD⁺/NADH ratio, and the distribution of NAD⁺ among cellular organelles can all affect their activity. Sirtuins thereby convert the metabolic coenzyme state into protein-modification and transcriptional-regulatory signals.

1.3 Deacetylation Is Not the Only Function of Sirtuins

SIRT1, SIRT2, SIRT3, and SIRT7 predominantly exhibit deacetylase activity. SIRT5 has strong desuccinylase, demalonylase, and deglutarylase activities; SIRT6 possesses both deacetylase and mono-ADP-ribosyltransferase activities; and SIRT4 exhibits multiple catalytic functions, including deacylation and ADP-ribosyltransferase activity. When evaluating individual members, assays should be selected according to their preferred acyl substrates, and total protein acetylation levels should not be used to represent the activities of all Sirtuins.

1.4 Localization and Functions of the Sirtuin Family

2 How NAD⁺ Metabolism Regulates Sirtuin Activity

2.1 Aging-Associated NAD⁺ Decline

Many aging tissues exhibit reduced NAD⁺ synthesis and increased NAD⁺ consumption. Reduced nicotinamide salvage synthesis mediated by NAMPT limits NAD⁺ regeneration, whereas increased levels of NAD⁺ hydrolases such as CD38 accelerate NAD⁺ consumption. Persistent activation of PARP by DNA damage also creates competition with Sirtuins for NAD⁺. A decline in NAD⁺ can simultaneously affect Sirtuins, PARP, CD38, and other NAD⁺-dependent processes and is not equivalent to reduced activity of a single Sirtuin member.

2.2 The NAD⁺ Salvage Pathway

Nicotinamide can be converted by NAMPT into nicotinamide mononucleotide, which is subsequently converted by NMNAT into NAD⁺. Nicotinamide riboside can also be converted into nicotinamide mononucleotide by NRK. Supplementation with nicotinamide riboside or nicotinamide mononucleotide can increase NAD⁺ levels in certain tissues and experimental models, but the resulting metabolic effects are also influenced by tissue uptake, precursor conversion, subcellular distribution, and the rate of NAD⁺ consumption.

2.3 Substrate Competition Among Sirtuins, PARP, and CD38

Sirtuins, PARP, and CD38 all consume NAD⁺. When DNA damage increases, PARP activation may reduce the amount of NAD⁺ available to Sirtuins. Chronic inflammation and aging-associated changes in immune cells may also increase CD38 activity. NAD⁺ supplementation experiments should therefore measure NAD⁺, NADH, nicotinamide, and related metabolites while analyzing changes in PARP and CD38 to avoid attributing all observed effects to Sirtuins.

3 Major Molecular Mechanisms Through Which Sirtuins Regulate Aging

3.1 DNA Damage Repair and Genomic Stability

SIRT1 and SIRT6 regulate chromatin structure and multiple DNA-repair proteins. Through the deacetylation of Ku70, WRN, XPA, and other repair factors, SIRT1 influences DNA double-strand break repair and nucleotide excision repair. SIRT6 participates in DNA-break recognition, chromatin remodeling, and repair-protein recruitment and maintains telomere and heterochromatin stability by regulating H3K9ac and H3K56ac.

3.2 Maintenance of Epigenetic States

Aging is accompanied by heterochromatin loss, altered histone modifications, and increased transcriptional noise. Nuclear SIRT1, SIRT6, and SIRT7 influence gene silencing, ribosomal DNA stability, and stress-responsive transcriptional programs by removing acetyl groups from histones and transcriptional regulators. Reduced Sirtuin activity may open certain silenced regions, but its effects depend on cell type, chromatin locus, and substrate composition.

3.3 Mitochondrial Metabolism and Oxidative Stress

SIRT3 is an important regulator of mitochondrial protein acetylation. It acts on fatty acid oxidation enzymes, tricarboxylic acid cycle enzymes, respiratory-chain proteins, isocitrate dehydrogenase 2, and superoxide dismutase 2. Enhanced SIRT3 activity can improve mitochondrial substrate utilization and antioxidant capacity, whereas SIRT3 deficiency may cause mitochondrial protein hyperacetylation, reactive oxygen species accumulation, and impaired metabolic adaptability.

3.4 Inflammation and NF-κB Signaling

SIRT1 can deacetylate the NF-κB subunit RelA/p65 and restrict the transcription of certain pro-inflammatory genes. SIRT6 can also regulate NF-κB-related gene expression through chromatin modification. The effects of SIRT2 on inflammation are context dependent. In some acute neuroinflammation models, SIRT2 inhibition can reduce inflammatory responses, whereas long-term SIRT2 deficiency may impair vascular, cardiac, or metabolic homeostasis.

3.5 Cellular Senescence and the SASP

Cellular senescence is characterized by stable cell-cycle arrest, persistent DNA-damage responses, chromatin remodeling, and the senescence-associated secretory phenotype (SASP). SIRT1, SIRT2, and SIRT6 can influence senescence programs through p53, p21, p16, NF-κB, and DNA-repair pathways. However, excessive Sirtuin activity may also support the survival of abnormal cells in certain tumor environments. Therefore, suppression of cellular senescence cannot be equated simply with a beneficial anti-aging effect.

4 Sirtuins and Mitochondrial Quality Control

4.1 The SIRT1–AMPK–PGC-1α Axis

SIRT1 can deacetylate PGC-1α, promoting mitochondrial biogenesis, fatty acid oxidation, and the expression of oxidative metabolic genes. AMPK senses changes in the AMP/ATP ratio, regulates NAD⁺ metabolism, and promotes SIRT1-related signaling. SIRT1 can also influence AMPK activity through nodes such as LKB1, forming a regulatory network that connects energy stress, mitochondrial renewal, and substrate utilization.

4.2 SIRT1 and PINK1/Parkin-Mediated Mitophagy

Through FOXO1-, FOXO3-, and PGC-1α-related transcriptional programs, SIRT1 can promote the expression of PINK1, Parkin, and certain autophagy genes. It can also regulate the acetylation states of ATG5, ATG7, LC3, and other autophagy-related proteins. SIRT1 additionally modifies the conditions for autophagy initiation through the AMPK–mTOR axis, facilitating the recognition and clearance of damaged mitochondria.

4.3 Mitochondrial Fusion and Fission

SIRT1 can regulate the acetylation state of mitochondrial dynamics proteins such as MFN2, whereas SIRT3 indirectly affects fusion, fission, and cristae stability through mitochondrial metabolism and oxidative stress. An increase in mitochondrial abundance does not necessarily indicate improved mitochondrial quality. Mitophagic flux, the balance between fusion and fission, and the function of newly generated mitochondria should be evaluated together.

4.4 SIRT3 and Mitochondrial Proteostasis

By regulating mitochondrial metabolic enzymes and antioxidant proteins, SIRT3 reduces the effects of oxidative damage on the respiratory chain and mitochondrial DNA. SIRT3-related protection is generally reflected by improvements in membrane potential, ATP production, oxygen consumption rate, and antioxidant capacity, rather than by a simple decrease in total reactive oxygen species levels.

5 Aging-Related Functions of Individual Sirtuin Members

5.1 SIRT1: Nutrient Sensing and Stress Adaptation

SIRT1 is the most extensively studied Sirtuin member. It acts on PGC-1α, FOXO, p53, NF-κB, LKB1, and autophagy-related proteins and participates in glucose homeostasis, fatty acid oxidation, inflammatory regulation, and survival under stress. The effects of SIRT1 are tissue dependent, and its functions in the liver, skeletal muscle, adipose tissue, brain, and immune cells cannot simply be substituted for one another.

5.2 SIRT2: Vascular, Cardiac, and Nervous Systems

SIRT2 can deacetylate α-tubulin, metabolic enzymes, and transcriptional regulators and participates in cell-cycle control and cytoplasmic proteostasis. The SIRT2–p66Shc–mitochondrial reactive oxygen species axis is associated with vascular aging, whereas the SIRT2–STAT3–CDKN2B axis participates in cardiac aging. SIRT2 inhibition may be protective in some models of neuroinflammation and neurodegenerative disease, indicating that its regulatory effects cannot be interpreted independently of disease stage and cell type.

5.3 SIRT3–5: Regulation of Mitochondrial Acylation

SIRT3 primarily removes acetylation from mitochondrial proteins, SIRT4 participates in the regulation of amino acid and lipid metabolism and insulin secretion, and SIRT5 principally controls protein succinylation, malonylation, and glutarylation. Together, these three members form a regulatory network for mitochondrial protein acylation. Changes in their functions can affect the respiratory chain, urea cycle, fatty acid oxidation, and redox homeostasis.

5.4 SIRT6: Genomic Stability and Lifespan Regulation

SIRT6 participates in DNA repair, telomere maintenance, chromatin stability, and the regulation of glucose and lipid metabolism. SIRT6 overexpression can extend lifespan and reduce frailty in certain mouse models, but its effects are influenced by sex, genetic background, and metabolic status. SIRT6 deficiency can cause severe genomic instability and premature-aging-like phenotypes, indicating that SIRT6 has a fundamental role in tissue homeostasis.

5.5 SIRT7: Nucleolar Function and Proteostasis

SIRT7 is primarily localized to the nucleolus and nucleus and participates in ribosomal RNA transcription, ribosome biogenesis, chromatin maintenance, and stress responses. SIRT7 dysfunction can affect the homeostasis of cells with high protein-synthesis demands and is associated with aging phenotypes in the heart, liver, and hematopoietic system.

6 Can Sirtuins Really Extend Human Lifespan?

6.1 Evidence for Lifespan Extension in Model Organisms

Increased yeast Sir2 expression can extend replicative lifespan under specific genetic and culture conditions. Some Sirtuin studies in nematodes and fruit flies have also observed lifespan changes. These findings are influenced by genetic background, dietary composition, transgene expression levels, and the definition of lifespan, and not all experiments have produced consistent results.

6.2 Evidence for Improved Healthspan in Mammals

In mice, enhancement of SIRT1-, SIRT2-, SIRT3-, or SIRT6-related functions can improve insulin sensitivity, exercise capacity, cardiovascular function, neurological status, and inflammatory conditions in certain models. Studies of SIRT6 overexpression and some SIRT1 activators have reported lifespan extension, but the effects are not entirely consistent across sexes, diets, and genetic backgrounds. Many studies provide clearer support for improved healthspan.

6.3 Boundaries of Evidence from Human Studies

Human studies currently focus mainly on Sirtuin expression, genetic variation, NAD⁺ metabolic levels, and interventions involving resveratrol, SRT2104, nicotinamide riboside, and nicotinamide mononucleotide. Some studies have observed changes in metabolic, inflammatory, or tissue-function indicators, but direct evidence that Sirtuin activation can extend the maximum human lifespan has not been established.

6.4 Healthspan Is Not Equivalent to Maximum Lifespan

Reducing metabolic abnormalities, frailty, inflammation, or organ dysfunction may improve healthspan without necessarily changing the maximum lifespan of a species. Determining whether Sirtuins exert longevity-promoting effects requires distinguishing among mean lifespan, median lifespan, maximum lifespan, disease burden, and disease-free survival. Conclusions cannot be drawn solely from changes in a single metabolic indicator or cellular-senescence marker.

7 Chemical Regulation of Sirtuins

7.1 Resveratrol and Other Natural Products

Resveratrol can enhance SIRT1-related metabolic and stress-response pathways, but its effects also involve AMPK, phosphodiesterases, redox signaling, and other targets. Direct activation of SIRT1 by resveratrol is dependent on substrate sequence, and not all biological effects of resveratrol can be regarded as SIRT1-specific activation.

7.2 Synthetic SIRT1-Activating Compounds

SRT1720 and SRT2104 are synthetic Sirtuin-activating compounds that enhance SIRT1 catalytic activity under specific substrate conditions and are used in studies of metabolism, inflammation, neurodegenerative changes, and healthspan. Their evaluation should combine direct enzyme-activity measurements, substrate deacetylation assays, and SIRT1 genetic-deficiency controls to distinguish SIRT1-dependent effects from nonspecific metabolic changes.

7.3 Sirtuin Inhibitors

Small-molecule inhibitors are available for SIRT1, SIRT2, and other family members. AGK2, AGK7, AK-1, AK-7, and SirReal 2 are primarily used in SIRT2-related research, whereas Salermide, Cambinol, and Sirtinol can affect both SIRT1 and SIRT2. Selectivity may vary with concentration, substrate, and experimental system. Inhibitor treatment should therefore be validated by measuring substrate acylation levels and using genetic interventions.

7.4 Targeted Protein Degradation

PROTAC Sirt2 Degrader-1 recruits an E3 ubiquitin ligase to induce SIRT2 protein degradation, thereby removing both the catalytic activity and noncatalytic scaffolding functions of SIRT2. Comparison with catalytic SIRT2 inhibitors can help distinguish phenotypes caused by enzymatic inhibition from those caused by complete loss of the protein.

7.5 NAD⁺ Precursor Supplementation

Nicotinamide riboside and nicotinamide mononucleotide can enter the NAD⁺ salvage pathway and increase NAD⁺ availability in certain cells and tissues. NAD⁺ precursors simultaneously affect Sirtuins, PARP, CD38, and redox metabolism. Dependence on a specific Sirtuin member can only be supported if the effect is concurrently attenuated by Sirtuin knockdown, inhibition, or catalytic inactivation.

8 Products Related to Sirtuins

8.1 Sirtuin Activators, Inhibitors, and Degraders

8.2 Recombinant Proteins and Antibodies

8.3 SIRT1–7 Human Protein Quantification Products

Through NAD⁺-dependent deacylation, Sirtuins regulate metabolism, genomic stability, mitochondrial function, and inflammation. Current evidence primarily supports their ability to improve healthspan but does not demonstrate that they can extend the maximum human lifespan.

References

[1] Ziętara P, et al. Why Is Longevity Still a Scientific Mystery? Sirtuins-Past, Present and Future. Int J Mol Sci. 2022 Dec 31;24(1):728.

[2] Wu QJ, et al. The sirtuin family in health and disease. Signal Transduct Target Ther. 2022 Dec 29;7(1):402.

[3] Grootaert MOJ, et al. Sirtuins in atherosclerosis: guardians of healthspan and therapeutic targets. Nat Rev Cardiol. 2022 Oct;19(10):668-683.

[4] Kaeberlein M, et al. The SIR2/3/4 complex and SIR2 alone promote longevity in Saccharomyces cerevisiae by two different mechanisms. Genes Dev. 1999 Oct 1;13(19):2570-2580.

[5] Roichman A, et al. Restoration of energy homeostasis by SIRT6 extends healthy lifespan. Nat Commun. 2021 May 28;12(1):3208.

[6] Zhang Y, et al. Sirtuin 2 deficiency aggravates ageing-induced vascular remodelling in humans and mice. Eur Heart J. 2023 Aug 1;44(29):2746-2759.

[7] Fernández-Ruiz I. Sirtuin 2 protects against cardiac ageing. Nat Rev Cardiol. 2023 Dec;20(12):796.

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[1] Resveratrol

[2] Methods of observation and detection of cellular autophagy processes