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Sirtuin 1
Sirtuin 1
Sirtuin 1
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SIRT1
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesSIRT1, SIR2L1, SIR2, hSIR2, SIR2alpha, Sirtuin 1
External IDsOMIM: 604479; MGI: 2135607; HomoloGene: 56556; GeneCards: SIRT1; OMA:SIRT1 - orthologs
Orthologs
SpeciesHumanMouse
Entrez

23411

93759

Ensembl

ENSG00000096717

ENSMUSG00000020063

UniProt

Q96EB6

Q923E4

RefSeq (mRNA)

NM_001142498
NM_001314049
NM_012238

NM_001159589
NM_001159590
NM_019812

RefSeq (protein)

NP_001135970
NP_001300978
NP_036370

NP_001153061
NP_062786

Location (UCSC)Chr 10: 67.88 – 67.92 MbChr 10: 63.15 – 63.22 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Sirtuin 1, also known as NAD-dependent deacetylase sirtuin-1, is a protein that in humans is encoded by the SIRT1 gene.[5][6][7]

SIRT1 stands for sirtuin (silent mating type information regulation 2 homolog) 1 (S. cerevisiae), referring to the fact that its sirtuin homolog (biological equivalent across species) in yeast (Saccharomyces cerevisiae) is Sir2. SIRT1 is an enzyme located primarily in the cell nucleus that deacetylates transcription factors that contribute to cellular regulation (reaction to stressors, longevity).[8][9]

Function

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Sirtuin 1 is a member of the sirtuin family of proteins, homologs of the Sir2 gene in S. cerevisiae. Members of the sirtuin family are characterized by a sirtuin core domain and grouped into four classes. The functions of human sirtuins have not yet been determined; however, yeast sirtuin proteins are known to regulate epigenetic gene silencing and suppress recombination of rDNA. The protein encoded by this gene is included in class I of the sirtuin family.[6]

Sirtuin 1 is downregulated in cells that have high insulin resistance.[10] Furthermore, SIRT1 was shown to de-acetylate and affect the activity of both members of the PGC1-alpha/ERR-alpha complex, which are essential metabolic regulatory transcription factors.[11][12]

In vitro, SIRT1 has been shown to deacetylate and thereby deactivate the p53 protein,[13] and may have a role in activating T helper 17 cells.[14]

Selective ligands

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Activators

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  • Lamin A is a protein that had been identified as a direct activator of Sirtuin 1 during a study on progeria.[15]
  • Resveratrol has been claimed to be an activator of sirtuin 1,[16] but this effect has been disputed based on the fact that the initially used activity assay, using a non-physiological substrate peptide, can produce artificial results.[17][18] Resveratrol increases the expression of SIRT1, meaning that it does increase the activity of SIRT1, though not necessarily by direct activation.[10] However, resveratrol was later shown to directly activate Sirtuin 1 against non-modified peptide substrates.[19][20] Resveratrol also enhances the binding between Sirtuin 1 and Lamin A.[15] In addition to resveratrol, a range of other plant-derived polyphenols have also been shown to interact with SIRT1.[21]
  • SRT-1720 was also claimed to be an activator,[16] but this now has been questioned.[22]
  • Methylene blue[23] by increasing NADH/NAD+ ratio.
  • Metformin activates both PRKA and SIRT1.[24]

Although neither resveratrol or SRT1720 directly activate SIRT1, resveratrol, and probably SRT1720, indirectly activate SIRT1 by activation of AMP-activated protein kinase (AMPK),[25] which increases NAD+ levels (which is the cofactor required for SIRT1 activity).[26][27] Elevating NAD+ is a more direct and reliable way to activate SIRT1.[27]

Inhibitors

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Interactions

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Sirtuin 1 has been shown in vitro to interact with ERR-alpha[11] and AIRE.[28]

Human Sirt1 has been reported having 136 direct interactions in interactomic studies involved in numerous processes.[29]

Yeast homolog

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Sir2 (whose homolog in mammals is known as SIRT1) was the first of the sirtuin genes to be found. It was found in budding yeast, and, since then, members of this highly conserved family have been found in nearly all organisms studied.[30] Sirtuins are hypothesized to play a key role in an organism's response to stresses (such as heat or starvation) and to be responsible for the lifespan-extending effects of calorie restriction.[31][32]

The three letter yeast gene symbol Sir stands for Silent Information Regulator while the number 2 is representative of the fact that it was the second SIR gene discovered and characterized.[33][34]

In the roundworm, Caenorhabditis elegans, Sir-2.1 is used to denote the gene product most similar to yeast Sir2 in structure and activity.[35][36]

Method of action and observed effects

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Sirtuins act primarily by removing acetyl groups from lysine residues within proteins in the presence of NAD+; thus, they are classified as "NAD+-dependent deacetylases" and have EC number 3.5.1.[37] They add the acetyl group from the protein to the ADP-ribose component of NAD+ to form O-acetyl-ADP-ribose. The HDAC activity of Sir2 results in tighter packaging of chromatin and a reduction in transcription at the targeted gene locus. The silencing activity of Sir2 is most prominent at telomeric sequences, the hidden MAT loci (HM loci), and the ribosomal DNA (rDNA) locus (RDN1) from which ribosomal RNA is transcribed.

Limited overexpression of the Sir2 gene results in a lifespan extension of about 30%,[38] if the lifespan is measured as the number of cell divisions the mother cell can undergo before cell death. Concordantly, deletion of Sir2 results in a 50% reduction in lifespan.[38] In particular, the silencing activity of Sir2, in complex with Sir3 and Sir4, at the HM loci prevents simultaneous expression of both mating factors which can cause sterility and shortened lifespan.[39] Additionally, Sir2 activity at the rDNA locus is correlated with a decrease in the formation of rDNA circles. Chromatin silencing, as a result of Sir2 activity, reduces homologous recombination between rDNA repeats, which is the process leading to the formation of rDNA circles. As accumulation of these rDNA circles is the primary way in which yeast are believed to "age", then the action of Sir2 in preventing accumulation of these rDNA circles is a necessary factor in yeast longevity.[39]

Starving of yeast cells leads to a similarly extended lifespan, and indeed starving increases the available amount of NAD+ and reduces nicotinamide, both of which have the potential to increase the activity of Sir2. Furthermore, removing the Sir2 gene eliminates the life-extending effect of caloric restriction.[40] Experiments in the nematode Caenorhabditis elegans and in the fruit fly Drosophila melanogaster[41] support these findings. As of 2006, experiments in mice are underway.[31]

However, some other findings call the above interpretation into question. If one measures the lifespan of a yeast cell as the amount of time it can live in a non-dividing stage, then silencing the Sir2 gene actually increases lifespan [42] Furthermore, calorie restriction can substantially prolong reproductive lifespan in yeast even in the absence of Sir2.[43]

In organisms more complicated than yeast, it appears that Sir2 acts by deacetylation of several other proteins besides histones.

In the fruit fly Drosophila melanogaster, the Sir2 gene does not seem to be essential; loss of a sirtuin gene has only very subtle effects.[40] However, mice lacking the SIRT1 gene (the sir2 biological equivalent) were smaller than normal at birth, often died early or became sterile.[44]

Inhibition of SIRT1

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Human aging is characterized by a chronic, low-grade inflammation level,[45] and the pro-inflammatory transcription factor NF-κB is the main transcriptional regulator of genes related to inflammation.[46] SIRT1 inhibits NF-κB-regulated gene expression by deacetylating the RelA/p65 subunit of NF-κB at lysine 310.[47][48] But NF-κB more strongly inhibits SIRT1. NF-κB increases the levels of the microRNA miR-34a (which inhibits nicotinamide adenine dinucleotide NAD+ synthesis) by binding to its promoter region,[49] resulting in lower levels of SIRT1.

Both the SIRT1 enzyme and the poly ADP-ribose polymerase 1 (PARP1) enzyme require NAD+ for activation.[50] PARP1 is a DNA repair enzyme, so in conditions of high DNA damage, NAD+ levels can be reduced 20–30% thereby reducing SIRT1 activity.[50]

Homologous recombination

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SIRT1 protein actively promotes homologous recombination (HR) in human cells, and likely promotes recombinational repair of DNA breaks.[51] SIRT1-mediated HR requires the WRN protein.[51] WRN protein functions in double-strand break repair by HR.[52] WRN protein is a RecQ helicase, and in its mutated form gives rise to Werner syndrome, a genetic condition in humans characterized by numerous features of premature aging. These findings link SIRT1 function to HR, a DNA repair process that is likely necessary for maintaining the integrity of the genome during aging.[51]

References

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Sirtuin 1

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Sirtuin 1 (SIRT1) is an NAD⁺-dependent protein deacetylase enzyme belonging to the sirtuin family of class III deacetylases, which are conserved from to mammals and play essential roles in cellular regulation. It functions primarily in the nucleus but can translocate to the , where it deacetylates both histones and non-histone proteins to modulate , , stress resistance, inflammation, and . As the closest mammalian homolog to Sir2, SIRT1 is a key sensor of cellular energy status, with its activity tightly linked to NAD⁺ levels, enabling adaptive responses to nutritional and environmental stresses. SIRT1 was first identified in 1999 through the cloning and characterization of human cDNAs encoding sirtuin homologs of Sir2, revealing it as one of seven mammalian sirtuins (SIRT1–7) with a 747-amino-acid structure featuring a conserved catalytic core of approximately 275 residues flanked by variable N- and C-terminal domains. This core domain binds NAD⁺ and facilitates deacetylation, producing , 2'-O-acetyl-ADP-ribose, and deacetylated substrates as byproducts. Early studies highlighted its role in silencing genes and extending lifespan in , prompting investigations into its mammalian functions, including reported activation by compounds like identified in 2003, although the direct mechanism remains debated; synthetic small-molecule activators such as the SRT series have been developed. In metabolism, SIRT1 promotes insulin sensitivity, glucose uptake, and lipid oxidation by deacetylating and activating targets such as PGC-1α, PPAR-α, and AMPK, while suppressing gluconeogenesis during fasting to maintain energy homeostasis. It also influences aging by mitigating oxidative stress, genomic instability, and cellular senescence through interactions with p53 and NF-κB, potentially extending lifespan in model organisms. In disease contexts, SIRT1 exhibits protective effects against neurodegeneration, cardiovascular disorders, diabetes complications, and inflammatory conditions like COPD and asthma by enhancing autophagy and reducing apoptosis, though it displays context-dependent dual roles in cancer, where it can either suppress or promote tumorigenesis depending on the tissue and stage. Due to these multifaceted roles, SIRT1 is a promising therapeutic target; as of 2025, activators including synthetic compounds like SRT2104 are in advanced clinical development for anti-aging, metabolic, and neuroprotective interventions.

Discovery and Molecular Basics

Discovery and Nomenclature

Sirtuin 1 (SIRT1) was identified in 1999 through a bioinformatics search for homologs of the Silent Information Regulator 2 (Sir2) protein, which is known for its role in epigenetic . In this seminal study, researcher Roger A. Frye characterized five human cDNAs encoding Sir2-like proteins, with SIRT1 exhibiting the highest to yeast Sir2p among the identified genes. These proteins were proposed to metabolize NAD+ and potentially possess ADP-ribosyltransferase activity, based on observations from bacterial homologs, marking the initial recognition of SIRT1 as part of a conserved family of NAD+-dependent enzymes across eukaryotes and prokaryotes. The nomenclature "sirtuin" was coined in this discovery work, deriving from "Sir2-like" to reflect the structural and functional similarities to the silencing proteins. The symbol SIRT1 was assigned to the human ortholog, located on chromosome 10q21.3, spanning approximately 33.7 kb with 11 exons. This naming convention extended to the broader family (SIRT1–7 in mammals), emphasizing their evolutionary conservation and shared catalytic core domain. Initial characterization linked SIRT1 to deacetylation activity in 2001, when it was demonstrated to function as an NAD+-dependent deacetylase of the tumor suppressor p53, thereby modulating p53-dependent transcriptional responses to DNA damage. This finding built on the yeast Sir2 precedent for gene silencing, suggesting SIRT1's involvement in similar repressive mechanisms through histone and non-histone protein deacetylation, though early assays also explored its potential ADP-ribosylation role.

Gene Structure and Expression

The human SIRT1 gene is located on 10q21.3 and spans approximately 33.7 kb, consisting of 11 exons that encode the NAD+-dependent deacetylase sirtuin-1 protein. This genomic organization reflects its evolutionary conservation as the mammalian ortholog of the Sir2 protein, which plays a key role in silencing and longevity pathways. The promoter region of SIRT1 contains binding sites for transcription factors such as and FOXO family members, which regulate its expression in response to cellular stress and metabolic cues; for instance, and FOXO3a bind to shared sites to promote SIRT1 transcription under conditions. SIRT1 exhibits high basal expression in metabolically active tissues, including the brain, heart, kidney, and liver, where it supports energy homeostasis and stress resistance. Its expression is upregulated during calorie restriction, enhancing longevity-associated pathways in multiple tissues such as muscle and adipose. Conversely, SIRT1 levels decline in aging tissues, contributing to reduced cellular resilience in organs like the brain and vascular endothelium. Alternative splicing of the SIRT1 pre-mRNA generates multiple isoforms, increasing functional diversity; notable variants include SIRT1-ΔExon8, which lacks part of the deacetylase domain and predominates under stress conditions, and other exon-skipping forms that modulate protein stability and activity. Epigenetic mechanisms further fine-tune SIRT1 expression, with of its promoter region leading to in pathological contexts such as induced by environmental factors like betel quid chewing; modifications, including at promoter-associated sites, also influence transcriptional accessibility.

Protein Structure and Catalytic Mechanism

Structural Features

Sirtuin 1 (SIRT1), the mammalian ortholog of Sir2, is a 747-amino-acid protein with a modular that includes an extended N-terminal domain, a conserved central catalytic core, and a C-terminal extension. The N-terminal domain, spanning residues 1–239, encompasses regulatory elements such as nuclear localization signals and sites for post-translational modifications that influence SIRT1 localization and activity. The C-terminal region, beyond the core, contributes to substrate specificity and allosteric control through intramolecular interactions. The catalytic core domain, comprising approximately residues 240–525, adopts a characteristic bilobal fold conserved across the sirtuin family. This core consists of a large Rossmann fold —formed by a six-stranded parallel β-sheet surrounded by α-helices—that binds the coenzyme NAD⁺, and a smaller zinc-binding featuring a three-stranded antiparallel β-sheet coordinated by a Zn²⁺ via four invariant residues (C371, C374, C395, C398). A deep cleft between the two subdomains serves as the substrate-binding site, accommodating acetylated residues of target proteins. Flexible linker regions, particularly around residues 230–240 and 520–540, connect these elements and permit dynamic conformational shifts for and . High-resolution crystal structures have elucidated these features in detail. The 2.5 Å structure of the human SIRT1 catalytic domain (residues 241–516) bound to NAD⁺ (PDB ID: 4I5I) highlights the open conformation of the Rossmann and zinc-binding lobes, with the NAD⁺ nicotinamide ring positioned near the catalytic (H363) in the cleft. Structures of activator-bound forms, such as the complex with and a fluorogenic substrate (PDB ID: 5BTR), reveal allosteric stabilization of a closed conformation, where the activator occupies a hydrophobic pocket adjacent to the substrate-binding cleft, promoting docking without directly interacting with the . These insights underscore the structural basis for SIRT1's allosteric modulation by small molecules and protein partners.

Enzymatic Activity and NAD+ Dependence

Sirtuin 1 (SIRT1) functions as a class III (HDAC), catalyzing the NAD+-dependent removal of acetyl groups from ε-amino groups of residues in protein substrates. This enzymatic activity couples deacetylation to the of NAD+, producing (NAM), 2'-O-acetyl-ADP-ribose (2'-OAADPR), and the deacetylated substrate as products. Unlike zinc-dependent classes I, II, and IV HDACs, SIRT1 relies on the β-nicotinamide ring of NAD+ for , linking its activity directly to cellular NAD+ levels and metabolic status. The reaction mechanism involves sequential binding of NAD+ and the acetylated substrate to the SIRT1 catalytic core, followed by nucleophilic attack of the substrate's lysine ε-nitrogen on the C1' carbon of NAD+'s ribose, which displaces NAM and forms a transient ADP-ribosyl-lysine imidate intermediate. In the subsequent deacylation step, His363 serves as a general base to deprotonate an activated water molecule, enabling its nucleophilic attack on the acetyl carbonyl of the intermediate and yielding the deacetylated product and 2'-OAADPR. The base exchange reaction, where NAM rebinds to the imidate instead of water, regenerates NAD+ and the acetylated substrate, acting as a reversible regulatory pathway; NAM further inhibits SIRT1 through noncompetitive product feedback, reducing catalytic efficiency.01121-4) Kinetic parameters for SIRT1 deacetylation include a Michaelis constant (Km) of approximately 50 μM for NAD+ and ~10 μM for acetyl-lysine substrates, reflecting moderate affinity that allows responsiveness to physiological NAD+ fluctuations. Allosteric activation, often substrate-specific and involving conformational changes at an auxiliary site near the substrate-binding tunnel, can enhance the maximum velocity (Vmax) by 2- to 5-fold without altering Km for NAD+, thereby increasing overall throughput for select acetylated peptides. The structural basis for NAD+ binding resides in the conserved Rossmann fold domain of the catalytic core, which accommodates the dinucleotide cofactor in an extended conformation essential for .34533-6/fulltext)

Biological Functions

Metabolic Regulation

SIRT1 plays a central role in maintaining by modulating key metabolic pathways in response to nutritional cues such as . During states, SIRT1 is upregulated in the liver, where it deacetylates the transcriptional coactivator PGC-1α, enhancing its activity to promote the expression of genes involved in and fatty acid β-oxidation. This deacetylation activates PGC-1α's interaction with s like FOXO1 and PPARα, thereby increasing hepatic glucose production to sustain blood glucose levels and mobilizing s for utilization. Similarly, SIRT1 deacetylates FOXO1, a forkhead , which further amplifies gluconeogenic gene expression, including (PEPCK) and glucose-6-phosphatase (G6Pase), ensuring adaptive metabolic shifts during nutrient deprivation. These mechanisms, including deacetylation of PGC-1α for mitochondrial biogenesis and FOXO1 for metabolic regulation, are particularly relevant in kidney tissues, where they improve fatty acid oxidation, reduce lipotoxicity, and balance energy homeostasis, especially in conditions like diabetic nephropathy. In addition to hepatic metabolism, SIRT1 contributes to , a process essential for (OXPHOS) and overall energy efficiency. SIRT1 directly deacetylates and activates the orphan ERRα, a key regulator of mitochondrial genes, leading to upregulated expression of OXPHOS components such as cytochrome c oxidase subunits. This activation is complemented by SIRT1's deacetylation of PGC-1α, which coactivates ERRα to drive mitochondrial proliferation and function, particularly in muscle and other energy-demanding tissues, including the kidneys for maintaining energy homeostasis under stress. SIRT1's effects on are interconnected with the AMPK pathway; AMPK activation during energy stress elevates NAD+ levels, thereby stimulating SIRT1 activity and reinforcing PGC-1α/ERRα signaling for enhanced mitochondrial capacity. SIRT1 is critically involved in insulin sensitivity and , with its dysregulation linked to pathogenesis. In insulin-resistant states, such as those observed in high-fat diet models, SIRT1 expression is downregulated in adipose and liver tissues, correlating with impaired and elevated hepatic glucose output. Studies in SIRT1 knockout models, particularly liver-specific deletions, demonstrate disrupted AKT signaling and reduced insulin-mediated suppression of , resulting in and impaired overall . This underscores SIRT1's protective role against metabolic dysfunction, where its activation could mitigate by restoring balanced glucose handling.

Cellular Stress Response and Longevity

Sirtuin 1 (SIRT1) plays a pivotal role in the by being activated under conditions of nutrient scarcity, such as , which elevates the NAD⁺/NADH ratio and thereby enhances SIRT1's deacetylase activity. This activation is crucial for promoting cell survival during stress, as SIRT1 deacetylates the tumor suppressor at residue 382, thereby inhibiting p53-mediated transcription of pro-apoptotic genes like Bax and Puma, which suppresses in response to DNA damage or oxidative insults. In this manner, SIRT1 shifts cellular priorities from to repair and adaptation, linking energy sensing to stress resilience. These anti-apoptotic and anti-senescence effects via p53 deacetylation are particularly important in kidney tissues, where they help counter oxidative stress and cellular senescence. In mitigating reactive oxygen species (ROS), SIRT1 regulates the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway by deacetylating Nrf2, which stabilizes the transcription factor and enhances its nuclear translocation to activate antioxidant response element (ARE)-driven genes, including superoxide dismutase (SOD), catalase (CAT), and heme oxygenase-1 (HO-1). This mechanism reduces oxidative damage in cells exposed to stressors like paraquat, preserving cellular integrity. Additionally, SIRT1 contributes to the DNA damage response by interacting with and deacetylating Ku70, a subunit of the Ku heterodimer in non-homologous end joining (NHEJ) repair, thereby promoting the relocation of Ku70 from Bax to DNA breaks and facilitating efficient repair of double-strand breaks induced by radiation or genotoxic agents. In kidneys, SIRT1 promotes autophagy and stress resistance through deacetylation of FOXO1/3, enhancing resilience against renal stressors. SIRT1's involvement in longevity is evidenced by its overexpression, which extends lifespan in model organisms; for instance, sir-2.1 overexpression in Caenorhabditis elegans prolongs mean lifespan through nicotinamide methylation pathways, while brain-specific SIRT1 transgenic mice exhibit delayed aging and up to 15% lifespan extension via hypothalamic regulation of homeobox genes. These effects align with the broader sirtuin pathway in aging, where SIRT1 activation mimics calorie restriction benefits, and recent studies on the SIRT1 activator SRT2104 demonstrate lifespan prolongation in metabolic disease mouse models by alleviating oxidative stress and enhancing neuronal protection.

Transcriptional Control

SIRT1 exerts transcriptional control primarily through its NAD+-dependent deacetylase activity, targeting both histones and non-histone proteins to modulate . As a class III , SIRT1 deacetylates specific lysine residues on histones, such as H3K9 and H4K16, promoting compaction and formation that leads to . This activity is crucial for repressing transcription at euchromatic regions, where deacetylation facilitates the recruitment of repressive complexes and inhibits access, thereby maintaining epigenetic silencing of target genes. Beyond histones, SIRT1 regulates transcription by deacetylating non-histone transcription factors. For instance, SIRT1 deacetylates the /p65 subunit of at 310, which attenuates its transcriptional activity and represses the expression of pro-inflammatory genes such as TNF-α and IL-6. Similarly, in , SIRT1 deacetylates SREBP-1c at key residues, reducing its stability, nuclear occupancy, and transactivation of lipogenic genes like (FASN) and (ACC), thereby inhibiting hepatic during fasting states. SIRT1 also influences circadian through deacetylation of the clock protein PER2. By binding to the CLOCK-BMAL1 complex in a circadian manner, SIRT1 promotes PER2 deacetylation, which enhances its ubiquitination and proteasomal degradation, fine-tuning the amplitude and period of core clock genes like Cry1 and Bmal1 to sustain rhythmic transcription. This mechanism links SIRT1 activity to NAD+ levels, which fluctuate diurnally, ensuring temporal control over metabolic and behavioral outputs.

Ligands and Pharmacological Regulation

Activators

Sirtuin 1 (SIRT1) activators encompass a range of natural and synthetic compounds that enhance its deacetylase activity, primarily through allosteric modulation or by increasing NAD+ availability, thereby influencing metabolic and stress response pathways. Among natural activators, , a found in grapes and , functions as an allosteric activator of SIRT1 by binding to its N-terminal domain, promoting a conformational change that facilitates substrate interaction and increases deacetylation efficiency. This activation has an EC50 of approximately 46 μM in cell-free assays, though the direct enzymatic effects of resveratrol on SIRT1 remain debated due to inconsistencies in substrate-specific activation observed in structural studies. Other natural polyphenols, such as fisetin, have been identified as direct and potent SIRT1 activators in foundational assays, ranking highly among compounds screened for sirtuin activation, while curcumin exhibits less direct activation, was not among the top activators in early polyphenol screens (e.g., Howitz et al., 2003), and its effects are often mediated through AMPK-dependent pathways. Another class of natural activators includes NAD+ precursors such as (NMN), which elevate intracellular NAD+ levels, the essential cosubstrate for SIRT1's catalytic activity, thereby indirectly boosting its function in cellular models of and neurodegeneration. Synthetic activators like SRT2104 represent potent, selective SIRT1 agonists developed through , demonstrating enhanced deacetylase activity and metabolic improvements in preclinical models. In a phase II clinical trial for moderate-to-severe , SRT2104 (up to 1 g daily for 12 weeks) was safe and well-tolerated, with no significant improvements in clinical disease severity scores, but 35% of patients achieved good to excellent histological improvement based on biopsies, alongside favorable profiles. A 2024 review highlights the potential metabolic benefits of SRT2104, including preclinical improvements in insulin sensitivity and , underscoring its therapeutic potential. , a biphenolic compound derived from bark but often explored in synthetic contexts for its , activates SIRT1 signaling by upregulating its expression and downstream pathways like Nrf2 and PGC-1α, as evidenced in models of ischemia-reperfusion injury where it reduced oxidative damage. Physiologically, elevates NAD+ levels by shifting cellular metabolism toward oxidative pathways and reducing NADH accumulation, which activates SIRT1 and contributes to extension in mammalian models. Emerging 2025 research on derivatives, such as methylated analogs, demonstrates their ability to boost SIRT1 activity via the NAMPT/SIRT1 axis in neuronal cell models of chemotherapy-induced (chemobrain), mitigating NAD+ depletion and restoring metabolic in doxorubicin-exposed cultures.

Inhibitors

SIRT1 inhibitors encompass small molecules, natural compounds, and physiological regulators that diminish its deacetylase activity, often by targeting the enzyme directly or indirectly affecting NAD+ availability. These inhibitors play roles in modulating SIRT1-dependent pathways, with selectivity varying among compounds. Among synthetic small-molecule inhibitors, EX-527 (also known as selisistat) is a potent and highly selective SIRT1 antagonist, exhibiting an IC50 of 38 nM in cell-free assays and demonstrating over 200-fold selectivity relative to SIRT2 and SIRT3. This compound binds to the NAD+-binding site of SIRT1, preventing cofactor interaction and thereby inhibiting deacetylation of substrates. Cambinol, another synthetic inhibitor, targets both SIRT1 and SIRT2 with micromolar potency (IC50 values around 56 μM for SIRT1), acting as a broad-spectrum sirtuin blocker; recent 2023 studies have explored its application in cancer models, where it induces senescence-like growth arrest and enhances chemotherapeutic sensitivity by suppressing SIRT1-mediated survival signals. Natural inhibitors include (NAM), a of SIRT1 that acts as a non-competitive inhibitor with respect to NAD+ by binding to an allosteric site, with an inhibition constant (Ki) in the low micromolar range (approximately 5-20 μM depending on conditions). Sirtinol, a naphthol-based derivative, serves as a reversible inhibitor of SIRT1 ( 131 μM) and SIRT2 ( 38 μM), with no effect on class I HDACs, and it promotes and in cancer cells by blocking SIRT1's prosurvival functions. Physiological downregulation of SIRT1 occurs through microRNA-mediated mechanisms, notably miR-34a, which binds to the 3' untranslated region of SIRT1 mRNA, repressing its translation and leading to reduced protein levels; this p53-responsive pathway fine-tunes SIRT1 expression in response to stress. Additionally, during DNA damage, poly(ADP-ribose) polymerase 1 (PARP1) competes with SIRT1 for the shared NAD+ pool, as PARP1 hyperactivation consumes up to 80% of cellular NAD+, thereby limiting SIRT1's cofactor availability and attenuating its activity.

Protein Interactions

Key Interacting Partners

Sirtuin 1 (SIRT1) engages in a wide array of protein-protein interactions that modulate its deacetylase activity and cellular localization. According to the STRING database, human SIRT1 participates in numerous predicted functional interactions, encompassing transcription factors, coactivators, and repair proteins, based on experimental, computational, and literature-derived evidence. Key interacting partners include the tumor suppressor p53, which SIRT1 deacetylates at lysine 382 (K382) to regulate its transcriptional activity. SIRT1 also binds the transcriptional coactivator PGC-1α (peroxisome proliferator-activated receptor gamma coactivator 1-alpha), targeting multiple lysine residues for deacetylation, thereby influencing mitochondrial biogenesis and energy metabolism. Similarly, SIRT1 interacts with the forkhead box O transcription factor FOXO3, deacetylating it at lysines K290 and K291 to enhance its nuclear retention and stress response functions. Additional prominent partners involve Ku70, a component of the DNA-dependent protein kinase complex, where SIRT1 binding promotes Ku70 deacetylation and facilitates repair of DNA double-strand breaks. In lipid homeostasis, SIRT1 associates with the nuclear receptor LXRα (liver X receptor alpha), deacetylating it to augment its role in cholesterol efflux and reverse cholesterol transport. Specific binding domains on SIRT1 mediate these associations; for instance, the N-terminal region interacts with DBC1 (deleted in breast cancer 1), an endogenous inhibitor that competes for substrate access. Conversely, the C-terminus of SIRT1 engages AROS (active regulator of SIRT1), a positive modulator that stabilizes SIRT1's active conformation. These interactions collectively fine-tune SIRT1's enzymatic output in response to cellular cues.

Functional Consequences of Interactions

The interaction between SIRT1 and leads to deacetylation of at 382, which represses transcriptional activity and thereby inhibits -dependent , promoting cell survival in response to DNA damage and . This mechanism allows cells to endure genotoxic insults without undergoing , as demonstrated in mammalian systems where SIRT1 overexpression similarly attenuates -mediated apoptotic responses. SIRT1 deacetylates the transcriptional coactivator PGC-1α, enhancing its activity and thereby promoting , oxidative metabolism, and overall mitochondrial function. Disruption of this SIRT1-PGC-1α interaction, as observed in hepatocyte-specific SIRT1 models, impairs oxidation and mitochondrial , contributing to hepatic and features of under high-fat dietary conditions. Within broader protein networks, scaffold proteins such as DBC1 (also known as CCAR2) bind directly to SIRT1 and inhibit its deacetylase activity, thereby modulating SIRT1-dependent downstream effects on cellular metabolism and stress responses. Recent studies have further elucidated how post-translational modifications, like ISGylation of SIRT1, disrupt this DBC1-SIRT1 association to restore SIRT1 function. Additionally, SIRT1 deacetylates the p65 subunit of , suppressing its transcriptional activation and facilitating resolution of inflammatory responses, as evidenced by 2024 investigations into SIRT1 activators that enhance this inhibitory axis to mitigate chronic inflammation.

Evolutionary Homologs

Yeast Homolog Sir2

Sir2, the founding member of the sirtuin family, serves as the primary ortholog of mammalian SIRT1 in the budding Saccharomyces cerevisiae. This NAD+-dependent deacetylase consists of 562 and exhibits predominant nuclear localization, where it associates with to modulate . A core function of Sir2 involves deacetylating s, particularly at residues on histone H4 and H3, which promotes the formation of and transcriptional silencing at ribosomal (rDNA) repeats. This activity represses recombination events within the rDNA locus, thereby stabilizing genome integrity and preventing the accumulation of extrachromosomal rDNA circles (ERCs), which are toxic aging factors in . Experimental evidence from and silencing assays demonstrates that Sir2 recruitment to rDNA requires interactions with nucleolar proteins like Net1, forming the RENT complex essential for silencing. Sir2 plays a pivotal role in yeast replicative lifespan regulation, where mother cells bud off daughters a finite number of times before . Overexpression of Sir2, achieved via extra genomic copies, extends replicative lifespan by approximately 30% in wild-type strains by enhancing rDNA silencing and reducing ERC formation. Conversely, deletion of SIR2 shortens replicative lifespan by about 50%, underscoring Sir2 as a limiting factor in pathways independent of its roles in mating-type or telomeric silencing. These effects were quantified through microdissection assays tracking daughter cell production from single mother cells. Calorie restriction (CR), a reduction in glucose availability, mimics Sir2 activation to extend lifespan, establishing a for sirtuin-mediated metabolic sensing. Seminal studies from 2000 showed that CR elevates NAD+ levels, boosting Sir2 deacetylase activity and replicative lifespan extension in a Sir2-dependent manner. Subsequent between 2005 and 2020 refined this model, revealing that while Sir2 accounts for part of CR's benefits through enhanced , parallel Sir2-independent pathways contribute to , as evidenced by additive lifespan extensions in sir2 mutants under CR. This body of work, including genetic and biochemical analyses, solidified Sir2's role in linking nutrient sensing to chromatin-based lifespan control.

Comparative Roles in Mammals

Mammalian sirtuins represent an evolutionary expansion from the single Sir2 protein in , resulting in seven homologs (SIRT1–SIRT7) that have diversified to regulate complex physiological processes in multicellular organisms. This diversification is evident in structural adaptations, such as the extended N-terminal domain in human SIRT1, which spans approximately 200 and facilitates interactions with regulatory proteins like AROS and DBC1, enabling nuanced control of its activity beyond the simpler regulation in Sir2. The core catalytic domain of SIRT1 exhibits approximately 40% sequence identity to that of Sir2, preserving the NAD+-dependent deacetylase mechanism while allowing for mammalian-specific functions in response to metabolic and stress signals. In terms of subcellular localization and primary functions, SIRT1 operates predominantly in the nucleus but can shuttle to the , where it emphasizes transcriptional regulation by deacetylating key factors such as , FOXO, and PGC-1α to modulate related to and stress response. In contrast, SIRT6 is strictly nuclear and more oriented toward processes, including and telomere maintenance through histone H3K9 and H3K56 deacetylation, thereby protecting genomic stability during aging and stress. SIRT7, primarily localized to the , focuses on ribosomal RNA synthesis and chromatin organization, deacetylating targets like histone H3K18 and components to influence nucleolar function and . These differences highlight how SIRT1's broader transcriptional scope complements the specialized DNA maintenance role of SIRT6 and the rRNA-centric activities of SIRT7. Despite this conservation in the catalytic core, mammalian sirtuins exhibit divergent roles in complex tissues, driven by tissue-specific expression patterns that adapt to organ-specific demands. For instance, SIRT1 shows relatively lower expression in the compared to other sirtuins like SIRT2, allowing for specialized neural regulation of and , whereas SIRT6 maintains higher levels in tissues requiring robust , such as the liver and heart. This tissue-specific divergence underscores the evolutionary adaptation of the sirtuin family to support mammalian in diverse physiological contexts, from metabolic adaptation in to genomic integrity in proliferative organs.

Roles in Disease and Therapeutics

Involvement in Cancer

Sirtuin 1 (SIRT1) exhibits a in cancer, functioning as a tumor suppressor in certain contexts by deacetylating key transcription factors such as and FOXO family members, which promotes and inhibits uncontrolled proliferation. Deacetylation of by SIRT1 reduces its transcriptional activity on pro-apoptotic genes, while simultaneously enhancing FOXO-mediated expression of cell cycle inhibitors like p21 and p27, thereby inducing replicative in response to genotoxic stress. This mechanism contributes to tumor suppression, as evidenced in models where SIRT1 activation limits replicative lifespan and prevents . In , SIRT1 expression is frequently downregulated, correlating with advanced tumor stages and poorer , with studies indicating reduced levels in a substantial subset of cases, potentially disrupting senescence pathways and facilitating tumorigenesis.00172-5) Conversely, SIRT1 can promote oncogenesis in other cancers by inhibiting and enhancing survival signaling. In , particularly , SIRT1 overexpression suppresses death receptor-mediated by stabilizing the anti-apoptotic protein c-FLIP via deacetylation of Ku70, with context-dependent effects highlighted in 2024 investigations showing that SIRT1 inhibition sensitizes leukemic cells to extrinsic apoptotic pathways. Similarly, in , SIRT1 is upregulated, contributing to tumor progression and resistance to therapy through various mechanisms, including modulation of activity and signaling. This pro-tumorigenic activity underscores SIRT1's role in maintaining cancer cell viability across diverse malignancies.

Implications in Metabolic and Neurodegenerative Diseases

Sirtuin 1 (SIRT1) plays a protective role in metabolic diseases by enhancing insulin sensitivity and mitigating . Activation of SIRT1 in liver, , and adipose tissues improves insulin signaling pathways, thereby counteracting the development of associated with . In preclinical models, SIRT1 overexpression or pharmacological activation reduces hepatic glucose output and promotes in peripheral tissues, demonstrating its potential to alleviate . Furthermore, SIRT1 agonists, such as , have been shown to attenuate hepatic steatosis and lipid metabolic disorders in high-fat diet-induced mouse models of non-alcoholic fatty liver disease (NAFLD), partly by modulating genes and enhancing defenses. In the context of obesity-related inflammation, SIRT1 exerts anti-inflammatory effects by suppressing signaling, a key regulator of pro-inflammatory responses in . This suppression inhibits the production of cytokines like TNF-α and IL-6, which contribute to chronic low-grade in obesity and exacerbate . Studies in obese models indicate that SIRT1 deficiency amplifies activation in macrophages and adipocytes, linking reduced SIRT1 activity to obesity-associated metabolic dysfunction. In renal diseases, particularly diabetic nephropathy, SIRT1 exerts protective effects through multiple deacetylation-dependent mechanisms. Deacetylation of transcription factors such as NF-κB reduces inflammation by inactivating p65 and suppressing pro-inflammatory cytokine production. SIRT1 promotes autophagy and stress resistance by deacetylating FOXO1 and FOXO3, enhancing their transcriptional activity to protect kidney cells from oxidative damage and senescence. It also enhances mitochondrial biogenesis via deacetylation of PGC-1α, improving energy metabolism and reducing mitochondrial dysfunction in diabetic conditions. Fibrosis is inhibited through repression of HIF-2α and deacetylation of Smad3/4 in TGF-β signaling pathways, attenuating extracellular matrix deposition and epithelial-mesenchymal transition. Anti-apoptotic and anti-senescence effects are mediated by deacetylation of p53, preventing cell death and cellular senescence in response to stress. Additionally, SIRT1 counters oxidative stress by activating antioxidant defenses and regulates metabolism by improving fatty acid oxidation, reducing lipotoxicity, and balancing energy homeostasis, which is particularly beneficial in diabetic nephropathy. SIRT1 also holds significant implications for neurodegenerative diseases, particularly through its regulation of and neuronal survival. In , SIRT1 deacetylates , promoting its degradation and reducing formation, which is a hallmark of the pathology. Loss of SIRT1 activity leads to increased acetylated tau levels, impairing proteasome-mediated clearance and contributing to neuronal toxicity. In , reduced SIRT1 levels in patient serum and brain tissue correlate with disease severity and cognitive decline, suggesting a role in vulnerability. Recent investigations, including a study, highlight the neuroprotective potential of , a SIRT1 modulator, in alleviating hypoxic-ischemic brain injury and stress in models, underscoring its therapeutic relevance for neurodegenerative conditions.

Therapeutic Targeting and Clinical Developments

SIRT1 activators have advanced into clinical development primarily for metabolic disorders, with SRT2104 emerging as a leading candidate. In a phase II trial for , a condition linked to , SRT2104 administration for 28 days was well tolerated but did not significantly improve glucose or insulin control, though it demonstrated effects in preclinical models relevant to metabolic health. Early-phase trials further indicated that SRT2104 is safe in patients with , with potential benefits on markers such as reduced and enhanced mitochondrial function observed in 2024 preclinical studies. Furthermore, a 2025 preclinical study demonstrated that SRT2104 exerts exercise-mimetic effects, reduces and , and improves muscle regeneration in models of . Resveratrol and its derivatives, known SIRT1 activators, have been evaluated in multiple clinical trials for conditions including and , showing modest improvements in endothelial function and markers but inconsistent effects on SIRT1 activity in humans. These compounds continue to inspire derivative development, with ongoing preclinical work focusing on enhanced for therapeutic applications in age-related metabolic decline. On the inhibitor side, selisistat (EX-527), a selective SIRT1 inhibitor, progressed to phase II trials for Huntington's disease, demonstrating good safety and tolerability over 12 weeks but was halted in 2013 due to lack of efficacy on disease progression. New selisistat analogs have shown promise in 2023 preclinical cancer models, where they suppress tumor progression by disrupting SIRT1-mediated survival pathways without significant off-target effects. Cambinol, a non-selective SIRT1/SIRT2 inhibitor, has been investigated for differentiation in cancer, inducing cell differentiation and impairing tumor growth in models by increasing expression of differentiation markers and promoting G2 arrest. studies confirm its antitumor activity, particularly in promoting and reducing proliferation in solid tumors. Therapeutic targeting of SIRT1 faces challenges, including selectivity issues due to structural similarities among isoforms, which can lead to off-target effects in clinical settings. As of 2025, updates on inhibitors targeting the NAMPT-SIRT1 axis highlight their potential in overcoming in cancers, with NAMPT blockade reducing NAD+ availability and sensitizing resistant tumors to through disrupted SIRT1-dependent metabolic reprogramming. These developments underscore the need for isoform-specific compounds to balance efficacy and safety in applications.

DNA Repair Mechanisms

Role in Homologous Recombination

Sirtuin 1 (SIRT1) plays a critical role in promoting (HR), a high-fidelity DNA double-strand break (DSB) repair pathway, by deacetylating key proteins involved in the process. Specifically, SIRT1 deacetylates the (WRN), a RecQ family member essential for HR, thereby enhancing its and activities and facilitating its recruitment to DSB sites. This deacetylation prevents inhibitory acetylation on WRN, allowing it to unwind DNA structures and promote strand invasion during HR, thereby favoring HR over (NHEJ), an error-prone alternative. Additionally, SIRT1 deacetylates NBS1, a component of the MRN complex, and RAD51, the central recombinase in HR, which enhances their stability, chromatin association, and recruitment to damage sites, thereby boosting RAD51 filament formation on single-stranded DNA. The mechanism of SIRT1's involvement in is tightly coupled to cellular through its NAD+-dependent deacetylase activity, where NAD+ levels—reflecting the energetic state—modulate SIRT1 function and thus link efficiency to metabolic conditions. During DNA damage, SIRT1 consumes NAD+ to deacetylate targets like WRN and NBS1, promoting end resection and while suppressing alternative pathways that could lead to mutations. SIRT1 deficiency disrupts this process, resulting in elevated genomic instability due to impaired and accumulation of unrepaired DSBs, as evidenced by increased chromosomal aberrations and sensitivity to genotoxic stress in SIRT1-null models. Experimental evidence underscores SIRT1's necessity for efficient HR. In human cells with SIRT1 knockdown via shRNA, HR efficiency is reduced by approximately 50%, alongside a milder 25% decrease in NHEJ, highlighting a preferential impact on HR. Similarly, SIRT1-deficient cells exhibit delayed and diminished RAD51 foci formation at DSBs, correlating with defective repair. In the context of leukemia, particularly chronic myeloid leukemia (CML) cell lines, SIRT1's binding to DSB sites via WRN promotes HR, and its inhibition exacerbates genomic instability, suggesting therapeutic potential in targeting SIRT1 to sensitize leukemia cells to DNA-damaging agents.

Interaction with DNA Damage Response Pathways

Sirtuin 1 (SIRT1) integrates into the DNA damage response (DDR) pathways by competing with for the shared cofactor , particularly during and single-strand break repair (SSBR). PARP1 activation upon DNA damage rapidly consumes NAD⁺ to synthesize poly(ADP-ribose) chains, thereby depleting cellular NAD⁺ pools and inhibiting SIRT1 activity, which limits its deacetylation functions in repair processes. This creates a regulatory balance: in mild damage, elevated SIRT1 promotes survival and repair, while severe PARP1 activation suppresses SIRT1 to favor pathways. SIRT1 further contributes to DDR checkpoint activation by deacetylating key kinases such as ataxia-telangiectasia mutated () and checkpoint kinase 2 (CHK2). Upon double-strand break induction, ATM recruits SIRT1 to damage sites, where SIRT1 deacetylates ATM to enhance its autophosphorylation and kinase activity, amplifying downstream signaling for arrest. Similarly, SIRT1 binds and deacetylates CHK2 at residues, stabilizing it against oxidative stress-induced degradation and promoting its to enforce G2/M checkpoint integrity during persistent DNA lesions. These modifications ensure coordinated DDR beyond , integrating SIRT1 into broader surveillance mechanisms. In non-homologous recombination contexts, SIRT1 promotes (NER) by deacetylating xeroderma pigmentosum complementation group A (XPA) protein, a core NER factor. UV-induced damage triggers SIRT1 to deacetylate XPA at specific lysines (e.g., Lys-63, Lys-67, Lys-215), enhancing XPA's interaction with and ATR , thereby facilitating damage recognition and repair complex assembly. This hypoacetylated state of XPA optimizes NER efficiency, protecting against UV-associated genomic instability. For irreparable DNA damage, SIRT1 modulates by suppressing and activity, delaying premature in response to chronic low-level . However, in lethal damage scenarios, reduced SIRT1 levels—due to PARP1-mediated NAD⁺ depletion—allow hyper, promoting and irreversible growth arrest to prevent propagation of mutations. This shift underscores SIRT1's role in tipping the balance toward when repair capacity is overwhelmed. Therapeutically, SIRT1 inhibition sensitizes cancer cells to by exacerbating DDR defects and promoting . Recent studies (2023–2025) demonstrate that SIRT1 inhibitors, such as selisistat, enhance efficacy in models by impairing checkpoints and increasing sensitivity. These findings highlight SIRT1 as a target for overcoming chemoresistance through DDR pathway disruption.

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