An Update on the Role of Sirtuins in the Prevention of the Aging Process: A Narrative Review

Abstract

In the context of research aimed at identifying the causes of the progressive decline in cellular and tissue functions characteristic of aging, in recent decades, increasing attention has been devoted to the sirtuin family. Sirtuins are named after the Sir2 protein of Saccharomyces cerevisiae, a product of the SIR gene family, known as “silent information regulator 2”. Sirtuins are NAD⁺-dependent protein deacetylases and deacylases characterized by a conserved catalytic domain of approximately 275 amino acids. The removal of acetyl groups from acetyl-lysine residues on proteins is critical in regulating a wide range of biological functions, including gene silencing, genome stability, longevity, metabolism, and cellular physiology. In humans, the sirtuin family comprises seven isoforms (SIRT1–SIRT7), each with specific substrate preferences and primarily, but not exclusively, localized in the nucleus (SIRT1, SIRT6, and SIRT7), cytoplasm (SIRT2), and mitochondria (SIRT3, SIRT4, and SIRT5). Sirtuins may regulate numerous cellular processes associated with survival and longevity, including transcription and DNA repair, inflammation, glucose and lipid metabolism, oxidative stress, mitochondrial function, apoptosis, autophagy, and stress resistance. Sirtuins’ dependence on NAD⁺ allows them to function as cellular energy sensors, linking metabolic demands to selective lysine deacylation in various subcellular organelles. The aim of this review is to provide an update on this family of molecules, describing their molecular structures, physiological functions, roles in aging processes, and potential to be modulated to serve as a strategy for promoting healthy aging.

1. Introduction

In the context of research aimed at identifying the causes of the progressive decline in cellular and tissue functions characteristic of aging, increasing attention has been devoted to the sirtuin family in recent decades. These molecules are thought to play a central role in integrating metabolic signals with epigenetic regulation, DNA repair, and oxidative stress responses. Sirtuins are named after the SIR2 protein of Saccharomyces cerevisiae, a product of the SIR gene family, known as “silent information regulator 2” [1,2].

The aim of this review is to provide an update on this family of molecules, describing their molecular structures, physiological functions, roles in aging processes, and potential to be modulated within the framework of modern preventive anti-aging medicine [3]. While several excellent reviews previously elucidated the functions of specific sirtuin isoforms—such as SIRT1 [4], SIRT1, and SIRT6 [5] and the mitochondrial sirtuins SIRT3 [1,6], SIRT6 [7,8], and SIRT7 [9,10]—or provided broad biological overviews of the entire family [1], the present review offers a distinct translational perspective. Specifically, this manuscript bridges the gap between the fundamental molecular mechanisms of the SIRT1-7 family and their practical application in modern preventive and anti-aging medicine. Unlike previous studies that primarily focused on basic biochemistry or isolated isoforms, this review uniquely integrates the updated enzymatic activities of all seven sirtuins with a comprehensive analysis of pharmacological modulators (both natural and synthetic STACs) and lifestyle interventions. By explicitly distinguishing between preclinical mechanistic data and human clinical evidence, we provide a holistic, clinically oriented framework while also acknowledging the current translational limitations in the field

2. Materials and Methods

2.1. Search Strategy

A narrative review of the literature was conducted using the PubMed/MEDLINE database to identify studies examining the role of sirtuins in aging and disease prevention. The search covered the period from January 2001 up to March 2026. The search strategy used the following keywords and MeSH terms, both individually and in combination: “sirtuins”, “aging”, “cellular senescence”, “human”, “wellness”, “health”, “inflammation”, “SIRT1”, “SIRT2”, “SIRT3”, “SIRT4”, “SIRT5”, “SIRT6” and “SIRT7”. The search strategy details are described in the Supplementary Materials. The literature search was carried out in sequential steps according to the original manuscript preparation and the review process requirements on 15 June 2025, 24 December 2025, 25 February 2026 and 7 March 2026.

2.2. Study Selection and Inclusion Criteria

Studies were selected based on relevance to the molecular mechanisms of sirtuins and their potential clinical translation. The inclusion criteria were: (1) full-text articles available in English; (2) original research (in vitro, animal models, and human clinical trials) or relevant reviews and meta-analyses; (3) publications providing mechanistic insights into isoform-specific functions or pharmacological modulation.

2.3. Evidence Appraisal

To address the translational gap, priority in data synthesis was given to primary human clinical trials and randomized controlled trials (RCTs) where available. Preclinical data (cellular and murine models) were included to elucidate molecular pathways but are explicitly distinguished from human evidence in the text. Articles lacking full text, duplicates, or articles with purely speculative conclusions without experimental support were excluded. In total, 204 references were selected for this review. The detailed study selection process is illustrated in the PRISMA-style flow diagram shown in Figure 1. For the purposes of translational appraisal, the highest level of supporting evidence for each major compound/intervention was categorized as follows: human randomized/clinical trial evidence, human observational/non-randomized evidence, animal-model evidence, or cell-based/mechanistic evidence only. Where sufficient data were available, each major subsection also briefly comments on dosing realism (i.e., whether the experimental exposure is plausibly achievable in humans) and on the principal controversies or translational limitations.

3. Molecular Structure of Sirtuins

Sirtuins (SIRTs) are NAD⁺-dependent protein deacetylases characterized by a conserved catalytic domain of approximately 275 amino acids [11].

The N- and C-terminal regions of SIRT proteins vary significantly in length, chemical composition, and susceptibility to post-translational modifications [12].

The removal of acetyl groups from acetyl-lysine residues on proteins is critical in regulating a wide range of biological functions, including gene silencing, genome stability, longevity, metabolism, and cellular physiology [13,14].

Sirtuins are highly conserved across both prokaryotes and eukaryotes and exist in various isoforms [15,16].

In humans, the sirtuin family comprises seven isoforms (SIRT1–SIRT7), each with specific substrate preferences and primarily, but not exclusively, localized in the nucleus (SIRT1, SIRT6, and SIRT7), cytoplasm (SIRT2), and mitochondria (SIRT3, SIRT4, and SIRT5) [4,6,17,18,19,20,21,22]. A comprehensive summary of the specific subcellular localizations, enzymatic activities, and sentinel pathways for each isoform is provided in

Table 1. Overview of mammalian sirtuin isoforms: localization, updated enzymatic activities, selected molecular substrates/pathways, and clinical relevance.

Isoform	Normal Subcellular Location	Enzymatic Activity	Major Substrates and Sentinel Pathways	Key Human Associations and Functions	Intervention Evidence Level
SIRT1	Nucleus/Cytoplasm [11]	NAD+-dependent deacetylase (major); deacylase (reported).	p53, PGC-1α, FOXO1/3, NF-κB, eNOS, LXR, PPARγ, HIF-1α, BMAL1, Ku70. Regulates mitochondrial biogenesis, autophagy, inflammation, and glucose/lipid homeostasis [1,2,23,24].	Metabolic syndrome/T2D, NAFLD, neurodegeneration, vascular dysfunction. Central mediator of caloric restriction and stress-adaptation programs; supports DNA repair and circadian regulation [1,25].	High: extensive preclinical evidence; multiple early-phase human trials with SIRT1-targeting STACs and NAD+ boosting strategies, with mixed efficacy [1,26].
SIRT2	Cytoplasm (shuttles to nucleus)	NAD+-dependent deacetylase [27].	α-Tubulin, FOXO1, PEPCK, NF-κB. Controls cytoskeleton dynamics, mitosis, gluconeogenesis and inflammatory signalling [28,29,30].	Neuro-degeneration, cancer, metabolic and/or inflammatory disorders. Context-dependent roles (tumor suppressor vs. promoter) and links to insulin resistance pathways [28,29,31,32,33].	Moderate: strong preclinical evidence; selective inhibitors widely used as chemical probes (e.g., AGK2), limited human interventional data [28,29,32,33,34].
SIRT3	Mitochondria	NAD+-dependent deacetylase (major mitochondrial deacetylase) [22,35].	SOD2, IDH2, LCAD, PDH, OPA1. Master regulator of mitochondrial acetylome: ROS detoxification, TCA/FAO, and mitochondrial dynamics [1,6,36,37].	Cardiovascular and metabolic diseases, neurodegeneration. Protects against oxidative stress and mitochondrial dysfunction; implicated in healthspan regulation [1,22,36,37,38].	Moderate: robust preclinical data for activators (e.g., honokiol) and NAD+ boosting; limited direct clinical interventional evidence [1,39].
SIRT4	Mitochondria (matrix)	NAD+-dependent deacetylase; mono-ADP-ribosyl-transferase; lipoamidase; deacylase (weak/variable) [35,40].	GDH (ADP-ribosylation), PDH complex (lipoamidase), MCCC. Regulates amino-acid flux, anaplerosis, insulin secretion and stress responses [20,35,36].	Cancer metabolism, insulin secretion and metabolic stress adaptation. Often described as a tumor-suppressive metabolic “brake” (context-dependent) [20,35,36].	Low: mainly mechanistic and disease-model studies; no established direct activators/inhibitors in clinical use [20,36,40].
SIRT5	Mitochondria (also cytosol/nucleus)	Desuccinylase, demalonylase, deglutarylase (major); weak deacetylase [41,42].	CPS1, SDH and multiple metabolic enzymes. Controls urea cycle, TCA/glycolysis and redox metabolism via lysine acylation [21,43].	Inborn metabolic phenotypes, cardiac stress responses; skeletal muscle aging; alveolar-epitheial cells senescence; vascular dysfunction; context-dependent roles in cancer metabolism [21,41,44,45,46].	Low: emerging preclinical evidence; pharmacology largely at probe stage (few selective, cell-active modulators) [21,41].
SIRT6	Nucleus	Deacetylase (H3K9ac, H3K56ac); mono-ADP- ribosyltransferase; efficient deacylase/defatty- acylase (regulates TNF-α secretion) [47,48].	Histones (H3K9ac/H3K56ac), PARP1, NF-κB; TNF-α (defatty- acylation). Genome stability, inflammatory tone, glucose/lipid homeostasis [8,49,50].	Progeroid syndromes, inflammation, metabolic disease, cancer. Neuro-degeneration. Longevity and DNA repair node; links chromatin state to systemic metabolism [8,48,49,51].	Moderate: strong genetic/animal-model evidence; multiple small-molecule activators/inhibitors in preclinical development [8,49,52,53,54].
SIRT7	Nucleus (nucleolus; chromatin-associated)	Deacetylase; RNA-stimulated lysine deacylase activity; deacylation events implicated in chromatin compaction [55,56].	H3K18ac (DSB repair/transcription), ATM; ribosome biogenesis factors; lineage factors. Coordinates NHEJ repair, ribosome biogenesis, and metabolic programs [9,10,57].	Cardiomyopathy, hepatic steatosis, cancer and immune regulation. Genomic stability safeguard [9,10,57].	Low: evidence mainly from cellular/animal models and genetics; emerging interest in inhibitors in oncology [9,10,57].

.

4. Functions of Sirtuins

Sirtuins may regulate numerous cellular processes associated with survival and longevity, including transcription and DNA repair, inflammation, glucose and lipid metabolism, oxidative stress, mitochondrial function, apoptosis [58], autophagy [59], and stress resistance [28,60,61].

Their dependence on NAD⁺ allows sirtuins to function as cellular energy sensors, linking metabolic demands to selective lysine deacylation in various subcellular organelles (Figure 2) [62].

Furthermore, the complex and sometimes divergent roles of the various sirtuin isoforms in promoting or suppressing aging processes are summarized in Figure 3.

4.1. Effects on DNA

SIRT1 is thought to play a crucial role in promoting heterochromatin formation, a structure associated with gene expression repression [60,63].

Several DNA repair proteins are regulated by SIRT1, including Ku70, poly(ADP-ribose) polymerase 1 (PARP1), and ATP-dependent helicases [63,64]. Notably, deacetylated KU70 forms complexes with the pro-apoptotic factor BAX (Bcl-2–associated X protein), sequestering it away from the mitochondria and preventing stress-induced apoptosis [65].

SIRT1 also regulates several transcription factors involved in stress response and metabolism, as detailed in Table 1 [1,2,64].

4.2. Effects on Inflammation

Sirtuins, especially SIRT1 and SIRT6, may influence the secretion of inflammatory mediators, regulate dendritic cell differentiation, and macrophage activation [1,66]. SIRT1 modulates the balance between pro-inflammatory Th1 helper T cells and anti-inflammatory FOX (forkhead box) P3(+) regulatory T cells [67].

SIRT6 negatively regulates NF-κB-dependent inflammatory responses [68] and controls the production of cytokines (IL-6), chemokines, and growth factors (e.g., TNF-α) during immune and acute inflammatory responses [69,70].

SIRT1 and SIRT3 may reduce the production of pro-inflammatory cytokines such as TNF-α, IL-6, and IL-1β and downregulate the NLRP3 (NOD-, LRR- and pyrin domain-containing protein 3), a multiprotein intracellular complex essential for innate immunity and inflammation [1].

5. Effects on Metabolism

5.1. Glucose Metabolism

SIRT1 can regulate glucose metabolism by upregulating AMPK (adenosine monophosphate-activated protein kinase) [1,71], a metabolic sensor that maintains energy balance at the cellular level and coordinates metabolic signaling across tissues [72,73].

Moreover, SIRT1 may enhance insulin sensitivity and lower blood glucose by downregulating protein tyrosine phosphatase 1B, a key negative regulator of insulin signaling [74].

SIRT1 also participates in gluconeogenesis, with a dual role: it can suppress hepatic glucose production by deacetylating transcription factor CRTC2 (CREB-regulated transcription coactivator 2), reducing gluconeogenic gene expression [75]; alternatively, it can stimulate the gluconeogenic program by deacetylating and activating FOXO1 (class O of forkhead box) and PGC1α [2], also modulating glycolytic gene transcription negatively [76].

SIRT2, SIRT3, and SIRT4 are believed to sustain gluconeogenesis especially during energy deprivation [2,42].

SIRT1, SIRT3, and SIRT6 may inhibit aerobic glycolysis by repressing HIF1α (hypoxia-inducible factor 1α), which otherwise suppresses glucose oxidation via the Krebs cycle.

In pancreatic β-cells, SIRT6 deacetylates FOXO1, enhancing GLUT2 (glucose transporter 2) expression, thereby preserving glucose-sensing capacity and systemic glucose tolerance [1].

5.2. Lipid Metabolism

Sirtuins are thought to be actively involved in lipid metabolism regulation [77].

SIRT1 deacetylates and destabilizes SREBP1c, reducing its binding to lipogenic gene promoters and suppressing fatty acid synthesis [78,79].

SIRT1 overexpression inhibits adipogenesis, whereas its inhibition promotes it. In mature adipocytes, increased SIRT1 activity promotes lipolysis and reduces adipose tissue mass. It promotes fat mobilization in white adipocytes by repressing PPAR (Peroxisome proliferator-activated receptors)-γ [80].

SIRT2 may also contribute to adipogenesis inhibition and lipolysis promotion during caloric restriction [2].

In the liver, SIRT1 controls lipid homeostasis by activating PPARα, a nuclear receptor essential for adaptive fasting responses. Hepatocyte-specific SIRT1 deletion impairs PPARα signaling and reduces fatty acid β-oxidation, while its overexpression enhances PPARα target gene expression [81].

SIRT3 appears to support hepatic fatty acid oxidation by activating LCAD (Long Chain Acyl-CoA Dehydrogenase), a key enzyme in long-chain fatty acid oxidation [82].

SIRT2 has also been shown to increase the expression of HNF4α (Hepatocyte Nuclear Factor 4α), positively impacting hepatic steatosis [28,29].

5.3. Oxidative Stress

Sirtuins may play a fundamental role in antioxidant regulation and redox signaling [83].

Specifically, SIRT1, SIRT2, and SIRT6 can regulate NRF2 (Nuclear erythroid 2-related factor 2), a key transcription factor for antioxidant and detoxifying gene expression, typically inactive under physiological conditions [57,84,85,86,87].

Additionally, the interplay between sirtuins and the FOXO family or PGC-1α significantly boosts cellular antioxidant capacity, as summarized in Table 1 [1,2,6,83,88,89,90,91,92,93,94,95].

5.4. Sirtuins and Mitochondrial Function

SIRT1 and SIRT6 contribute to the regulation of mitochondrial protein homeostasis by promoting antioxidant enzymes that reduce ROS (Reactive Oxygen Species) levels [85,88,96].

Mitochondrial sirtuins—SIRT3, SIRT4, and SIRT5—exhibit a distinct context-dependence, acting as pro-survival factors in healthy tissues while often functioning as tumor suppressors in oncology [4]. SIRT3 acts as the primary guardian of mitochondrial integrity in metabolically active tissues like the heart and kidney. Here, it exerts a pro-survival effect by deacetylating SOD2 and IDH2, thereby preventing ROS-mediated apoptosis during ischemia-reperfusion injury or fibrosis (see Table 1). Conversely, in the context of cancer, SIRT3 often acts as a tumor suppressor by opposing the Warburg effect; it forces cells to rely on OXPHOS (Oxidative Phosphorylation) rather than glycolysis, thereby curbing the rapid proliferation required by tumors. This explains the apparent contradiction where SIRT3 protects healthy cardiomyocytes from stress but can induce cell death or growth arrest in cancer cells by stripping them of their preferred metabolic fuel [97]. Similarly, SIRT4 generally acts as a “metabolic brake.” It inhibits glutamate dehydrogenase (GDH) and represses mitochondrial respiration. In healthy pancreatic β-cells, this regulates insulin secretion. However, in tumor biology, SIRT4’s repression of glutamine metabolism limits the anaplerotic flux essential for tumor growth, effectively acting as an anti-proliferative checkpoint [98,99]. SIRT5 catalyzes the removal of malonyl, succinyl, and glutaryl groups from mitochondrial enzymes. It plays a critical protective role in cardiomyocytes against ischemia-reperfusion injury and sustains ammonia detoxification in the liver via the urea cycle [36,100].

5.5. Apoptosis

The role of sirtuins in apoptosis is context-dependent. SIRT1 generally exerts anti-apoptotic effects by deacetylating key targets such as p53 and FOXO proteins, whereas SIRT2 may promote apoptosis under severe stress by upregulating BIM (Bcl-2-interacting mediator of cell death) [30,101,102].

Under severe stress conditions, SIRT2 promotes the expression of BIM, a FOXO target gene and potent pro-apoptotic factor, thereby enhancing apoptosis [30].

SIRT3 can exert both pro-apoptotic and anti-apoptotic effects depending on the context; in some cases, SIRT3 expression inhibits tumor cell proliferation by promoting apoptosis, whereas in models of stress-induced injury, it protects against various cellular stressors [1,103].

SIRT6 reduces high-glucose-level-induced apoptosis in podocytes by activating AMPK [89].

5.6. Specific Roles of SIRT7 in Aging and Metabolism

While SIRT1 and SIRT6 have been extensively studied, SIRT7 has recently emerged as a critical, albeit complex, regulator of aging and cellular senescence [9,10]. Beyond its established deacetylase activity, SIRT7 possesses strong deacylase functions, including desuccinylation and defatty-acylation. Crucially, SIRT7 plays a fundamental role in DNA repair mechanisms. It is rapidly recruited to DNA double-strand breaks (DSBs), where it deacetylates H3K18ac and modulates both the non-homologous end joining (NHEJ) and homologous recombination (HR) pathways, safeguarding genomic stability [9,10,57]. Interestingly, recent studies have revealed that SIRT7 exerts opposite effects on several aging-related metabolic processes compared to SIRT1 and SIRT6 [104]. For instance, while SIRT1 generally protects against hepatic steatosis, SIRT7 promotes hepatic lipid accumulation by suppressing the degradation of TR4 (Testicular Receptor 4) via the ubiquitin-proteasome pathway and inhibiting endoplasmic reticulum (ER) stress pathways [57]. Furthermore, SIRT7 acts as a negative regulator of thermogenesis and energy expenditure, contrasting sharply with the energy-boosting and metabolic-enhancing roles of SIRT1 and SIRT3 [9,10]. In the context of inflammation, the role of SIRT7 diverges significantly from other sirtuin isoforms. While SIRT1 and SIRT6 are predominantly anti-inflammatory, SIRT7 can exhibit tissue-specific pro-inflammatory characteristics under certain physiological stresses [105,106,107]. These unique metabolic and inflammatory profiles culminate in a paradoxical effect on longevity: recent in vivo evidence demonstrates that SIRT7 knockout mice exhibit a longer lifespan and delayed onset of age-related conditions, highlighting its distinct and highly specific role in the mammalian aging process compared to the rest of the sirtuin family [9,57].

6. Regulation of Sirtuins

Sirtuin activity is regulated not only at the transcriptional level but also post-translationally.

6.1. Transcriptional Regulation

SIRT1 expression is modulated according to physiological conditions: it increases under low energy availability and decreases in energy surplus. SIRT1 has binding sites for numerous transcription factors. Specifically, FOXO1, PPARα, PPARβ/δ, and CREB promote SIRT1 expression, whereas PPARγ and ChREBP (Carbohydrate Response Element Binding Protein) suppress it [2,108,109].

The tumor suppressor gene HIC1 (Hypermethylated in Cancer 1) also negatively regulates SIRT1 transcription.

p53 may also contribute to SIRT1 repression.

MicroRNAs (miRNAs) regulate sirtuin expression either by degrading primary transcripts or inhibiting translation [110,111,112].

DNA methylation further contributes to negative regulation of sirtuin expression [113].

6.2. Post-Translational Regulation

A key mechanism of post-translational regulation involves the cyclin B–Cdk1 complex, which phosphorylates specific sites on SIRT1, altering normal cell cycle progression [2].

JNK (c-Jun N-terminal kinase) also phosphorylates SIRT1 at three specific residues, particularly under oxidative stress, resulting in H3 histone deacetylation but not of p53 [114].

DYRK1 and DYRK3 kinases (dual-specificity tyrosine-regulated kinases) activate SIRT1 by phosphorylation, enhancing p53 deacetylation by SIRT1 and preventing apoptosis under genotoxic stress [115].

SIRT1 can also undergo SUMOylation, a modification that enhances its activity in cultured cells. Genotoxic stress, such as UV exposure or hydrogen peroxide, triggers SENP (SUMO-specific protease) to remove this modification, inactivating SIRT1 and promoting cell death [2].

6.3. Complex Formation

Sirtuins are further modulated, positively or negatively, through nuclear complex formation with other proteins [2,116].

6.4. Substrate Availability

AMPK regulates SIRT1 primarily by increasing the cellular NAD⁺/NADH ratio via the activation of NAMPT (nicotinamide phosphoribosyltransferase), the rate-limiting enzyme in the NAD⁺ salvage pathway [71,117]. While some evidence suggests AMPK may phosphorylate SIRT1, the NAD⁺-dependent activation is considered the dominant mechanism connecting cellular energy status to sirtuin activity [117].

Importantly, NAD⁺ availability decreases with age, reducing sirtuin activity and impairing nuclear-mitochondrial communication at the cellular level. These dynamic processes, both cellular and systemic, likely contribute to functional decline associated with aging and the pathogenesis of age-related diseases [114,115].

7. Sirtuin-Activity Regulating Compounds

Given the growing body of evidence on sirtuin activities, increasing efforts have focused on identifying regulatory compounds. On the one hand, sirtuin activators could be incorporated into therapeutic strategies aimed at extending human lifespan and reducing the impact of age-related diseases [62].

On the other hand, sirtuin inhibitors may play a role in controlling neurodegenerative diseases and tumor proliferation. A comprehensive overview of these pharmacological and lifestyle interventions, stratified by their primary target isoforms and level of clinical evidence, is provided in

Table 2. Pharmacological and lifestyle interventions reported to modulate sirtuin activity: targets and predominant evidence level.

Compound/Intervention	Class	Primary Sirtuin Target(s)	Evidence Level	Investigated Potential Effects
Resveratrol	Natural STAC (polyphenol)	SIRT1	Preclinical + mixed clinical	Metabolic/inflammatory modulation; endothelial function and biomarkers of SIRT1 activation [1].
Piceatannol & Butein	Natural STACs	SIRT1	Preclinical	SIRT1 activation and downstream metabolic/anti-inflammatory effects; used as SIRT1-activating probes in disease models [16,118].
Pterostilbene	Natural STAC (stilbene)	SIRT1 (putative)	Preclinical; limited human	Metabolic and anti-inflammatory effects; improved PK vs. resveratrol (evidence heterogeneous) [1].
SRT2104	Synthetic SIRT1 activator	SIRT1	Clinical phase I/II	Safety/tolerability; biomarker effects; cardiometabolic endpoints variably neutral/heterogeneous [119].
SRT1720	Synthetic STAC	SIRT1	Preclinical	Improved healthspan/lifespan in some murine models; mechanistic specificity debated [62].
Honokiol	Natural STAC	SIRT3	Preclinical	Mitochondrial protection, neuro/cardioprotection; reduced oxidative stress [120].
Cyanidin	Natural STAC (anthocyanidin)	SIRT6	Preclinical	In vitro SIRT6 activation and increased SIRT6 expression reported; anti-inflammatory effects in disease models [16,118].
1,4-Dihydropyridines	Synthetic STAC	SIRT3, SIRT5	Preclinical	Protection in ischemia–reperfusion and mitochondrial stress models [121].
MDL-800	Synthetic activator	SIRT6	Preclinical	Enhanced DNA repair/genome stability; anti-inflammatory and metabolic effects [122,123].
UBCS039	Synthetic activator (probe)	SIRT6	Preclinical	Autophagy modulation; anti-inflammatory and organ-protective effects in animal models [18,62].
Quercetin	Flavonoid	SIRT1/SIRT6	Preclinical; early human	Senescence/inflammation pathways; pleiotropic effects beyond sirtuins [124].
Fisetin	Flavonol	SIRT1/SIRT6	Preclinical; early human	Senescence modulation and anti-inflammatory effects; pleiotropic mechanisms [125].
Nicotinamide (NAM)	Vitamin B3	Pan-sirtuin inhibitor	Human/Preclinical	Context-dependent: may blunt sirtuin activity; relevant when discussing NAD+/sirtuin axis [58].
Selisistat (EX-527)	Selective inhibitor	SIRT1	Clinical	Well-characterized clinical safety in Huntington’s disease trials; useful tool for probing SIRT1 biology [18,62].
AGK2	Selective inhibitor (probe)	SIRT2	Preclinical	Neuroinflammation/cytoskeleton and metabolic signaling modulation in disease models [34,126].
3-TYP	Selective inhibitor (probe)	SIRT3	Preclinical	Mitochondrial acetylome/oncology models; tool compound [18,62].
OSS-128167	Selective inhibitor (probe)	SIRT6	Preclinical	Tool compound used to interrogate SIRT6 biology; effects depend on disease model [18,62].
NR/NMN	NAD+ precursors	Pan-sirtuin (indirect)	Clinical	Increase NAD+ availability; downstream effects on multiple sirtuins and metabolism [127].
Caloric restriction	Lifestyle	SIRT1/SIRT3 (indirect)	Human/Animal	Improved metabolic flexibility, inflammation reduction; classic upstream activator [2,128].
Exercise	Lifestyle	SIRT1/SIRT3 (indirect)	Human	Mitochondrial biogenesis and insulin sensitivity; interacts with NAD+ metabolism [129,130].

. To improve translational consistency, each major compound/intervention subsection below closes with a brief evidence-grading statement summarizing the highest level of support, dosing realism, and the main controversies/limitations relevant to clinical translation.

7.1. Sirtuin Activating Compounds (STACs)

These compounds may be of both natural and synthetic origin.

7.1.1. Main Sirtuin-Activating Compounds (STACs)

Resveratrol

In 2003, resveratrol was identified as the first activator of SIRT1. This polyphenol, commonly found in grapes, enhances cell survival by promoting SIRT1-dependent deacetylation of p53 [116].

Resveratrol has been reported to exert beneficial effects on glycemic control, HDL cholesterol levels, the total cholesterol/HDL ratio, and overall antioxidant capacity [131,132,133].

It also appears capable of reducing the proliferation of cancer cells in breast, cervical, and liver neoplasms. While resveratrol is supported by extensive preclinical data, human clinical evidence remains mixed; furthermore, achieving realistic dosing generally requires pharmacological intervention, as standard dietary sources are unlikely to replicate the concentrations used in experimental settings. The clinical translation of this polyphenol is further complicated by its low oral bioavailability and rapid metabolism, amidst an ongoing debate regarding whether its observed effects truly reflect direct SIRT1 activation or are the result of broader pleiotropic signaling.

Honokiol

Honokiol (HKL) is a biphenolic natural compound derived from the bark of magnolia trees, with anti-inflammatory, antioxidant, antitumor, and neuroprotective properties. It activates mitochondrial SIRT3 and doubles its expression [16]. It is reported to attenuate high glucose-induced peripheral neuropathy, to protect against diabetic retinal microvascular injury, to attenuate anesthesia/surgery-induced cognitive impairment and to relieve hippocampal neuronal damage in Alzheimer’s disease.

In experimental models, honokiol has been demonstrated to ameliorate alveolar epithelial cell senescence induced by silicosis and to restore mitochondrial dysfunction of the hippocampus in hepatic encephalopathy from ammonia neurotoxicity [120,134,135,136,137,138,139,140,141]. Current evidence for honokiol is primarily grounded in preclinical cell and animal models. A significant hurdle to its clinical application is the lack of human pharmacokinetic and tissue-exposure data, which makes it difficult to confirm if the SIRT3-modulating levels observed in experimental settings are readily achievable in humans. Consequently, the translation from organ-protective models to general anti-aging use remains a major controversy, pending results from controlled human trials.

Curcumin

Curcumin, a natural polyphenol extracted from Curcuma longa and widely used as a food additive and flavoring agent, activates SIRT1.

Its beneficial effects on muscle cells, particularly on myocardial cells, are interesting [142,143,144,145].

In a study on cortical neurons exposed to glutamate toxicity, it was shown to deacetylate the transcription coactivator PGC1α, thereby suggesting a neuroprotective function too [146]. Although curcumin is a well-known SIRT1 activator in preclinical research, its clinical “dosing realism” remains a subject of intense debate. Many of its mechanistic effects are described under conditions that are nearly impossible to match through routine dietary intake, and its notorious low bioavailability further complicates systemic exposure. Moreover, curcumin’s highly pleiotropic nature makes it challenging to definitively attribute its health benefits to a specific SIRT1-mediated pathway.

Quercetin

Quercetin is a ubiquitous flavonoid found in fruits and vegetables such as apples, berries, red onions, grapes, cherries, broccoli, peppers, cilantro, citrus fruits, and tea. Its anti-inflammatory properties and favorable effects on lipid metabolism and antioxidant enzyme activity are linked to its ability to enhance the AMPK/SIRT1/NF-κB pathway. Furthermore, by activating SIRT1, quercetin regulates mitochondrial autophagy and reduces endoplasmic reticulum stress [15]. At higher concentrations (several hundred micromoles), it can also stimulate SIRT6 activity [124,147]. Quercetin’s status as a sirtuin modulator is supported by extensive preclinical data and limited early human studies. However, a key limitation is that the concentrations required for effective SIRT6 activation may exceed typical human systemic exposure levels. This leads to significant controversy regarding its clinical efficacy, as its pleiotropic bioactivity often masks whether its observed effects are truly driven by direct sirtuin modulation in humans.

Ferulic Acid

Ferulic acid is a cinnamic acid substituted by a methoxy and a hydroxy group at positions 3 and 4 of the phenyl ring.

It is found mainly in Salvia rosmarinus, Camelia reticulata, oranges and wheat and has been reported as a metabolite produced by Saccharomyces cerevisiae. It has a role as a neuroprotective agent, a plant metabolite and an antioxidant. Ferulic acid exerts neuroprotective effects at low concentrations through activation of SIRT1 and SIRT7. At higher concentrations, it promotes neuronal differentiation and neurite outgrowth [15,148,149,150,151,152,153,154,155,156,157]. Evidence for ferulic acid is currently restricted to cell-based and animal studies, particularly regarding its neuroprotective role. There is a notable lack of “dosing realism,” as the high concentrations associated with SIRT1 and SIRT7 activation in vitro may not be achievable in vivo. Without controlled human intervention data, it remains uncertain if the observed biological effects are sirtuin-dominant or a result of other antioxidant mechanisms.

Fisetin

Fisetin, a flavonol present in strawberries, apples, persimmons, grapes, onions, and cucumbers [125], protects the liver from alcohol-induced damage by promoting SIRT1-mediated autophagy [158]. In assisted reproduction technology, fisetin delays postovulatory oocyte aging by upregulating SIRT1 [159].

Fisetin also suppresses chondrocyte senescence and mitigates osteoarthritic cartilage degradation by activating SIRT6 [160].

Experimental data suggest that fisetin enhances SIRT1 expression and plays a role in the epigenetic control of early adipogenesis [161].

Moreover, fisetin associated with luteolin can suppress oxidative stress by modulating sirtuins under in vitro diabetic conditions [162].

Finally, it must be noted that while polyphenols like resveratrol show promise in vitro, their low bioavailability and rapid metabolism in humans pose significant hurdles. The high doses often required to achieve sirtuin activation in animal models raise safety concerns regarding gastrointestinal tolerability and potential adverse effects in clinical settings [163]. Fisetin has garnered interest for its potential SIRT1 and SIRT6 activation, though evidence remains largely preclinical. In terms of dosing, meaningful sirtuin-modulating effects likely require supplemental intervention rather than standard dietary exposure. Its low bioavailability and the involvement of multiple non-sirtuin pathways represent major limitations, highlighting the need for human trials that specifically validate a sirtuin-mediated anti-aging benefit.

7.1.2. Synthetic STACs

These molecules exhibit various important pharmacological activities and share the ability to activate sirtuins, thereby showing additional anti-aging effects.

Metformin

Metformin, a potent anti-hyperglycemic agent, activates both SIRT1 and SIRT3. It activates AMPK/SIRT1/NF-κB pathway and induces mitochondrial dysfunction to drive caspase3/GSDME-mediated cancer cell pyroptosis [164,165]. Moreover, it is able to mitigate stress-induced premature cellular senescence by upregulating AMPKα at Ser485 phosphorylation induced SIRT3 expression and inactivating mitochondrial oxidants [166]. Treatment with metformin activates AMPK, which inhibits salt-induced hepatic inflammatory memory and cardiovascular damage by increasing SIRT3 expression [167]. While metformin is supported by robust human clinical evidence as an antidiabetic agent, its classification as a specifically sirtuin-mediated anti-aging drug rests primarily on preclinical data. Although standard clinical doses are easily achievable in humans, the causal contribution of SIRT1 and SIRT3 activation to its geroprotective effects remains unproven. This creates a controversy where sirtuin modulation may simply be a byproduct of broader AMPK and mitochondrial signaling.

Cilostazol

Cilostazol, an antiplatelet drug, enhances SIRT1-mediated autophagy, improving cell vitality [168]. The sirtuin-linked effects of cilostazol are supported almost exclusively by preclinical research. While therapeutic human dosing is well-established for its antiplatelet activity, an exposure-response relationship specifically directed at sirtuins has not yet been defined. The absence of human interventional studies remains a significant limitation, leaving it unclear if SIRT1-mediated autophagy contributes meaningfully to its clinical outcomes.

Statins

Statins modulate sirtuin expression by upregulating SIRT1 and SIRT2 and downregulating SIRT6. Through these mechanisms—primarily via SIRT1—statins contribute to lowering lipid levels and reducing risk factors such as diabetes, obesity, cardiovascular diseases, acute pulmonary embolism, and atherosclerosis [169]. It should be noted that while statins are proven to reduce cardiovascular risk in humans, the specific attribution of these benefits to SIRT1/SIRT6 modulation relies predominantly on mechanistic studies in cellular and animal models. Statins possess strong human clinical evidence for cardiovascular prevention, but their proposed sirtuin-mediated mechanisms are currently categorized at a preclinical evidence grade. While standard doses are clinically realistic, a major controversy lies in the difficulty of isolating how much of their systemic benefit is actually driven by SIRT1, SIRT2, or SIRT6 modulation versus their primary pleiotropic lipid-lowering and anti-inflammatory actions.

7.1.3. Novel Synthetic STACs

Recent research has led to the identification of novel synthetic STACs currently in experimental use. Noteworthy compounds include the following:

• SRT1720—Originally developed as a synthetic activator of SIRT1, this imidazothiazole derivative has been widely studied in preclinical models. While early debates questioned its specificity (suggesting potential off-target effects or assay artifacts), subsequent studies in mice demonstrated that SRT1720 improves insulin sensitivity, mitochondrial function, and endurance, mimicking the effects of caloric restriction via SIRT1 activation [62]. Supported by preclinical evidence, its human use remains uncertain as it has not yet translated into established clinical use. Its target specificity remains a point of repeated debate in the literature.
• SRT2104—This compound is a potent SIRT1 activator with the same imidazothiazole core. It has shown potential in modulating metabolic pathways in preclinical models, particularly in modulating metabolic and longevity-related pathways [119]. It crosses the blood-brain barrier, providing therapeutic benefit in certain neurodegenerative conditions [170]. One study found that it improves endothelial function and reduces serum LDL cholesterol levels in healthy smokers, suggesting its potential to counteract vascular aging in humans [171]. This compound is supported by early human clinical data (Phase I/II) alongside preclinical models. While its oral dosing is clinically realistic, efficacy signals remain heterogeneous and largely biomarker-based, with no definitive proof of disease-modifying or longevity benefits in humans.
• 1,4-Dihydropyridines—These heterocyclic pyridine derivatives are calcium channel blockers and potent selective activators of SIRT3 and SIRT5 [121]. SIRT3 activation counteracts cardiac hypertrophy in mice and reduces β-amyloid levels in vitro, alleviating cognitive deficits in Alzheimer’s models. SIRT5 activation protects against ischemia-reperfusion oxidative injury, offering therapeutic perspectives for heart failure, neurodegenerative diseases, and metabolic dysfunctions [16]. Evidence is currently preclinical, and no established human dosing regimen exists for sirtuin-targeted therapy. It remains unresolved whether their benefits reflect true isoform-selective activation or broader class effects.
• MDL-800, MDL-801, MDL-811—These small molecules, derived from 2-methylaniline, are SIRT6 activators with antitumor and protective effects on cardiovascular and neurodegenerative diseases [122,123]. These agents are in the preclinical stage, and their human dosing realism is entirely unknown. As experimental compounds, they currently lack any controlled human safety or efficacy data.

7.1.4. Other Natural STACs

In addition to the aforementioned polyphenols, butein (a chalcone) and piceatannol (a stilbenoid and metabolite of resveratrol) have demonstrated significant SIRT1-activating properties [1]. Piceatannol exhibits high structural similarity to resveratrol but possesses greater oral bioavailability and metabolic stability, making it a promising candidate for protecting against diet-induced metabolic dysfunction. Addressing the need for isoform-specific activation, cyanidin (an anthocyanin pigment) has been identified as a potent natural activator of SIRT6, promoting protective effects against cellular senescence and metabolic decline [16,118]. For compounds like piceatannol, butein, and cyanidin, the highest level of support remains preclinical or in vitro. A major limitation is the uncertainty regarding human exposure at the concentrations required for direct sirtuin modulation. Furthermore, polyphenol pleiotropy and variable bioavailability make it difficult to validate these as specific sirtuin-targeted interventions without controlled human trials.

7.1.5. Indirect Strategies for Regulating Sirtuin Activity

Rapamycin

Rapamycin (Sirolimus) is a macrolide immunosuppressant that functions as a potent inhibitor of the mechanistic target of rapamycin (mTOR). Unlike direct sirtuin activators, its connection to the sirtuin family is indirect, mediated through a complex nutrient-sensing network. Inhibition of mTOR by rapamycin has been shown to induce autophagy and extend lifespan in model organisms ranging from Saccharomyces cerevisiae to Mus musculus [59]. Mechanistically, this effect may involve the upregulation of SIRT1 expression, which contributes to blocking glucose-induced senescence [172], and the promotion of Sir2 association with ribosomal DNA in yeast [173]. Furthermore, the interplay between SIRT1 and mTOR is critical for autophagy regulation, where rapamycin-induced mTOR inhibition facilitates SIRT1-mediated cellular survival responses under stress [59,174]. Although rapamycin has established human clinical use in various indications, the evidence linking it to sirtuin-mediated anti-aging effects remains indirect and largely preclinical. While clinically achievable dosing is well-known, its geroprotective potential cannot be definitively attributed to sirtuin modulation alone. Moreover, significant concerns regarding its tolerability and side-effect profile remain a major controversy for its use in preventive medicine.

NAD⁺ Boosting

Beyond direct activation, indirect strategies to regulate sirtuin activity have been explored, including increasing sirtuin gene expression [126].

One such approach is the use of iso-nicotinamide (iso-NAM), which competes with nicotinamide, an endogenous sirtuin inhibitor, thereby relieving inhibition.

Another strategy involves increasing intracellular NAD⁺ concentrations by inhibiting its degrading enzymes such as CD38, or stimulating its biosynthesis via supplementation with precursors like nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN) [16,63,127]. Strategies like NR and NMN are supported by early human interventional evidence confirming their ability to raise NAD⁺ levels, whereas iso-NAM remains in the preclinical stage. While oral supplementation is highly realistic in humans, a persistent limitation is that biomarker improvements do not yet consistently translate into clinical anti-aging outcomes. Additionally, the indirect nature of this activation makes it difficult to credit any single sirtuin isoform for the observed benefits.

Sirtuin Inhibitors

Sirtuin inhibitors are primarily used in controlling cancer cell proliferation. In addition to established clinical compounds, new agents are being investigated in experimental research [175]. As a class, most sirtuin inhibitors serve primarily as preclinical research tools. Their dosing realism is generally only established for a small minority of compounds used in oncology-oriented research. Major controversies include significant off-target effects and a context-dependent biology that makes it difficult to extrapolate their use from tumor suppression to broader preventive geroscience.

Nicotinamide (NAM)

NAM inhibits sirtuins by binding to the “C-pocket” adjacent to the NAD⁺ binding site [63]. Supported by both human and preclinical evidence as a biologically relevant modulator, its human exposure is easily achievable. However, its context-dependent effects are controversial, as it may inhibit rather than beneficially activate sirtuin signaling.

Splitomicin

Splitomicin (2,7-dihydroxynaphthalene) and its analogs selectively inhibit SIRT1 and SIRT2 [176]. Several splitomicin analogs- such as HR73—have been developed and may be useful in cancer and other diseases by reactivating silenced genes, promoting apoptosis in tumor cells, or inhibiting oncogene transcriptional repressors, and may also offer a potential target for HIV treatment [16,177]. Currently supported exclusively by preclinical evidence, this compound functions primarily as a research scaffold rather than a viable therapeutic agent. Consequently, it lacks both human translational validation and a clinically established dosing framework for sirtuin-targeted applications.

Sirtinol

Sirtinol (2-hydroxy-1-naphthaldehyde) inhibits both SIRT1 and SIRT2 [17]. It induces growth arrest in MCF-7 breast cancer cells, H1299 lung cancer cells, and PC3 prostate cancer cells [175,177]. Currently situated strictly within the preclinical stage, its anticancer effects have been demonstrated predominantly in cell models. Significant concerns regarding selectivity and off-target interactions persist, and a clinically realistic dosing regimen for sirtuin-targeted applications has yet to be established.

Cambinol

Cambinol, a chemically stable compound sharing a pharmacophore with sirtinol and splitomicin, inhibits SIRT1, SIRT2, and weakly SIRT5 in vitro [178]. In vivo murine experiments showed that cambinol inhibited Burkitt lymphoma xenograft growth by inducing apoptosis through hyperacetylation of BCL6 and p53 proteins [175]. Although efficacy has been observed in murine xenograft models, human dosing parameters remain unknown. Evidence suggests that its anticancer activity has not been translated into controlled human studies and may not be explained solely by sirtuin inhibition.

Salermide

Salermide, a reverse amide, inhibits SIRT1 and SIRT2 in vitro. It selectively induces apoptosis in cancer cells by reactivating pro-apoptotic genes epigenetically silenced by SIRT1, triggering p53-independent programmed cell death. Notably, salermide does not induce apoptosis in healthy cells, highlighting its potential in treating neoplasms such as breast and non-small cell lung cancer (NSCLC) [179]. While promising cancer selectivity has been shown in experimental systems, this characterization remains limited to preclinical evidence. At present, no established human dosing framework exists, leaving its therapeutic potential unconfirmed outside of laboratory settings.

AGK2

AGK2 (2-Cyano-3-[5-(2,5-dichlorophenyl)-2-furanyl]-N-5-quinolinyl-2-propenamide) is a selective SIRT2 inhibitor. In experimental models, it reduced breast cancer cell proliferation, enhanced BCG vaccine efficacy, and demonstrated potent anti-HBV activity [180,181,182,183,184]. Best categorized as a research probe rather than a validated clinical intervention, its utility is confined to preclinical observations. Major hurdles regarding target selectivity, long-term safety profiles, and overall translational relevance remain incompletely defined.

Tenovins

Tenovins are benzoylthiourea derivatives identified as small-molecule inhibitors of SIRT1 and SIRT2. By inhibiting these deacetylases, they increase p53 acetylation and stability, thereby inducing apoptosis in cancer cells [185]. Functioning primarily as mechanistic tools in oncology research, these agents lack clinical validation. Despite their utility in experimental frameworks, no established protocols for human sirtuin-targeted dosing currently exist.

Suramin

Suramin, a polyanionic naphthylurea historically used for trypanosomiasis, is a potent inhibitor of SIRT1, SIRT2, and SIRT5 [186]. It exhibits strong antiproliferative, antitumor, antiviral, and reverse transcriptase inhibitory properties [177]. In contrast to other candidates, the parent drug possesses a history of human clinical use for alternative indications. Nevertheless, the specific evidence supporting sirtuin inhibition remains purely preclinical and mechanistic; while clinically achievable dosing is documented, broad polypharmacology and toxicity make it difficult to isolate a selective sirtuin-directed strategy.

Novel Synthetic Modulators and Probes

Recent pharmacological advancements have also led to the development of highly specific synthetic inhibitors and activators acting as valuable chemical probes. For instance, Selisistat (EX-527) is a selective SIRT1 inhibitor with reported clinical safety data from Huntington’s disease trials [18,62]. As previously mentioned, AGK2 serves as a selective SIRT2 inhibitor, modulating neuroinflammation and cytoskeletal dynamics [180,181,182,183,184]. Furthermore, compounds like 3-TYP (targeting SIRT3) and OSS-128167 (targeting SIRT6) are chemical probes used to interrogate isoform-specific biology in oncology and metabolic disease models. Additionally, synthetic allosteric activators have been developed, like UBCS039, which is a SIRT6-targeting activator/probe used in preclinical research, with reported effects on autophagy and organ-protective mechanisms [18,62]. Encompassing the clinically characterized SIRT1 inhibitor selisistat alongside several preclinical probes—including AGK2, 3-TYP, OSS-128167, and UBCS039—this group lacks uniform clinical validation. Human exposure-response data are available only for selisistat, while for the remaining agents, unresolved issues regarding selectivity, off-target activity, and disease-context dependence suggest they remain research tools.

8. Modulation of Sirtuin Activity Through Lifestyle Factors

8.1. Diet

Caloric restriction (CR) is a dietary regimen in which an organism receives at least 20% fewer calories than it would normally consume ad libitum, while maintaining adequate nutrition [60].

CR has been shown to increase maximum lifespan in mammals and delay the onset of age-related diseases [187,188].

The anti-aging effects of CR are also associated with activation of the sirtuin family (Table 2) [128,188]. Indeed, SIRT1, SIRT2, and SIRT3 are upregulated in response to caloric restriction [80,189,190,191,192].

Caloric restriction is supported by strong animal data and human physiological evidence, yet robust long-term trials with aging-specific endpoints remain limited. While the intervention is feasible in principle, defining a “dose” of restriction that is both safe and effective for durable sirtuin modulation in humans is still a challenge. The risk of transitioning from beneficial restriction to harmful undernutrition or sarcopenia remains a major point of clinical controversy.

8.2. Physical Exercise

Regular physical exercise positively influences sirtuin activity and/or expression [193].

Moderate-intensity, long-term training induces high expression of SIRT1–p53 and SIRT3–FOXO3a-dependent pathways in the heart, reducing apoptosis and oxidative stress [16,129,193].

Exercise appears to induce differential activation among sirtuin family members. SIRT1 and SIRT3 levels increase following acute exercise regardless of intensity, while SIRT2 levels remain unchanged [130].

Crucially, human data indicates a dose-response relationship regarding exercise duration. While acute exercise may transiently activate SIRT1, significant increases in mitochondrial SIRT3 protein content in human skeletal muscle appear to require chronic endurance training (e.g., >8 weeks). Short-term interventions often fail to elicit this mitochondrial response, suggesting that SIRT3 represents a long-term adaptation mechanism rather than an acute stress responder in humans [130].

Irisin is a hormone released by muscles during exercise, produced by the cleavage of the membrane protein FNDC5. Recent studies have highlighted the role of FNDC5/irisin in vascular aging, showing that this exerkine circulates within extracellular vesicles (EVs). EVs enriched in FNDC5/irisin increase the stability of SIRT6 in vascular smooth muscle cells, conveying much of the protective benefits of exercise against vascular senescence. Regular physical activity, through SIRT1 modulation, promotes neuroprotection and hippocampal plasticity and may counteract age-related cognitive decline [194,195]. Exercise stands as the most clinically realistic upstream sirtuin-modulating strategy, supported by high-level human interventional evidence. Its dosing realism is inherently high since it is directly implementable. However, significant heterogeneity in exercise modality, intensity, and duration prevents the definition of a universal “dose” required for reproducible sirtuin-mediated anti-aging effects.

9. Conclusions

Aging is a complex physiological process orchestrated by multiple biological and genetic mechanisms.

Cellular senescence is a state of permanent cell cycle arrest characterized by a stable and long-term loss of proliferative capacity, despite maintained viability and metabolic activity [196].

Numerous studies have shown that, over time, the epigenome accumulates alterations, such as aberrant methylation patterns and chromatin marker modifications, that cause profound changes in gene expression. This phenomenon, known as “epigenetic drift,” indicates a progressive failure to maintain epigenetic signatures, thereby compromising molecular and cellular functions.

Such changes increase the risk of age-related diseases, including cancer, cardiovascular diseases, diabetes, and neurodegenerative disorders [197,198,199].

Sirtuins serve as a central hub connecting energy metabolism, genomic surveillance, and redox balance. Their modulation represents a plausible strategy for mitigating age-related physiological decline, pending robust clinical evidence [118,200].

However, much of the current knowledge comes from experimental studies, and definitive clinical evidence, especially regarding the therapeutic efficacy of sirtuins in humans, is still in its early stages or pending confirmation [18,62].

Emerging scientific evidence suggests that sirtuin pharmacology should not aim solely at universal activation; rather, precise mapping of the therapeutic actions of each isoform in different tissues and clinical contexts is required [201].

Despite numerous promising findings from preclinical models, translating these results from animals to humans remains partial and complex.

Looking ahead, an integrated approach combining compounds specifically capable of activating or inhibiting individual sirtuins with healthy lifestyle interventions may form the paradigm of a new generation of preventive medicine, one that does not merely treat existing disease but seeks to maintain cellular and systemic homeostasis across the human lifespan [202].

Only through a multidisciplinary strategy—encompassing biochemistry, pharmacology, nutrition, and physical exercise—can the full potential of sirtuins be realized, transforming them from promising research molecules into concrete tools for anti-aging strategies and the treatment of chronic degenerative diseases [203,204].