The role of the SIRT1 and mTOR pathways in exercise-induced β-cell senescence reduction in type 2 diabetes mellitus

Abstract

Type 2 diabetes mellitus (T2DM) is characterized by insulin resistance, chronic hyperglycemia, and pancreatic β-cell dysfunction, driven in part by cellular senescence and chronic inflammation. The sirtuin 1 (SIRT1) and mechanistic target of rapamycin (mTOR) pathways play critical roles in regulating cellular metabolism, stress responses, and aging, making them key targets for mitigating β-cell senescence and T2DM progression. SIRT1, a NAD + -dependent deacetylase, enhances insulin secretion, reduces oxidative stress, and suppresses inflammation by modulating transcription factors such as NF-κB and PGC-1α. Conversely, mTOR signaling, when hyperactivated, promotes cellular senescence and metabolic dysfunction. Exercise has emerged as a potent non-pharmacological intervention. It upregulates SIRT1 activity through increased NAD⁺ levels and AMP-activated protein kinase (AMPK) activation, while also downregulating excessive mTOR signaling. These effects enhance autophagy, reduce oxidative stress, and improve mitochondrial function, thereby preserving β-cell mass and function. Preclinical and clinical studies demonstrated that exercise-induced SIRT1 activation and mTOR inhibition mitigate β-cell senescence, improve glucose homeostasis, and reduce the risk of T2DM. Pharmacological strategies targeting SIRT1 activation and mTOR inhibition, such as NAD + boosters and rapamycin analogs, show promise in preclinical models but require further clinical validation. Understanding the interplay between the SIRT1 and mTOR pathways offers novel therapeutic avenues for preserving β-cell function, preventing T2DM, and promoting healthy aging. Future research should focus on optimizing exercise regimens and developing targeted interventions to harness the synergistic benefits of SIRT1 activation and mTOR inhibition in metabolic health.

Graphical abstract

Introduction

The burden of non-communicable diseases (NCDs) continues to rise globally. According to the World Health Organization, NCDs account for approximately 74% of all global deaths, with over 41 million people dying annually, primarily due to CVDs, cancer, chronic respiratory diseases, and diabetes [1, 2]. In low- and middle-income countries, NCDs contribute significantly to premature mortality, accounting for nearly one-third of deaths among individuals under 60 years of age, compared to less than 10% in high-income countries [3, 4]. Among all NCDs, type 2 diabetes mellitus (T2DM) remains a leading public health challenge [5]. As of 2023, an estimated 537 million adults worldwide suffer from diabetes, with T2DM accounting for the vast majority of cases (IDF, 2023) [6]. The prevalence of T2DM is strongly influenced by modifiable risk factors such as sedentarism, obesity, smoking, advancing age, and male sex [7, 8]. A diet high in refined carbohydrates, added sugars, and processed foods is closely associated with increased risks of metabolic syndrome (MetS), T2DM, and cardiovascular diseases (CVDs) [9]. T2DM is intricately linked to obesity and aging, with accumulating evidence pointing to the role of cellular senescence in metabolic tissues in driving disease progression [10, 11]. These pathological changes contribute to β-cell dysfunction, chronic inflammation, and progressive insulin resistance—hallmarks of T2DM pathogenesis.

Pancreatic β-cells are key regulators of glucose homeostasis, releasing insulin, the main hormone that lowers blood glucose[12]. Early-stage T2DM is characterized by increased β-cell mass and insulin secretion as a compensatory mechanism in response to insulin resistance [13]. However, chronic metabolic stressors, including oxidative stress, endoplasmic reticulum (ER) stress, and inflammation, lead to β-cell dysfunction, and senescence, which ultimately fail insulin secretion [14]. Studies have demonstrated that aging amplifies declines in β-cell function [15]. Insulin resistance, itself causing β-cell senescence, triggers a vicious cycle accelerating T2DM progression [16]. The ER is indispensable for insulin biosynthesis, as it promotes the folding and post-translational processing of proinsulin into bioactive insulin. ER dysfunction results in impaired proteostasis and ER stress − both contribute to β-cell dysfunction, and through conjunction with oxidative stress, inflammation, and mitochondrial dysfunction, are implicated in the causal pathology of metabolic and age-related diseases [17, 18]. T2DM is primarily an age-related disease defined by declining β-cell mass and function, a result of an inadequacy to cater to the demands of increased insulin production associated with life in insulin-resistant states. In the face of increased metabolic demand, β-cells can initially compensate, but with age their proliferative potential declines, and senescent cells aggregate [19].

Cellular senescence, an irreversible cell cycle arrest induced by stressors including DNA damage, telomere shortening, and mitochondrial dysfunction, is critically involved in β-cell decline. Senescent cells exhibit a senescence-associated secretory phenotype (SASP) that promotes chronic inflammation and contributes to the pathogenesis of age-related diseases, including T2DM[20]. Indeed, the chronic exposure of β-cells to high insulin concentrations in the setting of T2DM can drive β-cell senescence, leading to irreversible impairment of insulin secretion and glucose homeostasis[20]. β-cell compensatory mechanisms, such as proliferation and hyperinsulinemia, ultimately fail to maintain glucose homeostasis, leading to the progression from normal glucose tolerance (NGT) to impaired glucose tolerance (IGT), and subsequently overt T2DM [21, 22]. β-cell function remains further impaired even after diabetes is diagnosed, and prevention of T2DM and preservation of β-cell function with early interventions to halt the progression of the disorder are of utmost importance. The mechanisms that drive β-cell senescence and dysfunction may provide novel therapeutic targets mitigate T2DM and its complications, particularly if the SIRT1 and mTOR pathways are involved.

SIRT1 pathway and mechanisms of action

The sirtuin (SIRT) protein family, belonging to class III histone deacetylase (HDAC III), is an evolutionarily conserved enzyme that resembles the yeast silent information regulator 2 (Sir2). They are NAD + -dependent enzymes that catalyze the deacetylation of histone and non-histone proteins [23]. SIRT1, the most characterized homolog among the sirt, is the most homologous to Sir2 [24]. It is essential for controlling several biological processes, such as cellular senescence [25], apoptosis[26], glucose and lipid metabolism [27, 28], oxidative stress, and inflammation [29]. Sirtuins, especially SIRT1, play an essential role in aging and age-related diseases, including obesity, T2DM, CVDs, cancer, and neurodegenerative diseases[30]. A recent study showed that SIRT1 expression is downregulated in several tissues and cells under insulin-resistant or glucose intolerance states [31, 32]. Most notably, SIRT1 regulates the activity of more than a dozen non-histone proteins by deacetylation, among these transcription factors, transcriptional coregulatory proteins, and histones. Such deacetylation activity allows SIRT1 to modulate systemic metabolism by regulating glucose and lipid homeostasis[33]. Despite the nuclear localization of SIRT1, it dynamically shuttles between the nucleus and cytoplasm in response to developmental signals as well as physiological or pathological stressors [34, 35].

Chronic low-grade inflammation caused by obesity is a critical factor in the onset of insulin resistance[36–38]. The role of adipose tissue, in addition to serving as an insulin target organ for lipid metabolism, is as an endocrine organ that releases adipose hormones, cytokines, and chemokines that modulate systemic insulin sensitivity. The corresponding example is adipocyte-secreted adipokines: leptin and adiponectin, which can enhance insulin sensitivity[39]. However, in obesity, adipocytes are a net contributor to lipolysis, releasing free fatty acids (FFAs) and proinflammatory cytokines via changes in metabolic and transcriptional programming[36–38]. This induces M1 polarization of macrophages, which secrete pro-inflammatory mediators like TNF-α, IL-1β, and resistin. Mediators responsible for these effects sensitize adipocytes to insulin resistance and propagate inflammatory pathways featuring insulin-targeting tissues, including the liver and skeletal muscle [38]. As a result, ectopic lipid accumulation along with higher levels of inflammatory mediators disturb insulin signaling and increase systemic insulin resistance [40].

Inflammation as a host defense pathway acting against infection and non-infectious stressors can cause tissue injury when not tightly controlled. Among these, key inflammatory cytokines such as IL-1β, IL-6, TNF-α, and CCL2 are known to orchestrate inflammatory responses. If local inflammation proceeds unchecked, it eventually becomes systemic, exacerbating tissue injury. Evidence suggests that SIRT1 has strong anti-inflammatory effects because it inhibits important inflammatory pathways, including NF-κB, HIF1α, AP-1, and p38 MAPK[41]. For instance, SIRT1 deacetylated the NF-κB p65 subunit at lysine 310, which inhibits NF-κB activity and decreases the expression of the proinflammatory cytokines[42, 43]. Likewise, SIRT1 binds to HIF1α and deacetylated it on lysine 374, preventing its transcriptional activity under hypoxic conditions[44]. SIRT1 deacetylates AP-1 and thus inhibits the transcriptional activity of the inflammatory factors IL-2, IL-8, and TNF-α[45]. Moreover, SIRT1 inhibits p38 MAPK phosphorylation, which reduces p38 MAPK proinflammatory signals[46].

The activity of SIRT1 is highly sensitive to cellular NAD + concentrations, which vary based on the metabolic and inflammatory status. Diminished NAD + availability results in decreased SIRT1 activity during hyperinflammation and associated organ injuries. Similarly, reduced SIRT1 activity and increased proinflammatory gene expression in alcohol-induced inflammation and oxidative stress are associated with decreased levels of NAD + [47]. On the other hand, SIRT1 activation, induced by the increase in the concentration of NAD +, induces a change from glycolysis to fatty acid oxidation during the wearing-off of acute to chronic inflammation. The transition is regulated by SIRT1 and SIRT6, which coordinate metabolic remodeling to inflammatory signals[48]. SIRT1 can find indirect routes to influence inflammatory signaling in various ways, such as acting on another class of regulatory proteins like AMPK and peroxisome proliferator-activated receptors (PPARs). Activated SIRT1 represses inflammatory responses, likely at least in part through AMPK activation, which inhibits NF-κB signaling[49]. Furthermore, SIRT1 controls the inflammatory state of macrophages and T lymphocytes to affect the metabolism in adipose tissue and systemic insulin sensitivity in the setting of obesity[32, 50, 51].

Pancreatic β-cell dysfunction is considered a hallmark of T2DM progression via inflammation and oxidative stress[52]. In other cases, hyperglycemia, FFAs, and proinflammatory cytokines like TNF-α lead to mitochondrial overproduction of Reactive oxygen species (ROS) in insulin-resistant or diabetic states. ROS activates serine/threonine kinases such as p38 MAPK, JNK, and IKK, leading to the phosphorylation of insulin receptor substrate 1 (IRS-1) on serine residues. The phosphorylation of IRS-1 at serine 478 compromises its tyrosine phosphorylation, giving rise to abrogated insulin signaling pathways and persistent inflammation[53, 54]. SIRT1 improves β-cell survival and functionality by protecting insulin secretion and glucose homeostasis [55]. Exercise is an effective non-drug strategy to increase SIRT1 levels: Endurance exercise increases the SIRT1 protein content in skeletal muscle[56]. In this regard, exercise may ameliorate inflammation, oxidative stress, and insulin resistance by enhancing the functional role of SIRT1, thus providing an attractive strategy for the prevention and treatment of the metabolic dysregulation encountered in MetS such as T2DM [57, 58].

SIRT1 anti-inflammatory mechanisms and its role in regulating diabetes via NF-κB signaling

SIRT1, a NAD-dependent deacetylase, plays a central role in regulating inflammatory responses, particularly through its interaction with the NF-κB signaling pathway — a key regulator of inflammation, immune response, and cellular stress. Chronic activation of NF-κB in metabolically active tissues such as adipose tissue, liver, and skeletal muscle under conditions of insulin resistance, obesity, and T2DM leads to systemic inflammation and impaired insulin signaling [59, 60]. SIRT1 suppresses the transcriptional activity of the p65 subunit of NF-κB by deacetylating it at lysine 310, thereby reducing the expression of pro-inflammatory cytokines such as TNF-α, IL-6, and MCP-1 [61, 62].

These anti-inflammatory effects of SIRT1 have been observed across various metabolic tissues:

• In adipose tissue, SIRT1 activation reduces macrophage infiltration and the secretion of inflammatory adipokines, improving systemic insulin sensitivity [63, 64].

• In the liver, SIRT1 inhibits hepatic NF-κB activity, which decreases inflammation and suppresses gluconeogenesis, contributing to improved glucose homeostasis [65, 66].

• In skeletal muscle, a major site of glucose uptake and energy metabolism, SIRT1 enhances mitochondrial biogenesis and oxidative metabolism through PGC-1α activation [67]. Endurance exercise increases SIRT1 expression and activity in skeletal muscle, partly through elevated NAD⁺ levels, leading to reduced NF-κB signaling, lower oxidative stress, and improved metabolic function [67, 68].

The crosstalk between SIRT1 and NF-κB is especially important in the context of β-cell senescence. Systemic inflammation originating from peripheral tissues such as skeletal muscle and liver can transmit inflammatory signals to the pancreatic islets, leading to local inflammation, ER stress, and ultimately dysfunction of β-cells [69, 70]. Therefore, the anti-inflammatory actions of SIRT1 in these tissues indirectly support β-cell health by limiting the release of SASP factors and inflammatory cytokines[70]. Physical exercise — including both aerobic and resistance training — acts as a powerful non-pharmacological intervention that activates SIRT1 across metabolically active organs and suppresses NF-κB signaling [71, 72]. These effects provide broad metabolic benefits, although different types of exercise may impact distinct pathways:

• Aerobic exercise primarily improves insulin sensitivity and reduces inflammation by enhancing mitochondrial function, and antioxidant capacity, and decreasing oxidative stress [73, 74].

• Resistance exercise exerts more indirect effects on metabolic improvement, mainly through increasing muscle mass and enhancing insulin sensitivity [75, 76].

Both types of exercise contribute to increased SIRT1 activity and reduction of senescence-associated inflammation, although their precise and relative mechanisms may differ. Overall, these findings indicate that SIRT1 plays a key role in modulating diabetes progression through the regulation of inflammatory responses, especially by suppressing NF-κB signaling. Moreover, physical exercise reduces chronic low-grade inflammation involved in T2DM progression through SIRT1 activation. SIRT1 suppresses the expression of inflammatory mediators by deacetylating the p65 subunit of NF-κB, and this effect has also been observed in pancreatic β-cells [61, 77]. Physical activity further enhances this anti-inflammatory effect and protects β-cells from pro-senescent cytokines such as IL-1β and TNF-α [78].

However, SIRT1 functions as a key molecular link between physical activity and metabolic health. While influenced by different types of exercise, all forms of physical activity led to reduced inflammation, improved insulin sensitivity, and protection of β-cell function. Future research should focus on optimizing exercise protocols to maximize SIRT1 activation and balanced mTOR inhibition in target tissues to improve metabolic outcomes (Table 1).

Table 1.

Effects of aerobic and resistance exercise on SIRT1 activation and inflammation reduction

Clear and strong effect

Possible or mild effect

No significant effect

Significant decrease

Potential or variable effect

Secondary modulation

SIRT1, mitophagy, and mitochondrial homeostasis

The SIRT1 signaling pathway plays a pivotal role in the regulation of mitochondrial homeostasis, particularly through its involvement in mitophagy — the selective degradation of damaged mitochondria [79, 80]. Mitochondrial dysfunction is a key contributor to metabolic disorders, including insulin resistance and T2DM, due to its impact on energy metabolism, oxidative stress, and cellular senescence [81, 82]. SIRT1 promotes mitochondrial quality control by enhancing mitophagy via deacetylation of key regulatory proteins such as PGC-1α, FOXO3a, and components of the mitochondrial fission/fusion machinery [83–85]. This process ensures the removal of dysfunctional mitochondria and supports the biogenesis of healthy mitochondria, thereby preserving cellular bioenergetics and reducing the accumulation of reactive oxygen species (ROS) [86].In pancreatic β-cells, where mitochondrial integrity is crucial for glucose-stimulated insulin secretion, SIRT1-mediated mitophagy serves as a protective mechanism against metabolic stress-induced dysfunction and senescence [87, 88]. Physical exercise has been shown to enhance SIRT1 activity through increased NAD + levels and AMPK activation, both of which are essential for the induction of mitophagy. Exercise-induced activation of SIRT1 not only improves mitochondrial turnover but also enhances insulin sensitivity and reduces inflammation, contributing to improved metabolic homeostasis [89, 90]. By promoting mitophagy, SIRT1 helps maintain β-cell function and survival under conditions of chronic metabolic stress, such as hyperglycemia and lipotoxicity [91].

Targeting this pathway through lifestyle interventions like exercise or pharmacological agents that activate SIRT1 may offer therapeutic potential in preventing β-cell failure and delaying the progression of T2DM [92]. Therefore, understanding the interplay between SIRT1 and mitophagy provides valuable insights into the molecular mechanisms underlying metabolic health and aging.

Therapeutic potential of the SIRT1 and mTOR pathways in T2DM

The members of the sirtuin family, particularly, SIRT1, SIRT2, and SIRT3, have recently been shown to act as a valuable therapeutic target for regulating glucose metabolism and β-cell function in the context of T2DM [93].

SIRT1 plays a central role in the regulation of metabolic homeostasis, in part through its inhibitory effects on the mTOR pathway [94, 95].

SIRT1 negatively regulates mTOR signaling by deacetylating key regulatory proteins such as tuberous sclerosis complex 2 (TSC2) and ULK1, both of which are crucial for autophagy induction [96, 97]. Deacetylation of TSC2 enhances its stability and activity, promoting the inhibition of Rheb, a small GTPase that directly activates mTORC1 [98]. Similarly, ULK1 deacetylation facilitates the initiation of autophagy, a process essential for maintaining cellular quality control under metabolic stress [99]. By modulating these components, SIRT1 effectively suppresses excessive mTORC1 activity, thereby enhancing mitochondrial function, reducing ER stress, and improving β-cell survival and insulin secretion —critical factors in the prevention of β-cell dysfunction and T2DM [89, 92, 100]. These NAD + -dependent deacetylases are key modulators of inflammation, oxidative stress, and mitochondrial activity, all of which are characteristics of insulin resistance and T2DM pathogenesis [101]. Novel therapeutic approaches based on the pharmacological activation of sirtuin, in addition to lifestyle changes including calorie restriction (CR) and exercise, have provided new strategies for treating T2DM [33]. Of these, SIRT1 has been the most studied, with activators such as resveratrol and synthetic compounds showing antidiabetic effects in preclinical models and small human trials [102]. CR-associated lifespan extension and postponement of age-associated diseases, such as diabetes, is highly correlated with the activation of a key CR mediator, SIRT1 [103]. In humans, CR has been associated with improvements in metabolic factors, including reductions in serum insulin, cholesterol, C-reactive protein, and TNF-α levels, as well as improvements in carotid intima-media thickness [104]. In young, nonobese individuals, 25% CR for six months upregulated SIRT1 and PGC-1α in skeletal muscle and improved mitochondrial function, visceral fat mass, insulin resistance, oxidative stress, and metabolic rate [105]. The result indicates that SIRT1 activation in the form of CR mimetic would be a novel therapeutic target for T2DM, especially in the context of excess energy intake and genetic predispositions affecting insulin signaling and obesity risk. Nonetheless, clinical data regarding SIRT1 activators as a means to improve insulin resistance and T2DM remain limited.

Intervention with the SIRT1 gene expression pathway is of potential direct benefit in preventing metabolic dysregulation in obesity and T2DM [55]. In pancreatic β-cells, SIRT1 promoted insulin secretion by repressing uncoupling protein 2 (UCP2), enhancing ATP production, and augmenting Ca2 + -dependent insulin exocytosis [33]. Notably, SIRT1 has also been shown to protect β-cells from oxidative stress and cytokine-induced damage via the inhibition of NF-κB signaling, demonstrating its therapeutic potential [55]. Regular physical exercise is an established intervention to prevent and ameliorate aging-related disease [57].

The interplay between SIRT1 and mTOR is further mediated by AMPK, which serves as a central energy sensor and molecular bridge between these two pathways [106]. SIRT1 activates AMPK through deacetylation and enhancement of its phosphorylation, particularly under conditions of increased NAD⁺ availability such as during calorie restriction or exercise[89, 107]. Activated AMPK then inhibits mTORC1 via phosphorylation of TSC2 and Rheb, reinforcing autophagy and mitochondrial biogenesis [108]. This SIRT1–AMPK–mTOR axis plays a pivotal role in coordinating cellular responses to metabolic stress, including hyperglycemia and lipotoxicity [106, 109]. At the systemic level, this interaction contributes to improved insulin sensitivity, reduced chronic inflammation, and better glucose and lipid homeostasis, highlighting its therapeutic relevance in metabolic diseases [89, 92, 100]. Targeting this axis through lifestyle interventions such as exercise or pharmacological agents may offer synergistic benefits in preserving β-cell function and promoting metabolic health. One example is exercise activating the sirtuin, specifically SIRT1, which for those new in the field confers many of the benefits of physical activity in organ dysfunction associated with age. Lifelong exercise reduces inflammation and enhances fat metabolism, which is partially mediated by SIRT1 and its downstream effectors PGC-1α and AMPK [58]. It has been reported that exercise causes upregulation of SIRT1 in animal models, but data in humans have been inconsistently described to date [110, 111]. The hypoglycemic effects of HIIT exercise have been observed due to improved metabolic profiles, which contribute to lower SIRT1 activity, while chronic cycling has been shown to increase the mRNA expression of SIRT1 in the skeletal muscle of T2DM individuals [112]. Training swimming also increased the gene and protein expression of SIRT1 in the pancreatic tissue, enhanced the antioxidant enzyme activity, and ameliorated the metabolic parameters in the preclinical setting [113]. The mTOR pathway is an essential regulator of cell growth, proliferation, survival, and autophagy. mTOR has two largely functionally distinct complexes, mTORC1, and mTORC2, which are activated by growth factors and nutritional and energy status. Specifically, the mechanistic target of rapamycin complex 1 (mTORC1) is a central modulator of aging and age-associated diseases, such as T2DM [114]. Increases in mTORC1 signaling lead to increased rates of protein synthesis, changes to protein folding, and an accumulation of damaged proteins, which have all been linked with cellular aging and dysfunction. mTORC1 inhibition extends lifespan and protects against age-related pathologies, such as T2DM [115, 116]. Translation initiation and elongation are governed by mTORC1 and its key targets, including 4EBP1 and S6K [116]. It has long been known that mice lacking the S6 kinase, a downstream target of mTORC1, live longer and display increased AMPK signaling, illustrating the intersection of mTOR and energy-sensing pathways [116]. Abnormal mTOR signaling in T2DM leads to β-cell dysfunction and insulin resistance; therefore, mTOR signaling is a potential therapeutic target for metabolic diseases. Nevertheless, these SIRT1 and mTOR signaling avenues show therapeutic promise in enhancing β-cell functionality and T2DM treatment [117–120]. Pharmacological agents, CR, or exercise activate SIRT1, leading to enhanced insulin secretion, reduced oxidative stress and inflammation, and improved mitochondrial function. Likewise, mTOR signaling modulation may be protective against age-related metabolic dysfunction and β-cell senescence. For in vitro translations, the ATP-sensitive potassium channels were more reliable and predictable than channel-induced depolarizations, while the aforementioned preclinical studies indicate that such pathways may indeed validly influence human subjects in the broader context of human studies. This knowledge, including SIRT1 activation and mTOR inhibition may provide synergistic β-cell functional preservation and T2DM body progression prevention strategy.

mTOR inhibition: role in β-cell function and potential side effects

mTOR is a central regulator of cellular metabolism, growth, and survival, integrating signals from nutrients, growth factors, and energy status to control key biological processes. mTOR functions through two distinct multiprotein complexes: mTORC1 and mTORC2, which have distinct molecular roles and functional outcomes, particularly in the context of β-cell function and metabolic health. mTORC1 is primarily responsible for regulating protein synthesis, cell growth, and autophagy, and its hyperactivation has been linked to age-related pathologies, including cellular senescence and metabolic dysfunction [121, 122]. In β-cells, mTORC1 overactivation contributes to ER stress, impaired insulin biosynthesis, and reduced proliferation — all hallmarks of β-cell failure in T2DM. Inhibition of mTORC1 enhances autophagy, reduces oxidative stress, and improves mitochondrial quality control, thereby protecting β-cells from chronic metabolic stressors such as hyperglycemia and lipotoxicity [123]. In contrast, mTORC2 plays a more nuanced role, primarily influencing cell survival, cytoskeletal organization, and insulin signaling via Akt phosphorylation [114]. While mTORC2 inhibition may preserve β-cell mass under certain conditions, it can also impair insulin signaling and glucose homeostasis, highlighting the need for balanced modulation of both complexes. The inhibition of mTOR signaling has emerged as a potential strategy to reduce SASP, which contributes to chronic inflammation and tissue dysfunction in aging and metabolic diseases [20, 124]. This effect is largely mediated through the induction of autophagy — a critical mechanism for clearing damaged organelles and maintaining cellular homeostasis [125–127]

In pancreatic β-cells, mTOR inhibition exerts protective effects through multiple mechanisms: (1) it alleviates ER stress while promoting proper proinsulin folding and maturation [128–130]; (2) it enhances β-cell proliferation, potentially compensating for the β-cell mass loss characteristic of T2DM [131, 132]; (3) it facilitates insulin biosynthesis to meet metabolic demands [133]; and (4) collectively these effects contribute to improved systemic glucose homeostasis and insulin sensitivity [134].

However, these benefits must be weighed against potential adverse effects. Prolonged or excessive inhibition of mTOR—particularly combined suppression of mTORC1 and mTORC2—can lead to immunosuppression, impaired wound healing, and metabolic syndrome (MetS) [135, 136]. For example, rapamycin and its analogs, which predominantly inhibit mTORC1, have been associated with increased infection risk due to their immunosuppressive properties [137]. Moreover, because mTORC2 plays a role in maintaining insulin signaling via Akt activation, its inhibition may paradoxically worsen glucose tolerance and lipid metabolism [138]. Therefore, while mTOR inhibition holds therapeutic promise for delaying β-cell senescence and improving metabolic function, targeting mTORC1 selectively —while preserving mTORC2 activity—may offer a more favorable outcome. Future studies should focus on tissue-specific and isoform-selective mTOR inhibitors, as well as combination therapies that balance autophagy enhancement with metabolic stability, to optimize benefits and minimize risks (Table 2).

Table 2.

SIRT1 and mTOR pathways in exercise-induced β-cell senescence

Author/Date	Subject characteristic	Exercise protocol	Sample	Biomarkers	Duration	Outcome
Hung-Wen Liu (2019) [124]	N = 16 male diabetic C57BLKS/J (db/db) mice	MET (5.2 m/min, 1 h/day, and 5 days/week)	Kidney- liver	SIRT1 NF-κB PGC1α	8 weeks	↑ SIRT1 ↓ NF-κB ↑ PGC1α
Dumke et al. (2022) [125]	N = 40 trained cyclists	3 h of intensive cycling performed on three consecutive days	Muscle	SIRT1 PGC-1α CC CS	3 day	↑ SIRT1 ↑ CC ↑ CS ↑ PGC1α
Ghasemi, Afzalpour, & Nayebifar (2020) [126]	N = 20 Overweight women (trained & untrained	3 sessions/week WT (4 × 30 s all-out cycling at.075 kg/kg BM)	Serum SIRT1	SIRT1	10 weeks	↑ SIRT1
Ghiasi et al. (2019) [89]	N = 28 Diabetic Wistar rats	ST (60 min/daily, 5 days/week)	Serum –pancreatic β cells	SIRT1 Albumin SOD GPX CAT MDA	12 weeks	↑ SIRT1 ↑ Albumin ↑ SOD  ↔ GPX  ↔ CAT  ↔ MDA
Gurd et al (2010) [97]	N = 9 (3 females and 6 males) healthy human	HIIT (1 h of 10 4 min intervals at 90% peak oxygen consumption separated by 2 min rest, 3 days per week)	Muscle	SIRT1 Cs β HCADS CC PGC-1a	6 weeks	↑ SIRT1 ↑ Cs ↑ β HCADS ↑ CC ↑ PGC-1a
Gharakhanlou & Bonab [95]	N = 40 women with T2DM	ST with an intensity of 45–65% of maximum HR	Blood	SIRT1 FGF-21 HDL	12 weeks	↑ SIRT1 ↑ FGF-21 ↑ HDL
Hooshmand-Moghadam et al. (2020) [127]	N = 30 Healthy elderly men	RT intensity of 60% 1RM (3 ×/week, 4 sets of the six exercise circuits	Blood	Sirt1 Sirt3 Sirt6 PGC1-α TE	12 weeks	↑ Sirt1 ↑ Sirt3 ↑ sirt6 ↑ PGC1-α ↑ TE
Lamb et al. (2020) [128]	N = 16 overweight, untrained individuals	SRRT (2 d/wk) full-body	Muscle	NAD +  NADH SIRT1 NAMPT	10 weeks	↑ NAD +  ↑ NADH ↑ SIRT1 ↑ NAMPT

BM Body mass, MET moderate exercise training, CC Cytochrome C, CS citrate synthase, WT Wingate test, ST swimming training, SOD superoxide dismutase, GPX glutathione peroxidase, CAT catalase, MDA malondialdehyde, HIIT high intensity interval training, β -hydroxyacyl-coenzyme A dehydrogenase = β HCADS, HR heart rate, HDL High density lipoprotein, FGF-21 fibroblast growth factor 21, RT resistance training, 1RM 1 repetition maximum, TE telomerase enzyme, SRRT self-reported resistance training, NAD + nicotinamide adenine dinucleotide, NAMPT nicotinamide phosphoribosyltransferase

Conclusion

SIRT1 regulates cellular senescence through both mTOR-dependent and independent pathways, while mTOR signaling reciprocally modulates SIRT1-mediated responses. Exercise emerges as a powerful non-pharmacological intervention that activates SIRT1 (primarily via NAD⁺ elevation) while suppressing pathological mTOR overactivation, collectively preserving β-cell function through enhanced autophagy, reduced oxidative stress, and improved mitochondrial homeostasis. The SIRT1-mTOR axis mediates critical exercise benefits including mitochondrial biogenesis, telomere maintenance, and anti-inflammatory adaptations—all vital for maintaining glucose homeostasis in T2DM. However, individual responses depend on genetic background (e.g., insulin signaling variants), dietary factors (e.g., NAD⁺ precursor intake), and metabolic status, highlighting the need for personalized approaches. While preclinical studies show promise for rapamycin analogs and NAD⁺ boosters, their clinical translation requires caution due to potential immunosuppression, metabolic disturbances, and oncogenic risks associated with chronic use. Future research should prioritize: 1) mechanistic studies of exercise-induced SIRT1/mTOR modulation in β-cells 2) tissue-specific responses across sirtuin isoforms (SIRT3/6) and mTOR mTORC2 and mTORC3 personalized strategies accounting for genetic-epigenetic variability. Longitudinal clinical trials must evaluate both the systemic effects across metabolic tissues (liver, muscle, brain) and risk–benefit ratios of pathway-targeted interventions, particularly for vulnerable populations. Such investigations will clarify how to optimally harness the SIRT1-mTOR axis to combat β-cell senescence and diabetes progression while minimizing adverse effects (Fig. 1).

Fig. 1.

Note: This data is mandatory

Authors’ contributions

All authors contributed significantly to the development of this research. R.H. was responsible for the study's conceptualization, design, and supervision, as well as reviewing and finalizing the manuscript. Z.H. conducted the literature review, collected and analyzed data related to the molecular mechanisms of SIRT1 and mTOR pathways in β-cell function, and drafted the initial version of the manuscript. A.K. contributed to the interpretation of findings, provided critical feedback during manuscript revision, and ensured scientific rigor in discussing the role of exercise in reducing cellular senescence in type 2 diabetes mellitus. All authors read and approved the final version of the manuscript and agreed to be accountable for all aspects of the work, ensuring its accuracy and integrity.

Funding

The author declares that the research did not receive any financial grants.

Data availability

Not applicable.

Declarations

Ethical approval

Not applicable.

Consent for publication

All authors provided input into the manuscript, reviewed the final draft, and provided consent for publication.

Conflict of interest

The authors affirm that the research was carried out without any commercial or financial relationships that could be interpreted as a potential conflict of interest.