Senolytic Interventions for Type 2 Diabetes: Current Evidence and Future Directions

Abstract

Cellular senescence, a phenomenon characterized by the accumulation of dysfunctional, metabolically active cells, is increasingly recognized to be a key player in aging-related metabolic disorders. It is accelerated by hyperglycemia through various molecular pathways, positioning it as a critical mechanism in the pathophysiology of type 2 diabetes mellitus (T2D) and a potential therapeutic target. Emerging evidence from animal and clinical studies suggests that the usage of senolytic drugs, which selectively deplete senescent cells, can improve blood glucose regulation and mitigate diabetic complications. However, despite the conceptual feasibility of this approach, several challenges remain in their translation to the clinic: the molecular mechanisms underlying the pathogenicity of cellular senescence in vivo remain incompletely understood, and organ-specific effects of senolytic administration are yet to be fully elucidated to ensure their safety and efficacy in clinical applications. This review explores the characteristics of cellular senescence and the senescence-associated secretory phenotype (SASP) in key tissues involved in glucose homeostasis, including the pancreas, liver, adipose tissue, and skeletal muscle and the potential applications of targeting cellular senescence as a therapeutic strategy for T2D management.

1. Introduction

Type 2 diabetes (T2D) is a chronic metabolic disorder characterized by sustained hyperglycemia resulting from insulin resistance and inadequate insulin production. As the most common form of diabetes, T2D accounts for approximately 90–95% of all diabetes diagnoses [1,2]. T2D typically develops in adulthood and is strongly linked to lifestyle factors including obesity, physical inactivity, and unhealthy dietary patterns. T2D progression is often gradual and may include polyuria, polydipsia, fatigue, blurred vision, and slow-healing wounds [1,3]. Without prompt management, T2D can lead to severe complications including cardiovascular diseases, nephropathy, neuropathy, and retinopathy [1,3]. Standard treatments typically involve lifestyle intervention, i.e., diet and exercise modifications, pharmacotherapy with agents such as metformin, and insulin therapy to regulate blood glucose levels [4]. Moreover, endocrine disorders particularly those related to obesity, diabetes, and thyroid dysfunction contribute significantly to the global healthcare burden, highlighting their role in increasing morbidity and mortality [2]. The global burden of diabetes has escalated dramatically over the past three decades. As of 2025, an estimated 800 million individuals are living with diabetes, quadrupling from 135 million cases in 1995 [5]. Projections show that this number could exceed 1 billion cases by 2050, positioning diabetes as one of the foremost public health challenges of the 21st century [6]. Contributing to this surge are the aging population and rising rates of obesity, both of which play critical roles in the development of T2D.

The incidence of T2D correlates with age, as physiological changes associated with aging, including decreased insulin sensitivity, impaired pancreatic beta-cell function, and increased visceral adiposity, significantly elevate the risk of disease onset [7,8]. In addition, aging is often accompanied by chronic low-grade inflammation and oxidative stress, which exacerbate metabolic dysregulation and contribute to the pathogenesis of T2D [9]. Cellular senescence, a phenomenon characterized by the accumulation of dysfunctional, metabolically active cells, is increasingly recognized to be a key player in aging-related metabolic disorders. Senescent cells secrete pro-inflammatory cytokines and factors promoting systemic dysfunction and insulin resistance, complicating glucose homeostasis [10,11]. Importantly, the diabetic microenvironment itself amplifies senescence in return in a feedback loop [12,13]. Moreover, older individuals with T2D face unique challenges such as frailty, cognitive decline, multimorbidity, and an increased risk of hypoglycemia due to altered drug metabolism and impaired counter-regulatory mechanisms, which complicate disease management [14].

While obesity remains a widely established risk factor for T2D, the impact of aging on diabetes risk is observed across the BMI spectrum. A recent analysis revealed that individuals over the age of 70 with a normal BMI exhibit a T2D prevalence comparable to that of younger individuals in their 30s with obesity [15]. Large registry studies have shown that the risk of T2D increases with age, irrespective of BMI; prevalence rises from 0.3% in individuals aged 20 years to 19.4% in those aged 70–79 years [15] and a recent cross-sectional study indicates that age modifies the influence of traditional risk factors, such as BMI and cholesterol, on the likelihood of developing T2D [8]. These findings highlight a critical gap in the mechanistic understanding of how aging potentiates T2D risk, independent of lifestyle factors [16]. In light of these observations, there is a compelling rationale for investigating age-related therapeutic interventions that specifically address aging-related metabolic dysfunctions and mitigate the risk of T2D. Senolytics, a class of compounds that selectively target and eliminate senescent cells, have emerged as a promising therapeutic strategy for mitigating age-related disorders. By reducing the burden of cellular senescence, senolytics offer the potential to ameliorate the metabolic dysfunctions driving T2D development, providing a novel approach to managing the onset of T2D.

2. Cellular Senescence and the Senescence-Associated Secretory Phenotype

Aging is characterized by a progressive decline in tissue and cellular function over an organism’s lifespan, often leading to chronic diseases such as metabolic disorders [17]. Despite its significance, the molecular mechanisms linking aging to systemic degeneration remain poorly understood. As organisms age, the accumulation of senescent cells in various tissues contributes to the progressive decline in cellular and tissue function [18,19].

Cellular senescence is accompanied by an inflammatory hypersecretory state, known as the senescence-associated secretory phenotype or SASP, characterized by growth arrest and upregulation of cell cycle inhibitors, such as p16 and p21, alongside structural and metabolic alterations and chronic DNA damage responses [20]. The SASP serves as the primary mediator of paracrine effects exerted by senescent cells on their surrounding tissue microenvironment, influencing various local and systemic biological functions through complex signaling networks [21,22]. Its heterogeneous composition is collectively shaped by cell type, senescence inducers, time, and microenvironmental conditions (Figure 1). Typically, the SASP encompasses diverse pro-inflammatory cytokines (IL-1α, IL-6, IL-8, TNFα, interferon-γ), chemokines, matrix remodeling factors, bioactive lipids, growth factors, microRNAs, non-coding RNAs, reactive oxygen species (ROS), and exosomes, each uniquely contributing to the SASP’s biological effects and resulting in diverse and at times conflicting biological outcomes [21,22]. The plethora of secreted factors both drive beneficial regenerative functions and detrimental inflammatory processes. While SASP-derived chemokines recruit immune cells to the site of inflammation, facilitating the clearance of senescent cells and promoting tissue repair through paracrine signaling of growth factors such as VEGF, HGF, and IGF-1 [23], the persistent secretion of pro-inflammatory cytokines and matrix-degrading enzymes promotes a chronic inflammatory milieu that progressively damages tissues and disrupts extracellular matrix integrity [24]. Additionally, SASP components propagate senescence in neighboring cells via paracrine signaling and amplify their secretory phenotype in a self-sustaining feedback loop, further exacerbating tissue dysfunction and inflammation [25,26].

3. Senescence as a Driver of Metabolic Dysfunction

Cellular senescence and the SASP are key contributors to aging-related metabolic decline, primarily through the establishment of a chronic pro-inflammatory milieu that disrupts insulin signaling. In metabolic tissues, sustained inflammation driven by senescent cells leads to systemic dysfunction characterized by insulin resistance, impaired glucose tolerance, dyslipidemia, and hypertension, collectively defining the clinical spectrum of metabolic syndrome [27,28,29]. Senescent cells in metabolic tissues exhibit distinct SASP profiles that actively impair neighboring cell function. Proteomic analyses reveal that senescent pancreatic β-cells exhibit an SASP uniquely enriched in factors such as activin A and matrix metalloproteinases, which impair neighboring β-cell function and promote immune infiltration [30]. This results in β-cell dysfunction, impaired glucose-mediated insulin secretion, and increased basal insulin output [31,32,33]. Preclinical models provide direct evidence for the systemic impact of senescent cells on metabolic dysfunction. Transplantation studies have demonstrated that senescent β-cells can induce systemic insulin resistance in healthy mice by propagating inflammatory signals that impair peripheral glucose uptake, recapitulating key features of T2D [31,34,35,36,37]. Conversely, the SASP-driven immune axis amplifies systemic inflammation while expanding the senescent phenotype to neighboring cells. Human islets from diabetic donors exhibit elevated senescence markers alongside SASP factors that impair β-cell function and promote local immune cell infiltration [38]. Notably, senescent adipose tissue has been shown to promote β-cell senescence in pancreatic islets via inflammatory signaling pathways, creating a feedback loop that accelerates T2D progression [31].

In the liver, the accumulation of senescent hepatocytes and non-parenchymal cells lead to the propagation of SASP-driven chronic inflammation and causally links to hepatic steatosis and fibrosis. Senescence in hepatic stellate cells and sinusoidal endothelial cells further impairs metabolic homeostasis through both cell autonomous and paracrine mechanisms and lose the ability to metabolize fatty acids efficiently [39] offering an explanation for non-alcoholic fatty acid disease and its frequent coexistence with T2D and obesity [39,40]. Supporting this, liver biopsies from 58 patients revealed that hepatocyte senescence was strongly associated with the severity of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis [41]. The endothelial-parenchymal crosstalk is increasingly recognized as an important, although underappreciated, mechanism in the progression of metabolic syndrome and T2D [39].

In the skeletal tissue, as the primary site of glucose disposal and a major determinant of basal metabolic rate, senescent satellite cells and myofibers exhibit reduced mitochondrial function and suffer from SASP-induced muscle fiber degeneration and decreased glucose uptake. This occurs through the downregulation of GLUT4 transporters and impaired insulin signaling, directly contributing to systemic glucose intolerance [40] and propagating local and systemic inflammation [42]. The experimental clearance of senescent hepatocytes reduced hepatic steatosis [39] and hyperinsulinemia [41] in aged, obese, and diabetic experimental animals; similarly, the in vivo clearance of senescent cells from skeletal muscle restores insulin sensitivity and muscular function [43,44,45], offering a proof of concept for the feasibility of senescence-driven therapeutic interventions. Lastly, it is known that metabolic tissue senescence exacerbates diabetes pathogenesis across subtypes. Cellular senescence has been implicated in senescence type 1 (via SASP-mediated immune activation) [35], type 2 (through insulin resistance-driven p21Cip1 activation) [46], and monogenic forms such as MODY linked to MAFA mutations that induce premature senescence [47]. These intersecting mechanisms—adipose senescence exacerbating insulin resistance, β-cell senescence impairing insulin secretion, and systemic SASP perpetuating inflammation—position cellular senescence as a unifying pathway through which aging and metabolic stressors converge to drive diabetes pathogenesis.

4. Metabolic Dysfunction as a Driver of Cellular Senescence

The diabetic microenvironment not only results from cellular senescence but actively promotes it, creating a self-reinforcing cycle of metabolic dysfunction and cellular aging (Figure 2). Insulin resistance itself accelerates β-cell senescence by upregulating senescence markers such as senescence-associated β-galactosidase (SA-β-Gal) and p16Ink4a, as well as inducing metabolic stress that triggers the release of pro-inflammatory SASP markers [31]. This inflammatory milieu exacerbates systemic insulin resistance, creating a self-reinforcing cycle that drives the progression of T2D [31]. Hyperglycemia-induced oxidative stress and mitochondrial dysfunction are central to this process, leading to damage in both mitochondrial and genomic DNA, including telomeric regions [11]. This triggers the DNA damage response (DDR), which orchestrates senescence through pathways centered around p53 and p16INK4a, resulting in cell cycle arrest and the amplification of SASP-derived IL-1β and CCL2 secretion [11]. Hyperglycemia additionally accelerates the accumulation of advanced glycation end products (AGEs), which in turn amplify senescence-associated inflammation [12,48]. Notably, HMGB1, an SASP-related molecule and agonist of AGE receptors, regulates senescence via p53-dependent pathways and enhances the secretion of pro-inflammatory SASP factors like IL-6 and MCP-1, expanding the senescent phenotype to neighboring cells [12,48]. These findings underscore the role of hyperglycemia and AGE signaling in driving premature senescence in the diabetic state.

Dyslipidemia introduces additional stressors that exacerbate cellular senescence in diabetes, with elevated ceramide levels inducing senescence markers in fibroblasts and endothelial cells via p53- and p38-dependent pathways while triggering pancreatic β-cell apoptosis [49]. Experimental models of diet-induced obese and ob/ob mice demonstrate that inhibiting ceramide synthesis reduces the SASP and directly improves glucose tolerance and insulin sensitivity, highlighting the interconnectedness of metabolic dysfunction and cellular senescence [50]. Finally, clinical evidence supports the notion that well-established diabetes treatments may extend beyond glucose control to modulate cellular aging mechanisms. Metformin, a cornerstone diabetes therapy, extends lifespan in experimental models and associates with a decrease in 2-year mortality in human patients, even when compared to other glucose-lowering medications [51,52]. Mechanistically, metformin disrupts IKK/nuclear factor κB signaling to inhibit SASP activity, alleviating inflammation and cellular dysfunction [53]. Similarly, acarbose has been shown to prolong lifespan in non-diabetic animal models, potentially through indirect effects on metabolic regulation and senescence suppression [51]. Taken together, these observations highlight the bidirectional relationship between metabolic dysfunction and cellular senescence while providing a platform for therapeutic targeting to disrupt this degenerative feedback loop.

5. The Discovery of Senolytics

The emergence of the SASP’s role in metabolic dysfunction has catalyzed research into therapeutic strategies targeting the accumulation of senescent cells, either by the way of senolytics, which selectively eliminate senescent cells, or by the way of senomorphics, which modulate the SASP itself without directly ablating the senescent cells. Senolytic compounds were first identified by a hypothesis-driven transcriptome screening by comparing senescent to proliferating human pre-adipocytes [54]. This revealed key anti-apoptotic pathways characteristic of senescent cells, collectively called SCAPs, which include tyrosine kinases, the BCL protein family, p53/p21 cascades, and the PI3 kinase/AKT pathway. The pharmaceutical targeting of this molecular network allows for the selective elimination of senescent cells while leaving normal cells unaffected.

Senomorphics provide an alternative strategy by suppressing the SASP without directly eliminating senescent cells. Targets for senomorphic interventions include pathways such as p38 MAPK, mTOR, NF-kB, and JAK/STAT and the neutralization of pro-inflammatory cytokines such as IL-1a and IL-6 using antibodies or small molecules [53,55]. One notable example of this class is metformin, which exhibits senomorphic properties by a reduction in NF-kB signaling and reduced oxidative species production [53]. Emerging therapies are expanding beyond small molecules to include molecular approaches such as CAR T cells, which target antigens on the surface of senescent cells [56,57]. To date, several experimental interventions across the above classes have demonstrated metabolic benefits, including improved glucose tolerance, improved insulin sensitivity, and reduced inflammatory markers.

5.1. Preclinical Trials

Early studies showing that caloric restriction enhances health and lifespan and associates with decreased senescent burden in animal models prompted the hypothesis that leveraging molecular tools to eliminate the accumulating senescent population would lead to visible health benefits [58,59]. This speculation was tested by the way of a transgenic murine model incorporating a suicide gene to selectively ablate senescent cells. FAT-ATTAC mice, developed in 2005, exclusively targeted senescent adipocytes, demonstrating improved metabolic outcomes [60]. Subsequently, building upon the FAT-ATTAC mice’s success, the INK-ATTAC genetic model was generated, which could ablate senescent cells highly expressing high levels of the p16Ink4a marker via the administration of a relatively inert drug [45,61].

In the context of T2D, the INK-ATTAC-mediated transgene elimination of senescent β-cells was shown to be profoundly beneficial both in mouse models of insulin resistance and in the high-fat diet (HFD) T2D mice model. In both cases, the targeted removal of senescent β-cells reduced pro-inflammatory SASP markers within pancreatic islets, restored insulin sensitivity, and significantly improved glucose tolerance [31,62]. Remarkably, even the partial deletion of senescent cells of approximately 30% was sufficient to alleviate metabolic dysfunction and age-related disease phenotypes [61,63]. These findings highlight the pathogenic role of senescent β-cells in driving T2D progression and establish their potential as therapeutic targets for senescence-modulating interventions

The development of advanced genetic tools has significantly propelled senescence-targeting research, enabling the precise manipulation of senescent cell populations in vivo. For instance, DTR transgenic lineage-tracing models facilitated the complete ablation of p16Ink4a-positive cells in experimental mice through diphtheria toxin administration [64]. Additional transgenic systems were developed to target other senescence markers, such as p21Cre and p19Arf, further demonstrating broad efficacy in alleviating age-related diseases [65,66].

In parallel with genetic approaches, the emergence of small-molecule senolytics has opened new avenues for therapeutic intervention. Dasatinib, a tyrosine kinase inhibitor, and quercetin, a naturally occurring flavonoid, were among the first-generation senolytics identified through hypothesis-driven screening. Dasatinib induces apoptosis in senescent cells by inhibiting Src tyrosine kinase pathways, while quercetin targets anti-apoptotic proteins such as Bcl-xL, effectively disrupting senescent cell survival mechanisms [67]. Dasatinib and quercetin (D + Q) combined treatment improved glucose metabolism, reduced adipose tissue inflammation, and alleviated metabolic dysfunction in obesity-related diabetes preclinical models [67] by significantly decreasing senescent markers [68]. Building on these studies, early efforts focused on identifying orally bioavailable molecules holding pre-existing FDA approval that could concurrently target multiple SCAPs. These advancements laid the foundation for the field of senolytics and represent a critical step toward developing scalable interventions to combat aging and age-related diseases [69]. An overview of the major molecular targets currently in use is reproduced in

Table 1. Current state of major senolytic families.

Class	Compound	Mode of Action	Outcome	Preclinical	Clinical	Clinical Trials
Tyrosine Kinase Inhibitors	Dasatinib	Src inhibitor	Reduces senescent cells; improves glucose metabolism	Yes	Yes	Phase II
Flavonoids	Quercetin	Targets BCL-2 and PI3K pathways	Reduces SASP factors; improves metabolic function; decreases inflammation	Yes	Yes	Phase I/II
Combination Therapy	Dasatinib + Quercetin (D + Q)	Combined targeting of SCAPs	Improves lifespan; physical function; glucose tolerance; reduces adipose inflammation	Yes	Yes	Phase II
Flavonoids	Fisetin	SASP inhibitor	Reduces epigenetic aging markers; decreases senescent cell burden	Yes	Yes	Phase II
BCL-2 Inhibitors	Navitoclax (ABT-263)	Pan-BCL family inhibitor	Induces apoptosis in senescent cells; alleviates age-related dysfunction	Yes	Yes	Phase I/II
BCL-2 Inhibitors	ABT-737	BCL-2/BCL-XL inhibitor	Induces apoptosis in senescent cells; reduces senescent burden in tissues	Yes	No	N/A
BCL-2 Inhibitors	A-1331852	Selective BCL-XL inhibitor	Induces apoptosis in senescent cells; improves tissue function	Yes	No	Preclinical
BCL-2 Inhibitors	A-1155463	Selective BCL-XL inhibitor	Induces apoptosis in senescent cells; reduces inflammation	Yes	No	Preclinical
USP7 Inhibitors	P5091	USP7 inhibitor	Promotes apoptosis in senescent cells; reduces SASP activity	Yes	No	Preclinical
HSP90 Inhibitors	17-DMAG	HSP90 inhibitor	Reduces senescence markers and inflammation	Yes	Yes	Phase I
HSP90 Inhibitors	Geldanamycin	HSP90 inhibitor	Reduces SASP activity; improves tissue function	Yes	No	N/A
HSP90 Inhibitors	Ganetespib	HSP90 inhibitor	Reduces senescence markers; improves healthspan	Yes	Yes	Phase II/III
p53-MDM2 Inhibitors	RG7112	MDM2 antagonist	Promotes apoptosis in senescent cells; reduces SASP	Yes	Yes	Phase I
p53-MDM2 Inhibitors	UBX0101	Inhibitor of p53/MDM2 interaction	Induces apoptosis in senescent cells; improves cartilage regeneration	Yes	Yes	Phase II
p53-MDM2 Inhibitors	FOXO4-DRI	Disrupts FOXO4-p53 interaction	Promotes apoptosis in senescent cells; improves tissue repair	Yes	Limited	Phase I
uPAR-directed CAR-T	GCAR1	Targets GPNMB	Eliminates senescent cells selectively; improves regeneration	Yes	Limited	Phase I
PROTACs	ARV825	BRD4 degrader	Degrades anti-apoptotic proteins in senescent cells	Yes	No	Preclinical
Natural Extracts	Curcumin	PI3K/AKT/mTOR inhibitor	Reduces inflammation and SASP activity	Yes	Yes	Phase I/II
Natural Extracts	Piperlongumin	PI3K/AKT/mTOR inhibitor	Induces ROS production; selectively kills senescent cells	Yes	No	Preclinical
Cardiac Glycosides	Ouabain	Na+/K+ ATPase inhibitor	Induces apoptosis in senescent cells; reduces lung fibrosis and tumor growth	Yes	Yes	Approved *
Cardiac Glycosides	Bufalin	Na+/K+ ATPase inhibitor	Selectively kills senescent cells; anti-tumor activity	Yes	No	Preclinical

* Approved for cardiovascular disease.

.

As of 2025, D + Q combined treatment remains the most validated intervention and has shown repeated efficacy across a range of conditions, including frailty, osteoporosis, insulin resistance, reduced lung capacity, and kidney disease [70,71]; in animal models of diabetes, its administration reduced senescent burden in visceral adipose tissue by half and correlated with improved glucose tolerance and insulin sensitivity [67]. To translate the effects of D + Q administration in human tissues, surgically excised tissues from diabetic obese patients were cultured with D + Q or a vehicle, provoking a notable decrease in senescent burden as well as in SASP-related pro-inflammatory cytokines IL-6, IL-8, and PAI-1 [72].

5.2. BCL-2 Family Inhibitors

BCL-2 family inhibitors have emerged as promising senolytic agents for targeting diabetes-related cellular senescence, particularly in pancreatic β-cells, which rely on anti-apoptotic proteins like BCL-2 and BCL-XL for survival. In T2D, senescent β-cells highly express these proteins, making them vulnerable to targeted inhibition [73]. Navitoclax (ABT-263), a non-selective BCL-2 family inhibitor targeting BCL-2, BCL-XL, and BCL-W, has been tested in experimental models of T2D and high-fat-diet (HFD)-induced metabolic dysfunction [31,74]. In these models, Navitoclax effectively reduced the burden of senescent β-cells, restored insulin secretory capacity, improved glucose tolerance, and decreased SASP presence in pancreatic islets. However, its clinical translation has been limited by dose-dependent thrombocytopenia due to its platelet toxicity via BCL-XL inhibition [73]. To address these challenges, Venetoclax (ABT-199), a selective BCL-2 inhibitor with minimal activity against BCL-XL, has been developed. Venetoclax has shown significant promise in preclinical studies by efficiently reducing senescent cell burden while minimizing adverse effects [35]. When paired with other agents such as A1331852 (a selective BCL-XL inhibitor) or MCL-1 inhibitors such as S63845, Venetoclax demonstrated synergistic effects that enabled a 20-fold reduction in therapeutic dosage while maintaining efficacy [75]. These combinations were effective not only in diabetic mouse models but also in human cell culture assays, highlighting their translational potential. Such combination strategies also reduce systemic toxicity while enhancing the selective elimination of senescent cells [75,76].

The tissue-specific nature of cellular senescence underlies the necessity for precision medicine approaches in targeting senescent cells during metabolic dysfunction. In advanced diabetes, pancreatic β-cells predominantly express p16Ink4a, marking them as the dominant senescent population, whereas senescent cells expressing p21Cip1- are more prevalent in visceral adipose tissue during the early stages of metabolic dysfunction [19,66,77,78]. Preclinical studies have demonstrated that clearance of p21high cells in obese mice restores insulin sensitivity more effectively than targeting p16high cells alone, which only mildly alleviates disease phenotypes [10,67,74,79]. This finding suggests that adipose tissue senescence plays a critical role in the early progression of metabolic dysfunction, whereas pancreatic β-cell senescence becomes more prominent in advanced disease stages.

Therapeutic strategies should reflect this distinction. Navitoclax preferentially eliminates p16high β-cells within pancreatic islets, offering targeted benefits for advanced diabetes. Conversely, dasatinib and quercetin (D + Q) target both p21high and p16high senescent populations across multiple tissues, providing broader therapeutic efficacy [10,67,74]. Clinically, these findings highlight the importance of tailoring senolytic interventions to specific disease contexts and patient populations. Early-stage therapies targeting p21high adipose tissue cells could prevent or delay insulin resistance onset, while interventions focused on p16high β-cells may be more effective for advanced type 2 diabetes (T2D).

5.3. HSP90 Inhibitors

HSP90 is a heat shock protein and ATP-dependent chaperone that allows the folding and degradation of a wide range of proteins necessary for survival signals. HSP90 inhibitors emerged as a novel class of senolytics through screens targeting autophagy regulation in senescence [80]. Among these, 17-DMAG has shown senolytic activity in vitro, selectively eliminating senescent human fibroblasts while sparing proliferating cells. In accelerated-aging mouse models (Ercc1−/∆), treatment with 17-DMAG reduced systemic tissue senescence, extended health span, and delayed the onset of age-related symptoms [80]. HSP90 inhibitors have shown promise in diabetic kidney disease, where proximal tubular epithelial cells undergo stress-induced senescence during diabetes [81].

5.4. p53 Network Disruption

The p53 pathway is a central regulator of cellular senescence and apoptosis, with senescent cells evading apoptosis through interactions between p53 and forkhead box protein O4 (FOXO4), which sequester p53 in the nucleus and prevent its translocation to mitochondria for caspase-mediated apoptosis [82]. To disrupt this interaction, the computationally designed retro-inverso FOXO4 peptide (FOXO4-DRI), mimicking the FOXO4-p53 binding interface and freeing p53 from nuclear sequestration, was developed to enable selective apoptosis of senescent cells [83]. Preclinical studies demonstrated that FOXO4-DRI restored physical function and extended healthspan in both accelerated aging and naturally aged mice by clearing senescent cells [84]. Clinically relevant features include its resistance to protease degradation due to its retro-inverso design, ensuring stability within the body.

Another promising approach involves targeting ubiquitin-specific peptidase 7 (USP7), a regulator of MDM2 stability that indirectly suppresses p53 activity. USP7 inhibitors restore p53 functionality, selectively inducing apoptosis in senescent cells while sparing proliferating counterparts [85]. Synergistic strategies combining USP7 inhibitors with BCL-2 family inhibitors, such as Navitoclax, have demonstrated enhanced senolytic efficacy across multiple tissues [85]. Although the direct inhibition of MDM2 has faced challenges due to toxicity concerns, alternatives such as USP7 inhibitors or FOXO4-DRI peptides hold substantial promise for clinical applications. In diabetes-related complications, restoring p53 activity could mitigate SASP-driven inflammation in pancreatic islets or adipose tissue while improving insulin sensitivity and glucose tolerance [86], making p53-targeting therapies highly relevant for metabolic diseases.

5.5. Natural Extracts

A cell-based screening of flavonoid compounds spotlighted fisetin, a naturally occurring polyphenol present in fruit and vegetables, as a selective senolytic able to kill senescent human and murine fibroblasts, as well as reduce senescence in human adipose explants [76]. In murine models of aging and diabetic disease, fisetin treatment reduced senescent cell burden systemically, mitigated diabetic nephropathy, and improved insulin sensitivity [87,88,89,90,91]. Curcumin and its metabolite o-vanillin were shown to reduce SASP factors by interfering with the NF-kB pathway; however, due to its low bioavailability, a synthetic broad-spectrum analog was eventually generated [92]. Similarly, pepper-derived piperlongumine was shown to deplete senescent fibroblasts in humans via the PI3K/AKT/mTOR pathway [85,93], and chemically modified synthetic analogs with augmented senolytic activity were subsequently developed [94].

5.6. Cardiac Glycosides

The high-throughput screening of chemical libraries has identified cardiac glycosides as a novel class of senolytic agents capable of selectively targeting senescent cells in both tumor and primary cell cultures. Among these compounds, proscillaridin A—derived from the foxglove plant—and digoxin—a widely used drug for heart failure—have shown potent senolytic activity [95]. Ouabain, another cardiac glycoside clinically used for arrhythmias, has also demonstrated efficacy in clearing senescent cells while reducing SASP-associated inflammation [95,96]. These compounds act by disrupting ion homeostasis via the inhibition of Na⁺/K⁺ ATPase and by inducing apoptosis in senescent cells without affecting healthy counterparts. Preclinical studies suggest that cardiac glycosides could be repurposed for age-related diseases such as diabetes and its complications, where cellular senescence plays a critical role in disease progression. Their established safety profiles in cardiovascular conditions make them attractive candidates for further investigation as senolytic therapies [95].

5.7. PROTAC Senolytics

Proteolysis-targeting chimeras (PROTACs) represent an innovative approach to senolysis by leveraging targeted protein degradation mechanisms. PROTACs consist of a protein-specific ligand tethered to an E3 ubiquitin ligase recruiter, enabling the selective degradation of senescent cells [97]. This design reduces drug exposure while enhancing specificity, extending activity, and minimizing toxicity compared to traditional small-molecule inhibitors. Initially developed for cancer therapeutics, PROTACs are now being explored for broader applications in age-related diseases such as diabetes and metabolic syndrome with demonstrated beneficial effects [98,99]. The intermittent dosing regimens required for PROTACs align with the turnover of senescent cells, offering a promising avenue for clinical translation.

Following early discoveries, close to a hundred small-molecule senolytics have been described [100]. From a clinical point of view, since senescent cells take approximately 1 to 6 weeks to fully develop in vitro and are unable to replicate, senolytic compounds can be conceivably administered once to twice a month; in experimental animal models, this has been so far shown to be non-inferior to continuous administration [72,101].

6. Clinical Trials

The clinical translation of senolytics for diabetes management has begun with encouraging preliminary results. Over 35 clinical trials of senolytic and senomorphic compounds have been completed or are underway or planned. Because the side effects of senolytics in humans are not yet fully known, and to maximize benefit–risk ratios, the first clinical trials opened to patients with serious health conditions. The first senolytic human pilot was conducted in 2019 on idiopathic pulmonary fibrosis, a progressive disease with no resolutive treatment. In this phase I study, 14 patients treated with combined oral D + Q at 100 mg/1250 mg 3 days weekly for 3 weeks showed symptoms amelioration [102]. However, it should be noted that the study was short-term and not placebo-controlled. This was later addressed in a follow-up randomized placebo-controlled trial enrolling 12 more patients with idiopathic pulmonary fibrosis [103]. In 2019, an open-label phase I clinical trial investigating D + Q in diabetic kidney disease demonstrated that D + Q administration provoked senescent cell elimination ameliorated insulin resistance and improved the estimated glomerular filtration rate [70], showing for the first time in the clinic that D + Q treatment depleted SASP factors as well as p16^INK4A- and p21^CIP1- senescent cells and led to improvements in kidney function [72]. Completed and ongoing clinical trials investigating the usage of senolytics in T2D as of 2025 are reproduced in

Table 2. Completed and ongoing clinical trials of senolytic or senomorphic compounds in T2D.

Senolytics Compound	Target Organs	Status	Condition or Disease	Identifier	Main Finding
Dasatinib + quercetin	Kidney	Completed	Diabetic kidney disease	NCT02848131	Reduced senescence; improved kidney function
Fisetin	Kidney	Ongoing	Diabetic nephropathies	NCT03325322	Due in 2026
Fisetin	Kidney	Ongoing	Diabetic kidney disease, insulin resistance	NCT03675724	Due at end of 2025
Fisetin	Kidney	Completed	SASP, osteoarthritis	NCT04210986	Data unavailable
Digoxin *	Adipose tissue	Not yet recruiting	Obesity, diabetes	NCT06240403	Due in 2028
Statins + ezetimibe	Systemic	Completed	Diabetes and hypercholesterolemia	KCT0003477	Reduced senescence; improved glycemia
UBX1325	Eye	Completed	Diabetic macular edema	NCT04857996	Data unavailable
UBX1325	Eye	Completed	Diabetic macular edema, neovascular	NCT04537884	Data unavailable
Semaglutide	Systemic	Completed	Prediabetes, T2D	NCT05786521	Data unavailable
Nicotinamide mononucleotide	Systemic	Completed	Prediabetes	NCT03151239	Increased insulin sensitivity
Metformin	Systemic	Completed	Diabetes, aging-related diseases	NCT02432287	Improved glucose; insulin
Canagliflozin	Kidney	Completed	Diabetic nephropathy	NCT02065791	Reduced progression; improved renal function
Dapagliflozin	Kidney Adipose tissue Adipose tissue	Completed Completed Ongoing	Diabetic kidney disease Obesity and metabolic disorders Obesity and metabolic disorders	NCT03036150 EUCTR2020-004835-26-IT NCT05975528	Reduced kidney failure and mortality Data unavailable Enrolling

* Approved for cardiovascular disease.

.

The D + Q success was followed in 2024 by encouraging results for phase I and IIa randomized clinical studies showing that a single injection of the BCL-XL inhibitor UBX1325 led to both statistical and clinical improvements in patients affected by diabetic macular edema. Remarkably, senolytic administration improved the vision of 62.5% of the patients who gained ≥5 letters, and 50% gained ≥10 letters, with no dose-limiting toxicities and a favorable safety profile throughout [104].

Following the encouraging results from the D + Q administration and preclinical studies showing the amelioration of diabetic nephropathy by fisetin administration, a handful of phase II trials administering fisetin for diabetic kidney disease are ongoing. Additionally, the concurrent administration of fisetin and D + Q is being investigated in the ongoing Alleviation by Fisetin of Frailty, Inflammation and Related Measures (AFFIRM) trial which is evaluating their effect on bone metabolism and insulin resistance.

Lipophilic statins have been shown to effectively act both as a senolytic, preferentially inducing apopotosis in senescent cells via the mevalonate pathway [105], and a senomorphic, decreasing the SASP in human tissue [106]. In 2024, a randomized controlled trial investigating the senolytic effects of statins on cellular senescence as a secondary outcome in patients with type 2 diabetes was completed. The combination of rosuvastatin and ezetimibe reduced senescent CD8+ T cells and, while independent of improvements in LDL-C, correlated with better glycemic control and reduced systemic inflammation [107,108].

Digoxin, a member of the cardiac glycosides family, has demonstrated senolytic activity in preclinical models of pulmonary fibrosis, atherosclerosis, and Alzheimer’s disease, as well as exhibiting senomorphic properties by regulating T cell populations and dampening SASP pro-inflammatory factors [95,109]. Due to its FDA approval for atrial fibrillation, digoxin has garnered interest as a potential senolytic compound in humans, and a phase II clinical trial investigating its effects in T2D patients is projected to be completed by 2028.

Sodium-glucose co-transporter-2 (SGLT2) inhibitors are a novel class of antidiabetic drugs, including dapagliflozin and canagliflozin, that control glycemia independently of insulin sensitivity or secretion by promoting glycosuria and enhancing ketone body production. As a result, these inhibitors differ from other antidiabetic drugs. While not generally classed as senolytics, studies have shown that SGLT2 inhibitors prevent the progression of diabetic kidney disease in mouse models and T2D patients through both glycemic and glucose-independent mechanisms, preventing the progression of diabetic kidney disease in diabetes mouse models [110,111].

Preclinical evidence suggests that sodium-glucose cotransporter 2 (SGLT2) inhibitors bolster systemic ketone body production, thereby reducing insulin resistance and oxidative stress. Ongoing clinical studies are exploring associations between SGLT2 inhibitor use and cellular senescence in patients with type 2 diabetes [112]. On the other hand, several clinical trials have trialed the usage of SGLT2 inhibitors in chronic kidney disease in T2D patients and showed that administration consistently reduced the risk of kidney disease progression [113,114]. Building upon the accumulating evidence suggesting a senolytic and senomorphic effect of SGLT2 inhibitors, clinical trials investigating the association between SGLT2 inhibitors use, inflammation, and senescence in T2D patients are underway (NCT05975528 and EUCTR2020-004835-26-IT).

Furthermore, novel compounds like nicotinamide mononucleotide (NMD) are emerging as potential interventions. In a recent double-blinded study, NMD administration over 10 weeks in prediabetic women with insulin resistance improved insulin sensitivity (NCT03151239). These findings suggest that NMD may counteract aging- and obesity-induced impairments in glucose metabolism [115]. Semaglutide, an FDA-approved GLP-1 receptor agonist for diabetes, demonstrates anti-inflammatory and anti-aging properties through activation of key signaling pathways compromised during aging. Specifically, semaglutide activates the AMPK/SIRT1/PGC-1α axis, which inhibits pro-inflammatory transcription factors like NF-κB and C/EBPα that regulate SASP expression [116]. Additionally, the semaglutide-induced depletion of polypyrimidine tract-binding protein-1 downregulates NF-κB activity, providing a mechanistic explanation for its ability to counteract SASP-associated inflammation [117]. Beyond its anti-inflammatory effects, semaglutide enhances transcriptional responses to oxidative stress and interacts with the ubiquitin–proteasome system and autophagy–lysosomal pathways responsible for the clearance of damaged aggregates such as SASP components [116]. These effects may explain preclinical findings showing systemic rejuvenation in mice treated with GLP-1 receptor agonists. Completed phase I–III trials have demonstrated semaglutide’s ability to improve HbA1c and fasting plasma glucose levels while showing potential longevity benefits [118,119]. These findings suggest that current therapies may modulate fundamental aging processes in addition to exerting metabolic benefits. In the phase IV MILES (Metformin in Longevity Study) clinical trial, metformin was shown to induce anti-aging transcriptional changes in adipose tissue, including the modulation of pathways associated with cellular metabolism, inflammation, and mitochondrial function. Preliminary results suggested metformin’s potential to counteract aging-related impairments in glucose metabolism and improve healthspan [120]. Upcoming large-scale randomized placebo-controlled clinical trials such as the TAME (Targeting Aging with Metformin) study aim to evaluate whether metformin can delay the onset of type 2 diabetes, as well as age-related conditions including cardiovascular disease, dementia, and cancer in older adults [121].

Finally, the intermittent dosing regimen typical of senolytic therapies (e.g., weekly or monthly administration) minimizes toxicity while maintaining efficacy, as senescent cells take weeks to fully develop and acquire a mature SASP. This administration pattern avoids continuous drug exposure, reducing side effects while effectively targeting senescent cell reservoirs. Future directions for senolytic development include dual-targeted approaches to address the molecular heterogeneity of senescence across tissues, as well as biomarker-driven personalization to match senolytic compounds with tissue-specific and patient-specific senescence profiles. Another promising strategy might involve combining senolytics with conventional glucose-lowering agents, particularly GLP-1 receptor agonists.

7. Caveats and Challenges

One caveat associated with the usage of senolytics in their current state is cell-type and tissue-specific selectivity, as senescent features are not necessarily exclusive to senescent cells. SA-β-gal and p16 expression also associate with terminally differentiated cells, such as post-mitotic adipocytes and others. Therefore, galactose-modified prodrugs that rely on beta-galactosidase activity would likely present with off-target effects. Off-target toxicity has been similarly observed in BCL-2 inhibitors. Clinical trials are still in their infancy, and there are inadequate data on the longer-term safety of senolytic administration. Concerns include unknown effects in the elderly and patients with pre-existing conditions. However, due to intermittent dosage administration and combined administration allowing lower dosages, such risks are likely inferior to existing drugs. Newer technologies such as PROTACs aim to effectively address this by permitting selective targeting of specific molecules. Even in their current state, targeting senescent cells in adipose tissue has been shown to be feasible and capable of alleviating metabolic dysfunction even when initiated in various stages of insulin resistance. By shifting the focus to fundamental biological mechanisms underlying diabetes, rather than merely to the management of symptoms, senolytics might represent a paradigm shift in therapeutic approach, with the potential to address diabetic complications through the deletion of cellular drivers of disease progression. However, challenges remain in optimizing tissue specificity, validating long-term outcomes, and determining optimal incorporation within existing clinical treatment algorithms.