Background: Cellular senescence, characterized by irreversible growth arrest and secretion of pro-inflammatory factors (SASP), is increasingly implicated in age-related diseases, including Alzheimer’s disease (AD), idiopathic pulmonary fibrosis (IPF), and immune aging. Senolytics, such as dasatinib plus quercetin (D+Q), selectively eliminate senescent cells and represent a novel therapeutic strategy.
Methodology: We reviewed findings from three pilot investigations: (1) an open-label trial of D+Q in early-stage AD assessing blood–brain barrier penetrance, target engagement, and safety; (2) a first-in-human study of intermittent D+Q in IPF evaluating safety, tolerability, and functional outcomes; and (3) a lifestyle intervention in sedentary adults with obesity examining the impact of increased moderate-to-vigorous physical activity (MVPA) on immune senescence markers.
Results: In AD, D+Q crossed the blood–brain barrier and demonstrated feasibility, with preliminary biomarker shifts but limited cognitive changes. In IPF, intermittent dosing was safe, with functional improvements in gait speed and walking distance rarely observed in progressive disease. In obesity, increased MVPA reduced p16^INK4a expression in immune cells, suggesting a senostatic effect. Across studies, adherence was high, and adverse events were generally mild.
Conclusion: These early studies establish the safety, feasibility, and biological plausibility of senolytic interventions. Both pharmacological and lifestyle approaches show promise in mitigating senescence, warranting larger randomized trials to evaluate long-term efficacy and biomarker-driven outcomes.

Senolytic therapy, Pulmonary fibrosis, Neurodegeneration, Alzheimer disease, Pilot studies.

Increased longevity has amplified the burden of Alzheimer’s disease (AD), now a leading cause of death without a proven disease-modifying therapy. While vascular and lifestyle risk factors contribute, aging is the strongest determinant: mortality from AD rises nearly 700-fold between ages 55 and 85, underscoring shared mechanisms between aging and neurodegeneration.[1-4] Cellular senescence is a fundamental aging process increasingly implicated in AD. Triggered by genomic and metabolic stress, senescent cells undergo irreversible cell-cycle arrest and adopt a SASP, releasing pro-inflammatory cytokines and proteases. Although initially protective, persistent SASP promotes chronic inflammation, damages neighboring cells, and accelerates tissue dysfunction. Senescent cells accumulate with age across multiple brain cell types, including neurons, astrocytes, microglia, and endothelial cells.[5-8]

Mounting evidence links senescence to tau pathology. Our work and others’ show that neurons with neurofibrillary tangles (NFTs) exhibit senescence-like gene expression signatures, with NF-κB–driven inflammatory pathways strongly upregulated. In tau-transgenic mice, tau induces senescence in glia and neurons, amplifying SASP spread and neurodegeneration. These findings suggest that tau-induced cellular senescence may be a central driver of AD pathology.[9-12] Senolytic drugs that selectively eliminate senescent cells offer a novel therapeutic avenue. Dasatinib plus quercetin (D+Q) effectively clears senescent cells, mitigates NFT burden, and reduces neuroinflammation in preclinical AD models, while early human trials in other chronic conditions demonstrate safety and functional benefit. On this basis, we are conducting an open-label pilot trial of senolytic therapy in individuals with early-stage AD.[13-16]

IPF is a chronic, progressive fibrotic lung disease that becomes increasingly common with age and carries a median survival of less than four years in newly diagnosed older adults. Aging contributes to IPF pathogenesis through oxidative stress, telomere attrition, DNA damage, inflammation, and extracellular matrix remodeling. A hallmark of aging, cellular senescence, is strongly implicated in IPF. Senescent cells adopt a senescence-associated secretory phenotype (SASP) characterized by pro-inflammatory cytokines, chemokines, proteases, and pro-fibrotic factors that promote tissue dysfunction. Senescence biomarkers, including p16^INK4A, γH2A.X, and telomere dysfunction, are enriched in IPF lungs and correlate with disease severity.[17]

Senolytic agents, which selectively eliminate senescent cells, emerged from a hypothesis-driven approach based on the observation that senescent cells resist apoptosis through senescent cell anti-apoptotic pathways (SCAPs). Bioinformatics and RNA interference studies identified SCAP components critical for senescent cell survival. Agents targeting these pathways were shown to induce apoptosis in senescent but not healthy cells. Dasatinib (D), a tyrosine kinase inhibitor used in leukemia, and quercetin (Q), a natural flavonoid targeting multiple SCAP components, were the first senolytics identified. Together (D+Q), they effectively clear senescent cells from multiple tissues.[18] Preclinical studies demonstrate that D+Q reduces senescent cell burden and SASP factors in human explants and alleviates age- and senescence-related disorders in mice, including osteoporosis, hepatic steatosis, vascular dysfunction, neurodegeneration, and bleomycin-induced pulmonary fibrosis. Importantly, D+Q improves lung function, body composition, and physical performance in animal models of fibrosis and aging.[19] These findings support senolytic therapy as a potential strategy for IPF. We therefore conducted the first-in-human pilot trial of intermittent D+Q in older adults with stable IPF to evaluate feasibility, retention, safety, and preliminary functional outcomes, with exploratory analyses of circulating SASP factors.[20]

Alzheimer’s disease (AD) is the leading cause of dementia, affecting more than 35 million people worldwide. Despite decades of research, therapeutic development for AD has been slow, costly, and marked by a >99% failure rate. Recently, disease-modifying agents targeting amyloid beta (Aβ) have demonstrated the ability to reduce brain amyloid burden; however, clinical benefits have been modest, highlighting the need for alternative or complementary approaches.[21] Most patients with AD exhibit multifactorial contributors to dementia, suggesting that targeting pathways beyond Aβ and tau may be required for meaningful therapeutic impact. One emerging area involves mechanisms of biological aging, particularly cellular senescence. Senescence is a complex stress response induced by stimuli relevant to AD pathogenesis, including DNA damage, proteotoxic stress, and mitochondrial dysfunction. While senescent cells evade apoptosis through activation of senescent cell anti-apoptotic pathways (SCAPs), they adopt a pro-inflammatory secretory phenotype known as the senescence-associated secretory phenotype (SASP). The SASP, composed of cytokines, chemokines, growth factors, and extracellular matrix remodeling enzymes, reinforces tissue dysfunction by spreading senescence signals to neighboring cells.[22]

Accumulation of senescent cells in the aging central nervous system has been documented across multiple cell types, including neurons, astrocytes, microglia, oligodendrocyte precursor cells, and endothelial cells. Preclinical studies suggest that these senescent populations contribute to tau pathology, neuroinflammation, and cognitive decline. Together, these findings implicate cellular senescence as a novel therapeutic target for AD and support exploration of senolytic agents to selectively eliminate senescent cells and attenuate disease progression.[23] A sedentary lifestyle is a major contributor to mortality, accelerated aging, and chronic diseases such as metabolic disorders, cardiovascular disease, and cancer. In contrast, physical activity is recognized as a safe and cost-effective medicine for promoting healthy aging. Despite this, the World Health Organization reports that one in five men and one in three women worldwide fail to achieve the recommended levels of moderate to vigorous physical activity. With 13% of the global population already aged 60 years or older, inactivity substantially increases the burden of aging and age-related diseases.[24]

Cellular senescence, an irreversible state of growth arrest caused by stress, is a central mechanism underlying aging. The accumulation of senescent cells that express markers such as p16INK4a and p21Cip1 contributes to premature aging and chronic disease. Senescent immune cells can accelerate systemic aging, whereas alleviating immune senescence delays decline. This has led to the development of senolytic therapies that selectively eliminate senescent cells and show promise in conditions including diabetic kidney disease and pulmonary fibrosis. However, no approved therapies currently target immune senescence. Physical exercise may act as a natural senolytic.[25] Previous studies show that higher exercise frequency correlates with lower p16INK4a expression in T lymphocytes, independent of age. However, little is known about the effects of objectively measured physical behaviors such as activity levels, sedentary time, standing, and sleep on immune cell senescence. This pilot study examines whether physical activity interventions can influence premature immune senescence in sedentary adults with obesity, providing insight into new strategies to reduce accelerated aging and extend health span.[26]

Breaking barriers: First clinical evidence of senolytics targeting Alzheimer’s disease: In a study by Gonzales et al., this open-label pilot trial evaluated dasatinib plus quercetin (D+Q) in older adults with early symptomatic Alzheimer’s disease (AD), with the primary objective of determining blood–brain barrier (BBB) penetrance. Secondary aims included assessing target engagement, safety, and tolerability of a 12-week treatment course, and exploring effects on cognition, functional status, physical performance, and MRI-derived neuroimaging markers. Adults aged 65 years and older with clinically diagnosed early-stage AD were screened using predefined inclusion and exclusion criteria. Five eligible participants were enrolled and completed up to 10 visits over a study period not exceeding 24 weeks. Participants received intermittent oral D+Q dosing for 12 weeks. Safety was monitored throughout using clinical assessments, laboratory testing, and adverse event reporting. Neuroimaging, cognitive, and physical assessments were conducted before and after treatment. Target engagement was evaluated through cerebrospinal fluid (CSF) and blood biomarkers, while MRI assessed structural and functional brain changes. Cognitive and functional outcomes provided a clinical context to biological measures. All study procedures were conducted at the University of Texas Health Science Center at San Antonio Glenn Biggs Institute for Alzheimer’s and Neurodegenerative Diseases. Findings from this pilot study are intended to establish feasibility and inform the design of a planned multisite phase II trial (NCT04685590).

Our pilot study (SToMP-AD vanguard) provides the first Alzheimer’s disease (AD)–relevant clinical data on the use of senolytics, specifically the dasatinib and quercetin (D+Q) combination. Intermittent dosing over 12 weeks was feasible and designed to reduce adverse events while preserving therapeutic activity. Preclinical work demonstrated that senescent brain cells accumulate over weeks, and their clearance with senolytics leads to partial reductions in neurofibrillary tangles (NFTs) and clinically favorable outcomes. These findings informed the intermittent administration strategy, which avoids continuous receptor occupancy yet achieves target engagement. Preliminary evidence suggests that senolytics can cross the blood–brain barrier in AD, consistent with prior animal and oncology data. This trial is positioned to generate critical safety, tolerability, and feasibility data while providing early signals of efficacy. Secondary measures include cerebrospinal fluid (CSF) tau and β-amyloid, hippocampal atrophy, and senescence-associated secretory phenotype (SASP) markers. Our preclinical studies showed that tau accumulation is tightly linked to cellular senescence, and senolytic-treated mice exhibited reduced tau burden with corresponding functional benefits. Accordingly, CSF tau will serve as a key early indicator of treatment-related changes.

A major challenge is the lack of universally accepted senescence biomarkers. To address this, we incorporated transcriptomic markers from AD brain tissue and mouse models, alongside a validated SASP composite score. These exploratory analyses will broaden the understanding of cellular senescence in AD. Overall, the trial establishes proof-of-concept for D+Q in early AD. Findings support feasibility and target engagement, providing the foundation for larger phase II studies and advancing senescence-based therapeutics for AD.[27]

Pilot study of intermittent dasatinib and quercetin in idiopathic pulmonary fibrosis: In a study by Justice et al., this was a single-arm, open-label pilot trial of intermittent dasatinib (100 mg/day) plus quercetin (1250 mg/day), administered orally for three consecutive days over three weeks (nine total doses), conducted at two U.S. clinical research centers. Safety monitoring included weekly laboratory chemistries, electrocardiography, adverse event questionnaires, and patient-reported outcomes on symptoms, fatigue, and respiratory health. Functional assessments comprised six-minute walk distance (6MWD), gait speed, chair-stands, Short Physical Performance Battery (SPPB), grip strength, and spirometry (FVC, FEV1). Frailty was evaluated using a laboratory-based frailty index (FI-LAB). Biological endpoints included circulating SASP factors-IL-6, MCP-1, activin A, apelin, MMP1, MMP7, and osteopontin quantified by multiplex assays and ELISA. Selected senescence-associated microRNAs (miR-146a-5p, miR-34a-5p, miR-16-5p) were measured by qPCR.

Eligible participants were ≥50 years with confirmed idiopathic pulmonary fibrosis (IPF), body mass index 19–35 kg/m², stable disease, intact cognition, and no recent exacerbations. Exclusion criteria included advanced hepatic or renal dysfunction, significant cardiac disease, organ transplantation, or conflicting medications. Women were required to be postmenopausal. Concomitant antifibrotic therapy (nintedanib or pirfenidone) was permitted if stable for ≥8 weeks; nintedanib was withheld on dosing days to avoid interaction. Approximately 17 were screened; 14 enrolled (12 non-Hispanic white, 2 Hispanic white). All completed the intervention with 100% retention. Biospecimens were obtained fasting and analyzed in batches at Mayo Clinic. Pre/post comparisons of functional and biochemical outcomes were performed using paired t-tests; exploratory significance was defined at p ≤ 0.1 to guide endpoint selection for future randomized trials.

Around 14 participants (2 women; mean age 70.8 ± 7.9 years) with stable IPF (7 on nintedanib, five on pirfenidone, 2 untreated) were enrolled, mostly at UTHSCSA (n = 12). Disease severity was mild in 4, moderate in 8, and severe in 2. Retention and adherence were excellent (100%; 127/126 doses), with one extra dose taken unintentionally. All assessments were completed except one SPPB, which was missed due to hospitalization. Adverse events were generally mild-to-moderate, reversible, and consistent with prior IPF trials, including respiratory symptoms (n = 14), skin irritation/bruising (n = 14), and gastrointestinal discomfort (n = 12). Two severe headaches and one serious event (multifocal pneumonia with pulmonary edema) occurred, with full recovery. No changes in weight, vitals, or chemistries were seen.

Significant improvements were observed in 6MWD (+21.5 m), 4-m gait speed, chair-stands, and SPPB (p < .05), with ≥5% functional gains in most participants. Grip strength, spirometry, quality of life, and fatigue were unchanged. SASP factors showed trends toward reduction with moderate correlations to functional gains, consistent with preclinical findings.[28]

SToMP-AD pilot trial: CNS penetrance and safety of dasatinib plus quercetin in early Alzheimer’s disease. In a study by Gonzales et al., Safety and adherence were assessed through review of vital signs, medications, and adverse events at each visit. Laboratory testing included complete blood counts, metabolic, liver, and lipid panels at scheduled intervals, with coagulation and HbA1c testing at baseline and follow-up. ECGs were performed periodically, and data were reviewed annually by an independent safety monitoring board. Adherence was tracked using clinic administration counts, pill bottle checks, and home diaries. Cognitive and functional outcomes included changes in MoCA and CDR-SOB from baseline to post-treatment. Additional cognitive tests assessed memory, executive function, language, and fluency, while neuropsychiatric symptoms were evaluated using the Geriatric Depression Scale and Neuropsychiatric Inventory. Functional status was measured by the Lawton IADL scale and CDR ratings.

Brain MRI was acquired on a 3T Siemens scanner using standard structural, diffusion, and gradient echo sequences. Pre- and post-treatment scans were registered and parcellated to quantify brain and hippocampal volume, as well as gray and white matter density. Blood and CSF were collected under fasting conditions, processed within 2 hours, and stored at −80°C. Drug concentrations of dasatinib, quercetin, and metabolites were quantified via HPLC/MS/MS. Biomarkers of senescence and the SASP were assayed using multiplex immunoassays, while Alzheimer ’s-related biomarkers (pTau, Aβ, GFAP, NFL, total tau) were measured using Simoa® and Lumipulse platforms. Data were managed in REDCap and analyzed with SPSS v28. Paired t-tests compared baseline and post-treatment changes in clinical, imaging, and biomarker outcomes. Statistical significance was defined as p < 0.05 without correction for multiple comparisons due to the exploratory design.

The SToMP-AD trial was a Phase I, single-site, open-label pilot study assessing CNS penetrance of dasatinib (D) and quercetin (Q) in older adults with early-stage AD. Over 20–24 weeks, participants completed 11 study visits. Twenty-one were screened, 13 underwent in-person evaluation, and five participants (aged 70–82 years, median 76; 40% female; 80% non-Hispanic White, 20% Hispanic) enrolled between March 2020 and April 2021. All displayed CSF biomarkers were consistent with AD (Aβ42: 295–647 pg ml−1; tau: 385–917 pg ml−1; pTau181: 62–147 pg ml−1). Study drugs (100 mg D; 1,000 mg Q) were administered orally in six 2-week cycles. Post-treatment, D was detected in plasma (12.7–73.5 ng ml−1) and in CSF of four participants (0.281–0.536 ng ml−1; CSF: plasma ratio 0.421–0.919%). Q was detectable in plasma post-treatment (3.29–26.3 ng ml−1) but not in CSF.

No significant baseline-to-post-treatment changes were observed in MoCA, CDR-SOB, functional measures, or MRI volumes. HVLT-R Immediate Recall declined significantly. ADRD biomarkers remained stable, with a trend toward higher CSF Aβ42 (t(4) = 2.34, P = 0.0795). CSF GFAP increased (p = 0.0285), while other analytes remained unchanged. Plasma SASP factors IL-17E, IL-21, IL-23, IL-17A/F, IL-17D, IL-10, VEGF, IL-31, MCP-2, MIP-1β and MIP-1α decreased; YKL-40 increased. In CSF, TARC, IL-17A, I-TAC, eotaxin-2, eotaxin, and MIP-1α decreased, while IL-6 increased. Six AEs occurred, three after intervention (two mild, one moderate hypoglycemia). All resolved within 1–16 d. No serious AEs occurred. BMI, blood pressure, and most labs remained stable, except for a mild cholesterol increase (169.2 ± 35.5 vs 179.4 ± 40.0 mg dl−1, P = 0.044). Drug adherence was 100%; all five participants completed the trial.[29]

Impact of a 12-week Fitbit-based physical activity intervention on cellular senescence in sedentary adults with obesity: In a study by Chen et al., between September and December 2020, 153 adults were screened telephonically, 63 were further evaluated in the laboratory, and 45 met eligibility criteria for a cross-sectional baseline assessment. Inclusion criteria were Chinese adults aged 18–45 years, physically inactive (<150 min/week MVPA), sedentary (>8 h/day sitting), BMI ≥25 kg/m², normotensive (<140/90 mmHg), nonsmokers, nondrinkers, free of cardiovascular disease, diabetes, or recent injuries, and not on medication in the past three months. Sample size was estimated using GPower with an effect size of 0.283, requiring 28 participants for adequate power. To account for attrition, more than 40 were recruited; 40 were randomized into a two-arm RCT (20 per group) of a 12-week Fitbit-based physical activity (PA) intervention, while five declined participation. Ethical approval was granted (CREC Ref. No.:2020.551-T), and informed consent was obtained.

Anthropometric measurements included height, weight, BMI, body fat, and VO₂max (Bruce protocol). Physical behaviors such as activity, sedentary time, standing, sleep, and steps were measured using activPAL™ for five consecutive days pre- and post-intervention. Intervention participants used Fitbit Inspire 2 watches to achieve >12,000 steps/day for ≥5 days weekly, monitored via a web-based platform with researcher feedback. Controls maintained a usual lifestyle. Fasting blood samples were collected at baseline and follow-up for serum and PBMC isolation. RNA was extracted for qPCR analysis, while senescence-associated secretory phenotypes (IL-1β, IL-6, IL-8, CCL2, ICAM-I, VEGF, PAI-I) were quantified by Luminex multiplex assay or ELISA. Data were analyzed using Pearson correlation, generalized linear models, and generalized estimating equations (SPSS v26), with significance set at p<0.05.

The demographic, anthropometric, and behavioral characteristics of 45 participants (mean age 31.71 ± 7.30 years). Cross-sectional analysis showed that chronological age, VO2max, body fat, and blood pressures were not associated with log2-transformed p16INK4a or p21Cip1 levels in PBMCs of sedentary adults with obesity (p > 0.05). MVPA was independently and inversely correlated with p16INK4a (B = −8.83, 95% CI −15.98 to −1.68, p = 0.02) and p21Cip1 (B = −8.30, 95% CI −14.74 to −1.85, p = 0.01), while no significant correlation was found with LPA, vigorous PA, standing, sedentary behavior, or sleep duration (p > 0.05). BMI and daily steps correlated with both markers (p < 0.05), but significance was lost after adjustment (p > 0.05). These results suggest insufficient MVPA as a key driver of immune cell senescence in sedentary adults with obesity.

A 12-week RCT investigated PA intervention effects. The intervention group showed significant increases in MVPA (p = 0.004) and steps (p = 0.04 (activPAL™); p < 0.01 (Fitbit)) versus controls. Other behaviors, including sedentary time, LPA, and sleep, were unchanged (p > 0.05). MVPA increases did not alter BMI, body weight, body fat, or VO2max (p > 0.05). Importantly, the intervention significantly reduced elevated p16INK4a in PBMCs (interaction p = 0.04), but had no effect on p21Cip1 or SASP factors, including IL-1β, IL-6, TNF-α, IL-8, CCL2, ICAM-I, VEGF, and PAI-I (p > 0.05). No adverse events were reported.[30]

Table 1: Summary of outcomes from pilot studies of senolytic and lifestyle interventions targeting cellular senescence

The pilot investigations reviewed here underscore the transition of senolytic strategies from preclinical promise toward early clinical translation. Collectively, these studies support the conceptual shift in which cellular senescence is viewed not merely as a biomarker of aging, but as a modifiable therapeutic target with the potential to alter the natural history of diverse chronic diseases. By evaluating interventions across Alzheimer’s disease, idiopathic pulmonary fibrosis, and obesity-associated immune senescence, the emerging evidence highlights both pharmacological and lifestyle-based avenues for senescence modulation, thereby broadening the translational relevance of this approach.

In Alzheimer’s disease, where therapeutic development has historically been characterized by slow progress and high failure rates, the SToMP-AD pilot trial provides important proof-of-concept data. The demonstration that dasatinib penetrates the blood–brain barrier addresses a critical barrier to central nervous system drug delivery and confirms the feasibility of targeting senescent cells in the brain. Although no significant cognitive or functional gains were observed within the short treatment window, the observed shifts in biomarkers, including reductions in senescence-associated secretory phenotype mediators and trends toward increased cerebrospinal fluid amyloid beta concentrations, align with preclinical findings in which senolytics reduced tau pathology and attenuated neuroinflammation. Importantly, the intermittent dosing regimen was safe and well tolerated in older adults with symptomatic disease, a group often vulnerable to adverse effects and polypharmacy. These results justify progression to larger phase II trials, which will be required to determine whether senolytic therapy can meaningfully alter the trajectory of cognitive decline and neurodegeneration.

The idiopathic pulmonary fibrosis study further substantiates the potential benefits of senescent cell clearance in human disease. Participants demonstrated measurable improvements in functional outcomes, including six-minute walk distance, gait speed, and chair-stand performance, despite no significant changes in spirometry or quality-of-life metrics during the brief study period. The persistence of these benefits beyond the pharmacologic half-life of dasatinib and quercetin suggests that the underlying mechanism may involve durable changes in tissue biology, such as reduced pro-fibrotic signaling or alterations in extracellular matrix remodeling. These findings mirror preclinical observations that senolytic therapy enhances physical resilience and delays frailty. Adverse events, while relatively common, were mild to moderate in severity, reversible, and consistent with previous IPF trial experiences. The occurrence of a single pneumonia case underscores the need for vigilant safety monitoring but does not detract from the broader conclusion that intermittent senolytic dosing is feasible in this population. Given the progressive and refractory nature of IPF, the observed functional improvements, if validated in larger, controlled trials, could represent a clinically significant advance.

The lifestyle-based intervention in sedentary adults with obesity extends the evidence base by demonstrating that cellular senescence can be modulated through non-pharmacological means. Increased daily moderate-to-vigorous physical activity over a 12-week period resulted in a significant reduction in p16^INK4a expression in immune cells, a marker of premature immune aging. This effect was independent of chronological age, body mass index, or cardiorespiratory fitness, thereby implicating physical inactivity as a primary determinant of immune senescence in this population. While p21^Cip1 expression and circulating senescence-associated secretory phenotype cytokines remained unchanged, these findings suggest that physical activity may preferentially influence specific senescence pathways, distinct from those targeted by pharmacological senolytics. The intervention was feasible, well-tolerated, and free of adverse events, supporting its scalability as a practical, low-cost strategy with broad public health implications.

Across these studies, several themes emerge. Senolytic approaches, whether pharmacologic or lifestyle-based, are feasible and generally safe when applied intermittently. The interventions produced biologically meaningful signals, including biomarker modulation, functional gains, and reductions in senescence-associated gene expression. High adherence across all studies underscores participant acceptability and supports the practicality of implementing senolytic interventions in clinical or community settings. Together, these strengths provide a compelling rationale for continued investment in the field of senescence-targeted therapeutics.

Nonetheless, important challenges remain. The lack of standardized, validated biomarkers of senescence limits the ability to compare outcomes across studies and hinders the establishment of robust treatment-response relationships. Many candidate markers are tissue-specific, and it remains uncertain which best capture systemic senescence burden or therapeutic efficacy. The small sample sizes, open-label designs, and limited follow-up periods characteristic of these early trials restrict definitive conclusions regarding efficacy and long-term safety. Moreover, for complex conditions such as Alzheimer’s disease and idiopathic pulmonary fibrosis, longer-term studies are essential to establish whether senolytic therapies can meaningfully modify disease progression rather than provide transient functional improvements.

Future work must prioritize randomized, controlled trials enrolling larger and more diverse populations. These trials should integrate longitudinal biomarker panels, advanced imaging modalities, and multidimensional functional assessments to capture the broad biological and clinical effects of senolytic interventions. Optimization of dosing schedules, evaluation of combination strategies with established therapies, and identification of subgroups most likely to benefit will be critical. Furthermore, the findings from the lifestyle trial emphasize the importance of public health approaches, suggesting that interventions such as increased physical activity may complement or even substitute pharmacological senolytics, particularly in preventive or early disease contexts.

In summary, the current body of evidence establishes feasibility, safety, and biological plausibility for senolytic strategies in humans. While definitive efficacy has yet to be demonstrated, these early findings provide the groundwork for the next phase of clinical investigation and support the view that targeting cellular senescence may represent a transformative therapeutic paradigm in aging medicine.

Cellular senescence is a central driver of aging and age-related diseases, including Alzheimer’s disease, IPF, and obesity-related immune decline. Accumulated senescent cells and their pro-inflammatory SASP contribute to neurodegeneration, fibrosis, and immune dysfunction. Senolytic therapies, particularly dasatinib plus quercetin (D+Q), selectively eliminate these cells and show early promise.

Pilot studies demonstrate feasibility, safety, and biological activity: in Alzheimer’s, intermittent D+Q penetrated the blood–brain barrier and shifted biomarkers, while in IPF, therapy improved physical performance, which is rare in this progressive disease. Lifestyle interventions, such as increased physical activity, also reduced immune senescence, underscoring the role of non-pharmacological “natural senolytics.”

Despite small samples and limited follow-up, these findings provide proof-of-concept, bridging preclinical promise with clinical translation. Senolytics may represent a paradigm shift in aging medicine, offering strategies to delay, prevent, or modify age-related disease.

Not reported

No funding

Corresponding Author:
Samatha Ampeti
Independent Researcher, Department of Content
medtigo India Pvt Ltd, Pune, India
Email: ampetisamatha9@gmail.com

Co-Authors:
Mansi Srivastava, Raziya Begum Sheikh,Patel Nirali Kirankumar, Shubham Ravindra Sali
Independent Researcher, Department of Content
medtigo India Pvt Ltd, Pune, India

All authors contributed to the conceptualization, investigation, and data curation by acquiring and critically reviewing the selected articles. They were collectively involved in the writing, original draft preparation, and writing – review & editing to refine the manuscript. Additionally, all authors participated in the supervision of the work, ensuring accuracy and completeness. The final manuscript was approved by all named authors for submission to the journal.

Not applicable

None

None

https://doi.org/10.63096/medtigo30612313

Mansi S, Samatha A, Raziya BS, Patel NK, Shubham RS. Senescence and Beyond: Exploring Senolytic Strategies for Chronic Disease.  medtigo J Pharmacol. 2025;2(3):e30612313. doi:10.63096/medtigo30612313 Crossref