Cellular Senescence, SASP, and Senolytic Targeting of Age-Related Pathologies

discovery extend well beyond oncology: senescent cells accumulate at the causal loci of atherosclerosis, osteoarthritis, idiopathic pulmonary fibrosis, Alzheimer's disease, type 2 diabetes, and venous valvular insufficiency

The therapeutic implication is direct: if senescent cells and their SASP are pathogenic drivers

2. PATHOPHYSIOLOGY AND MOLECULAR MECHANISMS

2.1 Triggers and Pathways of Cellular Senescence

Senescence is induced through two principal convergent pathways. The p53/p21^Cip1 axis is activated primarily by DNA double-strand breaks and telomere dysfunction, while the p16^INK4a/retinoblastoma (Rb) pathway responds more broadly to oncogenic signalling, epigenetic stress, and chromatin disruption. Both pathways converge on stable hypophosphorylation of the Rb protein, locking the cell in permanent G1 or G2/M arrest. Critically, unlike quiescent or terminally differentiated cells, senescent cells remain transcriptionally active and metabolically hyperactive — a dissociation between proliferative arrest and cellular viability that defines their unique pathological character. [^1]

A cardinal molecular feature distinguishing senescent cells is the accumulation of cytoplasmic chromatin fragments (CCFs) derived from nuclear or mitochondrial DNA. These CCFs are recognised as damage-associated molecular patterns (DAMPs) by the cGAS-STING (cyclic GMP-AMP synthase / stimulator of interferon genes) innate immune sensing pathway. Activation of cGAS-STING is now understood to be the predominant upstream driver of SASP gene transcription, operating through downstream activation of NF-κB and IRF3/IRF7 transcription factors. [^2] Additional amplifying signals arise from activation of the NLRP3 inflammasome and from mTORC1-driven translation of SASP component mRNAs.

Senescent cells evade their own pro-apoptotic SASP through coordinate upregulation of anti-apoptotic members of the BCL-2 protein family — BCL-2, BCL-XL, and MCL-1 — which function as intracellular survival shields by sequestering pro-apoptotic BH3-only proteins (BAX, BAK, BIM, PUMA, NOXA). This dependency on pro-survival BCL-2 family members represents the central therapeutic vulnerability that senolytics exploit. [^3]

2.2 Composition and Consequences of the SASP

The SASP is not a uniform secretory profile but a dynamic, context-dependent secretome whose composition varies by cell type, senescence inducer, and microenvironmental conditions. Its core components, comprehensively catalogued in a 2024 Nature Reviews Molecular Cell Biology review by Wang, Han, Elisseeff, and Demaria, include: [^1]

• Interleukins: IL-1α (a primary SASP "master regulator" acting via autocrine amplification), IL-1β, IL-6, IL-8
• Chemokines: CCL2 (MCP-1), CXCL1, CXCL10, which orchestrate paracrine immune recruitment
• Matrix metalloproteinases: MMP-1, MMP-3, MMP-9, MMP-12 — enzymes that degrade extracellular matrix, destabilise atherosclerotic plaque, and irreversibly damage venous valve leaflet architecture
• Growth factors and mitogens: HGF, VEGF, GDF-15, amphiregulin
• Reactive oxygen species (ROS) and lipid mediators

The pathological consequences of chronic SASP elaboration are protean. In the vascular endothelium, SASP-derived IL-6 and MMP-9 impair nitric oxide bioavailability, increase arterial stiffness, and accelerate atherogenic plaque progression. [^4] In venous tissues, MMP-mediated degradation of collagen and elastin within valve leaflets disrupts the structural integrity prerequisite for competent venous valvular function, contributing to chronic venous insufficiency. Crucially, once extracellular matrix scaffolding within valve leaflets is disrupted by MMP activity, the anatomical damage is largely irreversible — making early senolytic intervention conceptually more attractive than late repair.

The cGAS-STING axis also drives a phenomenon termed "senescence spreading" or paracrine senescence: SASP components, particularly TGF-β and ROS, can induce senescence in adjacent proliferating cells, creating a self-amplifying cycle of tissue dysfunction. [^2]

2.3 Senescent Cell Survival Pathways (SCAPs): The Pharmacological Target

Kirkland and Tchkonia at the Mayo Clinic characterised the pro-survival networks of senescent cells — termed senescent cell anti-apoptotic pathways (SCAPs) — as comprising the BCL-2 family axis, the PI3K/AKT/mTOR pathway, p21-mediated inhibition of caspase-3, HSP90-dependent chaperone activity, and the HIF1-α-mediated metabolic reprogramming pathway. [^5] This multi-pathway redundancy explains why single-agent senolytic strategies may be insufficient for certain cell types and why combination approaches (e.g., dasatinib + quercetin) are synergistically effective.

3. CLINICAL MANIFESTATIONS OF PATHOLOGICAL SENESCENT CELL ACCUMULATION

The accumulation of SASP-active senescent cells underlies a spectrum of disorders collectively termed "senescence-driven diseases." The clinical burden is substantial and age-dependent:

Cardiovascular and vascular disease. Senescent endothelial cells and vascular smooth muscle cells (VSMCs) are enriched at atherosclerotic plaque sites. A review in the Journal of Cardiovascular Aging (Hall and Lesniewski, 2024) documents that endothelial senescence drives both macrovascular atherosclerosis and microvascular dysfunction through SASP-mediated impairment of endothelial vasorelaxation and barrier function. [^4] Preclinical data from hypercholesterolaemic pig models demonstrate that navitoclax-mediated senolysis reduced coronary plaque cross-sectional area by approximately 40% in the right coronary artery and increased fibrous cap thickness — suggesting plaque stabilisation, not merely growth inhibition. [^6] Venous endothelial senescence is equally consequential: SASP-driven MMP activity within venous valvular tissue produces irreversible structural damage that contributes to the pathogenesis of chronic venous insufficiency and reflux.

Idiopathic pulmonary fibrosis (IPF). IPF is now understood as a paradigmatic senescence-driven disease. Senescent alveolar epithelial cells accumulate in fibrotic foci, where their SASP

Alzheimer's disease and neurodegeneration. Senescent glial and neuronal cells accumulate in the ageing brain, and their SASP amplifies neuroinflammation through microglial activation.

Metabolic disease and frailty. Senescent preadipocytes and adipocytes in visceral fat contribute to insulin resistance and systemic inflammaging.

Chronic kidney disease. Diabetic kidney disease is characterised by accumulation of senescent tubular and glomerular cells.

4. DIAGNOSTIC APPROACH

4.1 Biomarkers of Cellular Senescence

The clinical detection of senescent cell burden remains a significant translational challenge. No single circulating biomarker is sufficient. Current approaches, validated in published clinical trials, rely on a multi-modal framework:

Tissue-level markers:

• p16^INK4a and p21^Cip1 immunohistochemistry (the most commonly used histological senescence markers; both were reduced by dasatinib + quercetin in human adipose and skin biopsies in the landmark EBioMedicine pilot study) [^7]
• Senescence-associated β-galactosidase (SA-βgal) activity, reflecting expanded lysosomal mass
• Telomere-associated DNA damage foci (TAF)

Circulating SASP markers:

• Plasma IL-1α, IL-6, IL-8, TNF-α
• Circulating MMP-9 and MMP-12
• GDF-15 (growth differentiation factor 15), an emerging systemic senescence biomarker

In the Hickson et al. (2019) EBioMedicine trial, treatment with dasatinib + quercetin for 3 days reduced circulating IL-1α, IL-6, MMP-9, and MMP-12 within 11 days, providing the first direct human evidence that senolytics reduce SASP-associated circulating factors. [^7]

4.2 Identification of Patients with High Senescent Cell Burden

As emphasised in a 2025 translation review by Khosla, beneficial senolytic effects are most likely in individuals with sufficiently elevated baseline senescent cell burden. Candidate populations include: older adults (>65 years) with age-related frailty, patients with IPF, diabetic kidney disease, obesity-associated metabolic syndrome, and individuals with premature ageing syndromes. [^8] Biomarker-stratified patient selection will be a prerequisite for adequately powered phase 2/3 trials.

5. MANAGEMENT AND TREATMENT: SENOLYTIC PHARMACOLOGY

5.1 Classification of Senolytic Agents

Senolytics are defined operationally by their capacity to selectively induce apoptosis in senescent cells while sparing proliferating and quiescent cells, assessed across independent senescence models. Kirkland and Tchkonia proposed a modified Koch’s postulate framework for senolytic validation. [^5]

Agent	Class	Primary Target	Senolytic Cell-Type Specificity
Quercetin	Flavonol	PI3K, BCL-2, redox	HUVECs, preadipocytes, fibroblasts
Fisetin	Flavonol	BCL-2, BCL-XL, redox	HUVECs, adipocytes (cell-type-restricted)
Dasatinib	Tyrosine kinase inhibitor	SRC, BCR-ABL, PI3K/AKT	Preadipocytes
Navitoclax (ABT-263)	BH3 mimetic	BCL-XL, BCL-2, BCL-W	HUVECs, fibroblasts
A1331852 / A1155463	BCL-XL selective inhibitor	BCL-XL	HUVECs, fibroblasts

5.2 Quercetin: Mechanisms and Evidence

Quercetin (3,3’,4’,5,7-pentahydroxyflavone) is a broadly expressed dietary flavonol with pleiotropic intracellular activities. Its senolytic mechanism is multifactorial: it inhibits PI3K/AKT survival signalling, modulates BCL-2 family expression, and exerts copper/iron-catalysed pro-oxidant effects that are selectively toxic to senescent cells, which accumulate higher intracellular concentrations of redox-active metals. [^9] As a monotherapy, quercetin demonstrates modest senolytic activity; its potency increases substantially in combination with dasatinib, which targets complementary SCAPs (specifically SRC kinase-dependent survival signalling in preadipocytes). Dasatinib and quercetin are, by this reasoning, rationally synergistic: each targets SCAP arms that the other does not. [^5]

In the first-in-human senolytic trial (Hickson et al., EBioMedicine 2019), nine patients with diabetic kidney disease received three oral doses of dasatinib 100 mg + quercetin 1000 mg. Adipose tissue biopsies at 11 days post-treatment demonstrated statistically significant reductions in p16^INK4a- and p21^Cip1-expressing cells, SA-βgal activity, crown-like structures (a marker of macrophage accumulation around senescent adipocytes), and circulating SASP factors. [^7] The “hit-and-run” pharmacology was notable: despite elimination half-lives of under 11 hours, biological effects on senescent cell burden persisted for at least 11 days, consistent with the weeks required for senescent cell reaccumulation. [^5]

A phase I placebo-controlled pilot RCT of dasatinib + quercetin in IPF (Nambiar et al., EBioMedicine 2023) confirmed feasibility and general tolerability with an intermittent regimen (3 consecutive days/week for 3 weeks). No serious adverse events related to the combination were reported, though sleep disturbances and anxiety were noted in 4/6 treated participants. [^10]

A phase I proof-of-concept trial in mild Alzheimer’s disease (Gonzales et al., Nature Medicine 2023) demonstrated CNS penetrance of both agents, with dasatinib and quercetin detectable in cerebrospinal fluid, and reported preliminary reductions in neurodegeneration biomarkers in cerebrospinal fluid. [^11]

5.3 Fisetin: Mechanisms and Evidence

Fisetin (2-(3,4-dihydroxyphenyl)-3,7-dihydroxy-4H-chromen-4-one) is a naturally occurring flavone found in strawberries, apples, mangoes, and persimmons. Among ten dietary flavonoids screened in a systematic comparison by Yousefzadeh, Fuhrmann-Stroissnigg, Robbins, Niedernhofer and colleagues, fisetin exhibited the most potent senolytic activity. [^12]

Zhu and colleagues at the Kirkland laboratory were the first to formally identify fisetin as a senolytic agent, demonstrating that it selectively induces apoptosis in senescent human umbilical vein endothelial cells (HUVECs) but not in proliferating HUVECs, while showing cell-type specificity (it was not senolytic in senescent IMR90 human lung fibroblasts or primary preadipocytes at the doses tested). [^13] This cell-type selectivity is a pharmacologically important feature: it implies that fisetin’s mechanism is not a non-specific cytotoxic effect but depends on the particular SCAP architecture of individual senescent cell types.

The molecular basis of fisetin’s selectivity has been illuminated by computational modelling. A 2024 study by Spiegel in Chemistry employing quantum mechanics and molecular dynamics simulations demonstrated that fisetin binds effectively to BCL-2 and BCL-XL at their BH3-binding grooves. Fisetin also displayed exceptional geroprotective radical-scavenging activity against hydroxyl, superoxide, and peroxyl radicals, surpassing reference antioxidants including ascorbate. [^14] A complementary mechanistic analysis proposed that fisetin’s pro-oxidant activity in the presence of copper and iron — metals that accumulate at elevated concentrations in senescent cells — contributes to its selective cytotoxicity. [^9]

In preclinical models, intermittent fisetin treatment of both progeroid and wild-type aged mice reduced p16^INK4a and p21^Cip1 expression in multiple tissues, restored tissue homeostasis, and extended both median and maximum lifespan. Crucially, late-life intervention — initiated in the final 25% of the animals’ lifespan — was sufficient to produce significant benefit, a pharmacologically encouraging finding for translational human application. [^12]

In vascular disease models, intermittent fisetin combined with lipid-lowering produced additive reductions in perivascular adipose tissue inflammatory markers including IL-6 and TNF-α, suggesting synergy between senolytic clearance and conventional cardiovascular risk factor management. [^15] A primate study demonstrated that combined dasatinib + fisetin reduced epidermal p16^INK4a-positive and p21^Cip1-positive cells in older rhesus macaques at 7 weeks post-treatment with no adverse outcomes. [^16]

As of 2025, ClinicalTrials.gov lists 32 ongoing registered studies on fisetin, predominantly in ageing populations with frailty, cognitive impairment, and metabolic disease — an indication of substantial translational momentum. [^8]

5.4 Navitoclax and BCL-XL–Selective Inhibitors

Navitoclax (ABT-263) is a potent pan-BCL-2 family inhibitor (targeting BCL-2, BCL-XL, and BCL-W) originally developed as an anticancer agent. It is senolytic across multiple cell types including HUVECs, IMR90 fibroblasts, and murine embryonic fibroblasts, operating through direct BH3-mimetic displacement of pro-apoptotic proteins from their anti-apoptotic binding partners. [^17] Its principal clinical limitation is dose-dependent thrombocytopenia arising from BCL-XL inhibition in platelets, which lack the capacity for mitochondrial-independent survival after BCL-XL loss.

A 2020 study in Aging Cell by González-Gualda and colleagues demonstrated that galacto-conjugation of navitoclax — exploiting the high lysosomal SA-βgal activity in senescent cells to release the drug selectively within those cells — produced a prodrug (Nav-Gal) with a higher senolytic index and substantially reduced platelet toxicity in ex vivo human blood samples. [^18] This prodrug strategy exemplifies next-generation senolytic engineering aimed at improving therapeutic windows.

More selective BCL-XL inhibitors (A1331852, A1155463) identified by Zhu and colleagues demonstrate senolytic activity in HUVECs and fibroblasts with potentially lower haematological toxicity than navitoclax. [^13]

5.5 Senomorphics: An Alternative Pharmacological Strategy

Distinct from senolytics, which eliminate senescent cells, senomorphics (also termed SASP inhibitors) suppress the secretory output of senescent cells without inducing apoptosis. Agents with senomorphic activity include rapamycin (mTORC1 inhibition, suppressing SASP translation), metformin (AMPK activation with downstream NF-κB inhibition), and JAK1/2 inhibitors such as ruxolitinib (blocking IL-6 and other JAK-dependent SASP signalling). [^1] The senomorphic approach avoids the SASP entirely, potentially valuable when senescent cell preservation is beneficial (e.g., wound healing, post-surgical tissue remodelling), and may be more suitable for continuous rather than intermittent administration. The two strategies are not mutually exclusive and may ultimately be applied in combination.

5.6 Dosing Strategy: The "Hit-and-Run" Paradigm

A defining feature of senolytic pharmacology is the “hit-and-run” dosing regimen. Because senolytics act during a brief window of pro-survival pathway inhibition, and because senescent cells require weeks to reaccumulate after clearance, intermittent short-course administration (typically 2–3 consecutive days per cycle, repeated monthly or less frequently) is pharmacologically justified and clinically practical. This contrasts with the continuous dosing required for conventional anti-inflammatory agents and minimises cumulative drug exposure. The elimination half-lives of both dasatinib (<11 hours) and quercetin are short, yet biological effects on senescent cell burden persist well beyond drug clearance. [^5]

6. SAFETY, LIMITATIONS, AND FUTURE DIRECTIONS

The safety profile of flavonoid senolytics (fisetin and quercetin) is broadly favourable. No serious adverse events attributable to quercetin or fisetin have been reported in published clinical trials at the doses tested. The principal concerns with non-flavonoid senolytics are more significant: navitoclax produces dose-dependent thrombocytopenia and neutropenia, limiting its therapeutic window; dasatinib, an FDA-approved tyrosine kinase inhibitor for CML, carries risks of pleural effusion, cardiovascular events, and haematological toxicity with chronic use (though these are less pertinent to brief intermittent senolytic dosing).

Several critical limitations circumscribe current evidence:

1. Sample sizes. Completed human senolytic trials involve small cohorts (range: 5–64 participants). The first registered clinical study directly demonstrating senescent cell clearance in human tissues enrolled only nine subjects. [^7] Results are hypothesis-generating, not practice-changing.
2. Cell-type and context specificity. No currently known senolytic agent eliminates all senescent cell types with equal efficacy. Fisetin’s senolytic activity in HUVECs was not replicated in IMR90 fibroblasts or preadipocytes. [^13] BCL-XL dependence varies across tissues. BH3 profiling may ultimately be required to match senolytic agents to the specific anti-apoptotic dependencies of target tissues in individual patients.
3. Heterogeneity of human senescence. The 2025 translation review by Khosla identifies inter-individual heterogeneity in senescent cell burden as a major obstacle: benefits are most likely in those with high baseline senescent cell load, requiring validated biomarker-based patient stratification. [^8]
4. Long-term effects. Chronic or excessive senolytic administration risks impairing beneficial senescence-dependent processes including wound healing, tissue repair, and immune surveillance. The optimal frequency, duration, and timing of senolytic courses in humans remains undefined.

Tumour suppression concerns

Senescence is a primary tumour-suppressive barrier. The SASP has both anti- and pro-tumorigenic roles depending on context, and a sustained reduction in senescent cell burden could theoretically reduce this barrier. Preclinical evidence to date does not support increased tumorigenesis risk from senolytics, but long-term oncological surveillance will be required in future trials.

As of 2025, over 26 registered clinical trials are investigating senolytics and 32 are examining fisetin. Target conditions include frailty, IPF, diabetic kidney disease, osteoarthritis, osteoporosis, Alzheimer’s disease, and post-transplant complications. The Translational Geroscience Network is coordinating parallel multi-site trials to accelerate phase 2/3 data generation. [^8]

CONCLUSION

The discovery that senescent cells function not as passive bystanders but as active, SASP-elaborating instigators of tissue pathology represents a conceptual revolution in ageing biology with direct clinical implications. The SASP — encompassing pro-inflammatory cytokines, chemokines, and tissue-destructive MMPs — constitutes a mechanistic link between cellular ageing and the chronic inflammatory burden underlying cardiovascular disease, fibrosis, neurodegeneration, and metabolic syndrome. [^1][^2][^3]

Flavonoid senolytics, particularly fisetin and quercetin, offer a pharmacologically compelling strategy to selectively eliminate the most tissue-destructive senescent cell populations by exploiting their dependency on BCL-2/BCL-XL anti-apoptotic survival. Their cell-type specificity, low-toxicity profiles, favourable pharmacokinetics for intermittent dosing, and early human proof-of-concept data collectively position them as the most translationally mature senolytic candidates currently available. [^5][^7][^12][^13]

The practising physician should understand that cellular senescence and the SASP are not theoretical constructs: they are measurable, pharmacologically targetable biological processes whose dysregulation contributes directly to conditions encountered daily in clinical practice. Chronic venous insufficiency with valvular destruction, atherosclerotic plaque instability, pulmonary fibrosis, and age-associated frailty all carry a demonstrable senescent cell component. The question is no longer whether senescent cells cause harm

Full clinical translation requires adequately powered randomised trials with biomarker-stratified patient selection, validated circulating SASP biomarker panels, and long-term oncological safety data. This review is based on an initial structured literature search; the rapidly evolving clinical trial landscape will undoubtedly yield additional evidence in the near term.

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2. Zhu Y, Armstrong JL, Tchkonia T, Kirkland JL. Cellular senescence and the senescent secretory phenotype in age-related chronic diseases. Curr Opin Clin Nutr Metab Care. 2014;17(4):324-8. doi:10.1097/MCO.0000000000000065

3. Copp\u00e9 JP, Desprez PY, Krtolica A, Campisi J. The senescence-associated secretory phenotype: the dark side of tumor suppression. Annu Rev Pathol. 2010;5:99-118. doi:10.1146/annurev-pathol-121808-102144

4. Ohtani N. The roles and mechanisms of senescence-associated secretory phenotype (SASP): can it be controlled by senolysis? Inflamm Regen. 2022;42:11. doi:10.1186/s41232-022-00197-8

5. Kirkland JL, Tchkonia T. Senolytic drugs: from discovery to translation. J Intern Med. 2020;288(5):518-536. doi:10.1111/joim.13141

6. Hickson LJ, et al. Senolytics decrease senescent cells in humans: Preliminary report from a clinical trial of Dasatinib plus Quercetin in individuals with diabetic kidney disease. EBioMedicine. 2019;47:446-456. doi:10.1016/j.ebiom.2019.08.069

7. Wissler Gerdes EO, et al. Strategies for Late Phase Preclinical and Early Clinical Trials of Senolytics. Mech Ageing Dev. 2021;200:111591. doi:10.1016/j.mad.2021.111591

8. Zhu Y, et al. New agents that target senescent cells: the flavone, fisetin, and the BCL-XL inhibitors, A1331852 and A1155463. Aging (Albany NY). 2017;9(3):955-963. doi:10.18632/aging.101202

9. Wang Y, He Y, Rayman MP, Zhang J. Prospective Selective Mechanism of Emerging Senolytic Agents Derived from Flavonoids. J Agric Food Chem. 2021;69(46):13418-13430. doi:10.1021/acs.jafc.1c04379

10. Nambiar A, et al. Senolytics dasatinib and quercetin in idiopathic pulmonary fibrosis: results of a phase I, single-blind, single-center, randomized, placebo-controlled pilot trial. EBioMedicine. 2023;90:104481. doi:10.1016/j.ebiom.2023.104481

11. Gonzales MM, et al. Senolytic therapy in mild Alzheimer\u2019s disease: a phase 1 feasibility trial. Nat Med. 2023;29(10):2481-2488. doi:10.1038/s41591-023-02543-w

12. Yousefzadeh MJ, et al. (Faculty Opinions recommendation) Fisetin is a senotherapeutic that extends health and lifespan. EBioMedicine. 2018. [Also reviewed in Faculty Opinions 2019.]

13. Zhu Y, Doornebal EJ, Pirtskhalava T, et al. New agents that target senescent cells: the flavone, fisetin, and the BCL-XL inhibitors, A1331852 and A1155463. Aging. 2017;9(3):955-963. doi:10.18632/aging.101202

14. Spiegel M. Fisetin as a Blueprint for Senotherapeutic Agents \u2013 Elucidating Geroprotective and Senolytic Properties with Molecular Modeling. Chemistry. 2024. doi:10.1002/chem.202403755

15. Nicolai EN, Hagler MA, et al. Effects of Chronic, Intermittent Senescent Cell Clearance in Combination with Lipid Lowering on Inflammation in Perivascular Adipose Tissue. ATVB. 2019;39(Suppl 1):361. doi:10.1161/atvb.39.suppl1.361

16. Colman R, Tchkonia T, et al. Effect of Combined Dasatinib and Fisetin Treatment on Senescent Cell Clearance in Monkeys. Innovation in Aging. 2020;4(Suppl 1). doi:10.1093/geroni/igaa057.432

17. Zhu Y, Tchkonia T, Fuhrmann-Stroissnigg H, et al. Identification of a novel senolytic agent, navitoclax, targeting the Bcl-2 family of anti-apoptotic factors. Aging Cell. 2016;15(3):428-435. doi:10.1111/acel.12445

18. Gonz\u00e1lez-Gualda E, et al. Galacto-conjugation of Navitoclax as an efficient strategy to increase senolytic specificity and reduce platelet toxicity. Aging Cell. 2020;19(4):e13142. doi:10.1111/acel.13142

19. MacDonald JA, Bradshaw GA, et al. Apoptotic priming in senescence predicts specific senolysis by quantitative analysis of mitochondrial dependencies. Cell Death Differ. 2025. doi:10.1038/s41418-024-01431-1

20. Hall SA, Lesniewski LA. Targeting vascular senescence in cardiovascular disease with aging. J Cardiovasc Aging. 2024;4. doi:10.20517/jca.2023.45

21. Gonz\u00e1lez I, Maldonado-Agurto R. The role of cellular senescence in endothelial dysfunction and vascular remodelling in arteriovenous fistula maturation. J Physiol. 2025. doi:10.1113/JP287387

22. Cuollo L, Antonangeli F, Santoni A, Soriani A. The Senescence-Associated Secretory Phenotype (SASP) in the Challenging Future of Cancer Therapy and Age-Related Diseases. Biology. 2020;9(12):485. doi:10.3390/biology9120485

23. Khosla S. Translating Senolytics From Mice to Humans. Innovation in Aging. 2025;9(Suppl 2). doi:10.1093/geroni/igaf122.679

Disclosure of interests: The author declares no conflicts of interest. This article does not constitute clinical guidance and does not recommend senolytic therapy outside of registered clinical trial protocols.

[^1]: Wang et al., 2024. The senescence-associated secretory phenotype and its physiological and pathological implications. Nature reviews. Molecular cell biology.

[^2]: Ohtani, 2022. The roles and mechanisms of senescence-associated secretory phenotype (SASP): can it be controlled by senolysis?. Inflammation and Regeneration.

[^3]: Kirkland & Tchkonia, 2020. Senolytic drugs: from discovery to translation. Journal of Internal Medicine.

[^4]: Hall & Lesniewski, 2024. Targeting vascular senescence in cardiovascular disease with aging. The Journal of Cardiovascular Aging.

[^5]: Sukhanov et al., 2025. Abstract 4364300: The Senolytic Navitoclax (ABT263) Reduces Coronary Atherosclerosis and Upregulates Plaque Stability in Atherosclerotic Pigs. Circulation.

[^6]: Hickson et al., 2019. Senolytics decrease senescent cells in humans: Preliminary report from a clinical trial of Dasatinib plus Quercetin in individuals with diabetic kidney disease. EBioMedicine.

[^7]: Khosla, 2025. Translating Senolytics From Mice to Humans. Innovation in aging.

[^8]: Wang et al., 2021. Prospective Selective Mechanism of Emerging Senolytic Agents Derived from Flavonoids. Journal of Agricultural and Food Chemistry.

[^9]: Nambiar et al., 2023. Senolytics dasatinib and quercetin in idiopathic pulmonary fibrosis: results of a phase I, single-blind, single-center, randomized, placebo-controlled pilot trial on feasibility and tolerability. EBioMedicine.

[^10]: Gonzales et al., 2023. Senolytic therapy in mild Alzheimer’s disease: a phase 1 feasibility trial. Nature Medicine.

[^11]: Kennedy & Tsai, 2018. Faculty Opinions recommendation of Fisetin is a senotherapeutic that extends health and lifespan. Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature.

[^12]: Zhu et al., 2017. New agents that target senescent cells: the flavone, fisetin, and the BCL-XL inhibitors, A1331852 and A1155463. Aging.

[^13]: Spiegel, 2024. Fisetin as a Blueprint for Senotherapeutic Agents – Elucidating Geroprotective and Senolytic Properties with Molecular Modeling. Chemistry.

[^14]: Nicolai et al., 2019. Abstract 361: Effects of Chronic, Intermittent Senescent Cell Clearance in Combination with Lipid Lowering on Inflammation in Perivascular Adipose Tissue. Arteriosclerosis, Thrombosis and Vascular Biology.

[^15]: Colman et al., 2020. Effect of Combined Dasatinib and Fisetin Treatment on Senescent Cell Clearance in Monkeys. Innovation in aging.

[^16]: Zhu et al., 2016. Identification of a novel senolytic agent, navitoclax, targeting the Bcl‐2 family of anti‐apoptotic factors. Aging Cell.

[^17]: González-Gualda et al., 2020. Galacto‐conjugation of Navitoclax as an efficient strategy to increase senolytic specificity and reduce platelet toxicity. Aging Cell.

[^18]: MacDonald et al., 2025. Apoptotic priming in senescence predicts specific senolysis by quantitative analysis of mitochondrial dependencies. Cell Death and Differentiation.