Senolytics: A Pharmacological Strategy for the Elimination of Senescent Cells as a Promising Direction in Geroprotection

1. Introduction. Cellular Senescence as a Fundamental Mechanism of Age-Related Pathology

Aging is a multifactorial biological process driven by the progressive accumulation of molecular and cellular damage. Among the key «hallmarks of aging,» systematically defined by López-Otín et al. in 2013 and expanded in 2023, cellular senescence occupies a prominent position. This is a state of irreversible cell cycle arrest wherein the cell retains metabolic activity but loses its proliferative capacity.

Senescent cells accumulate in tissues with age and in response to various stressors: telomere attrition, oxidative stress, oncogene activation, and DNA damage. A critical property of these cells is the secretion of pro-inflammatory cytokines, chemokines, proteases, and growth factors — a phenomenon known as SASP (senescence-associated secretory phenotype). It is the SASP that mediates chronic, low-grade systemic inflammation («inflammaging»), which underlies the pathogenesis of atherosclerosis, osteoarthritis, neurodegenerative diseases, sarcopenia, idiopathic pulmonary fibrosis, and several oncological conditions.

Experimental studies by Jan van Deursen’s group (Mayo Clinic, 2011) convincingly demonstrated that the selective clearance of senescent cells in INK-ATTAC transgenic mice led to a significant delay in age-related degenerative changes and an increase in healthspan. These data became the starting point for the formation of a novel pharmacological direction: senolytic therapy.

2. Senolytics: Definition, Classification, and Mechanism of Action

Senolytics (from Latin senescens — aging, and Greek lytikos — destructive) are a class of pharmacological agents capable of selectively inducing apoptosis (programmed cell death) in senescent cells, while minimally affecting healthy proliferating and quiescent cells. The term was coined in 2015 by James Kirkland and Tamara Tchkonia from the Mayo Clinic.

The mechanism of senolytic selectivity is based on the fact that senescent cells, to maintain their viability and resistance to apoptosis, activate specific survival pathways — so-called SCAPs (senescent cell anti-apoptotic pathways). These include:

• The BCL-2 family (BCL-2, BCL-xL, BCL-W) — anti-apoptotic proteins that block the release of cytochrome c from mitochondria;
• The PI3K/AKT pathway — a key signaling cascade that suppresses pro-apoptotic factors;
• p53/p21 signaling and its interaction with serpins (PAI-1, PAI-2);
• Tyrosine kinase receptors (e.g., EphB receptors), which provide paracrine survival support.

Senolytic drugs disrupt one or more of these pathways, leading to a cascading activation of caspases and the death of the senescent cell. It is crucial to emphasize that senolytics do not «rejuvenate» cells; rather, they eliminate them, allowing the tissue niche to recover through the proliferation of neighboring functional cells and the activation of resident stem cells.

3. List of Major Senolytic Agents

To date, several dozen compounds with senolytic activity are being studied in preclinical and clinical trials. Below is a list of the most significant agents, grouped by their mechanism of action.

3.1. BCL-2 Family Inhibitors

• Dasatinib — a tyrosine kinase inhibitor originally developed for chronic myeloid leukemia therapy. In combination with quercetin (the D+Q regimen), it is the most extensively studied senolytic protocol. Dasatinib predominantly eliminates senescent adipocytes and mesenchymal progenitor cells.
• Navitoclax (ABT-263) — a highly selective inhibitor of BCL-2, BCL-xL, and BCL-W. It has demonstrated pronounced senolytic activity in models of pulmonary fibrosis, atherosclerosis, and radiation damage. Its main limitation is dose-dependent thrombocytopenia caused by BCL-xL inhibition in platelets.
• ABT-737 — a predecessor of navitoclax, used primarily in preclinical models.

3.2. Natural Flavonoids and Polyphenols

• Quercetin — a flavonol widely distributed in the plant kingdom. It inhibits the PI3K/AKT pathway and tyrosine kinases. As a monotherapy, it shows moderate senolytic activity against senescent endothelial cells; in combination with dasatinib, it yields a synergistic effect.
• Fisetin — a flavonoid isolated from strawberries, apples, and onions. Studies by Laura Niedernhofer’s group (University of Minnesota, 2018) showed that fisetin possesses the most pronounced senolytic activity among natural flavonoids, surpassing quercetin in selectivity against senescent fibroblasts and endothelial cells.
• Piperlongumine — an alkaloid from Piper longum, which induces oxidative stress predominantly in senescent cells.

3.3. HSP90 Inhibitors and Other Agents

• Ganetespib (STA-9090) — an HSP90 chaperone inhibitor that disrupts the stabilization of anti-apoptotic proteins in senescent cells.
• 17-DMAG — a geldanamycin analog, also targeting HSP90.
• UBX0101 — a peptidomimetic that blocks the MDM2/p53 interaction; it was developed by Unity Biotechnology for the treatment of knee osteoarthritis.
• FOXO4-DRI — a peptide that disrupts the interaction between FOXO4 and p53, leading to p53-mediated apoptosis of senescent cells. Developed by Peter de Keizer’s group (Erasmus MC, 2017).

4. Senolytics in Food and Senolytic Plants

Significant interest lies in the possibility of obtaining senolytic compounds from dietary sources. Although the concentrations of active substances in food are substantially lower than the pharmacological doses used in clinical studies, epidemiological data indicate a correlation between a polyphenol-rich diet and the attenuation of age-related pathologies.

Plants and Foods with Confirmed Content of Senolytic Compounds:

It should be specifically noted that thermal processing and bioavailability significantly affect the actual concentration of active compounds. For example, the bioavailability of quercetin from onions is much higher than from apples due to differences in glycoside forms. Fisetin from strawberries has relatively low bioavailability upon oral administration, which stimulates the development of liposomal and nanoparticle delivery forms.

5. Clinical Trials and Current Status

As of 2024-2025, several clinical trials of senolytics in humans have been completed or are in active phases:

• Idiopathic Pulmonary Fibrosis (IPF): A Phase I pilot study (Justice et al., 2019, Mayo Clinic) showed that a course of dasatinib and quercetin (D+Q) improved the physical functionality of patients (increased 6-minute walk distance).
• Diabetic Nephropathy: A Phase I study (Hickson et al., 2019) demonstrated a reduction in SASP markers in adipose tissue and skin following a three-day course of D+Q.
• Alzheimer’s Disease: Phase I/II trials are underway using dasatinib and quercetin (NCT04063124).
• Osteoarthritis: Trials of UBX0101 (Unity Biotechnology) yielded mixed results; the program was subsequently adjusted.
• Post-COVID Syndrome: Pilot studies of senolytics have been initiated to eliminate senescent cells, the accumulation of which is associated with persistent inflammation following SARS-CoV-2 infection.

6. Availability of Senolytics: Can They Be Purchased?

The question of the commercial availability of senolytics requires a differentiated answer.

Prescription drugs (dasatinib, navitoclax) are registered as anti-cancer agents and are dispensed strictly by prescription. Their use as senolytics is currently in the clinical trial stage and is not approved by regulatory agencies (FDA, EMA) for anti-aging therapy. Independent acquisition and use of these drugs outside clinical protocols are fraught with serious risks: immunosuppression, thrombocytopenia, hepatotoxicity, and cardiotoxicity.

Dietary supplements (BADs) based on quercetin, fisetin, curcumin, and resveratrol are widely available on the market and sold over the counter. However, several critical caveats must be emphasized:

1. The dosages in supplements are generally much lower than those used in preclinical senolytic protocols (e.g., for fisetin, mouse studies used doses of ~100 mg/kg, which, when translated to human equivalents, significantly exceeds standard supplement doses).
2. The quality, purity, and bioavailability of commercial supplements vary widely and are not always verified by independent laboratory controls.
3. The in vivo senolytic effect of oral plant flavonoids at standard dosages remains a subject of scientific debate and cannot be considered proven.

Thus, to date, there are no approved senolytic drugs for over-the-counter anti-aging therapy. All application regimens remain in the experimental stage.

7. Conclusion

Senolytic therapy represents one of the most promising directions in 21st-century translational gerontology. The concept of selectively eliminating senescent cells, unlike previous approaches, targets not the slowing of damage accumulation, but the removal of already formed pathological cell populations, opening fundamentally new possibilities for treating age-related diseases. Nevertheless, before widespread clinical implementation, a number of fundamental challenges must be addressed: optimizing dosing regimens (intermittent vs. continuous), developing tissue-specific senolytics, creating reliable in vivo biomarkers of senescent burden, and conducting large-scale Phase III randomized clinical trials.

Recent Developments (2025-2026)

First human signals in brain aging. The STAMINA pilot (2025) gave intermittent dasatinib plus quercetin to 12 older adults with mild cognitive impairment and slow gait: treatment was feasible with no related serious adverse events, and reductions in the SASP marker TNF-alpha correlated with cognitive gains on the MoCA scale. Complementary biomarker work from the SToMP-AD phase 1 trial confirmed dasatinib reaches the cerebrospinal fluid and dampens inflammatory gene expression. A Phase 2 randomized trial in Alzheimer’s disease is now underway — the first rigorous efficacy test of senolytics against neurodegeneration.

1. Millar C.L. et al. «A pilot study of senolytics to improve cognition and mobility in older adults at risk for Alzheimer’s disease.» EBioMedicine, 2025; 113: 105612. DOI: 10.1016/j.ebiom.2025.105612 — STAMINA trial.
2. Garbarino V.R. et al. «Evaluation of exploratory fluid biomarkers from a phase 1 senolytic trial in mild Alzheimer’s disease.» Neurotherapeutics, 2025. DOI: 10.1016/j.neurot.2025.e00591
3. Orr M. «Clinical Trials of Senolytics in Alzheimer’s Disease Treatment and Prevention.» 2025. PMC12761975 — Review: Phase 2 RCT now underway.

Sources and Key Research Centers

1. Mayo Clinic, Robert and Arlene Kogod Center on Aging (Rochester, Minnesota, USA) — James L. Kirkland and Tamara Tchkonia group. Pioneering work on senolytics (D+Q regimen).
2. Buck Institute for Research on Aging (Novato, California, USA) — Judith Campisi group. Foundational research on SASP and cellular senescence.
3. University of Minnesota, Institute on the Biology of Aging and Metabolism — Laura J. Niedernhofer and Paul D. Robbins group. Discovery of the senolytic activity of fisetin (2018).
4. Erasmus Medical Center (Rotterdam, Netherlands) — Peter L. de Keizer group. Development of the FOXO4-DRI peptide (2017).
5. López-Otín C. et al. «Hallmarks of aging: An expanding universe.» Cell, 2023; 186(2): 243-278. DOI: 10.1016/j.cell.2022.11.001
6. Zhu Y. et al. «The Achilles’ heel of senescent cells: from transcriptome to senolytic drugs.» Aging Cell, 2015; 14(4): 644-658. DOI: 10.1111/acel.12344
7. Justice J.N. et al. «Senolytics in idiopathic pulmonary fibrosis: Results from a first-in-human, open-label, pilot study.» EBioMedicine, 2019; 40: 554-563. DOI: 10.1016/j.ebiom.2018.12.052
8. Yousefzadeh M.J. et al. «Fisetin is a senotherapeutic that extends health and lifespan.» EBioMedicine, 2018; 36: 18-28. DOI: 10.1016/j.ebiom.2018.09.015
9. ClinicalTrials.gov — U.S. National Library of Medicine registry of clinical trials. (Search keywords: senolytic, senescent cells, dasatinib quercetin).
10. National Institute on Aging (NIA), NIH — Interventions Testing Program (ITP) and grant support for senolytic and geroprotective research.