Senolytics: The New Hope for Slowing Aging

Aging is the most significant risk factor for chronic diseases. This is largely due to the accumulation of senescent cells, damaged cells that stop dividing but persist in tissues. While cellular senescence is a natural mechanism to prevent the spread of damaged or cancerous cells, its prolonged presence contributes to chronic inflammation, tissue dysfunction, and degenerative diseases. Over time, these "zombie" cells accumulate as the immune system's ability to clear them declines, promoting conditions such as arthritis, cardiovascular disease, diabetes, and neurodegeneration.

The senescence-associated secretory phenotype (SASP), a mix of inflammatory molecules released by senescent cells, disrupts normal tissue function and accelerates aging. Researchers have identified senolytics, a class of drugs that selectively eliminate these dysfunctional cells, as a potential strategy to delay or prevent multiple age-related disorders simultaneously, rather than tackling each disease individually.

Preclinical studies have demonstrated that senolytic drugs can effectively eliminate senescent cells in animal models, leading to improvements in various age-related conditions. For instance, research has shown that removing these cells in mice results in delayed progression of diseases such as osteoporosis, muscle loss, and cardiac dysfunction.¹

Mechanism of Action

Senescent cells stop dividing and resist apoptosis by activating survival pathways while releasing inflammatory molecules (SASP) that cause tissue damage. Senolytics counter this by blocking these survival mechanisms, forcing senescent cells to undergo apoptosis while sparing healthy cells. Eliminating these harmful cells reduces inflammation, restores tissue function, and slows aging.

For example, BCL-2 inhibitors such as Navitoclax block anti-apoptotic proteins, while tyrosine kinase inhibitors like Dasatinib interfere with the survival pathways that senescent cells depend on. Natural flavonoids, including Quercetin and Fisetin, can suppress SASP and induce apoptosis in certain senescent cells.²

Importantly, senolytic therapy is administered in a "hit-and-run" manner, meaning the drugs are given intermittently to minimize side effects and allow tissues to regenerate healthy cells.

Key Senolytic Compounds

Different senolytic agents have been identified, each targeting specific types of senescent cells.

1. Dasatinib (D) – An FDA-approved cancer drug that eliminates senescent fat progenitor and endothelial cells. In animal models, a single dose improved cardiovascular function within days.

2. Quercetin (Q) – A natural flavonoid that targets endothelial and bone-marrow-derived senescent cells, often combined with Dasatinib for broader senolytic action.

3. Fisetin – A plant-derived senolytic that extends lifespan in mice and reduces systemic inflammation. It is considered one of the safest senolytic candidates and is currently in human clinical trials for frailty reduction.

4. Navitoclax (ABT-263) – A potent BCL-2 inhibitor that eliminates senescent cells in bone marrow and blood vessels but carries a risk of thrombocytopenia (low platelet count).³

5. UBX1325 (Foselutoclax) – A newer senolytic targeting senescent cells in the retina, currently being tested for age-related macular degeneration and diabetic macular edema.⁴

UBX1325 (foselutoclax) is an investigational senolytic developed by UNITY Biotechnology for retinal diseases like diabetic macular edema (DME) and wet age-related macular degeneration (AMD). It inhibits BCL-xL, a protein that helps senescent cells survive, promoting their selective elimination in the retina. In clinical trials, UBX1325 has shown promise.

A Phase 1 study confirmed its safety and potential benefits for retinal endothelial cells in DME patients. In the Phase 2 BEHOLD trial, a single injection led to significant improvements in Best Corrected Visual Acuity (BCVA) over 48 weeks.The Phase 2 ENVISION study in wet AMD did not meet its primary endpoint but suggested greater efficacy in patients with longer disease duration. The ongoing Phase 2b ASPIRE study is evaluating UBX1325 in DME patients unresponsive to standard care, with results expected in early 2025. By clearing senescent cells in the retina, UBX1325 offers a novel approach that could address underlying disease mechanisms beyond current treatments. Beyond these, next-generation senolytics are being developed to improve specificity and reduce side effects.

Research and Clinical Trials

Studies on senolytics have produced encouraging results in animal models. A landmark study published in 2015 demonstrated that administering Dasatinib in combination with Quercetin to aged mice alleviated various age related deficits. The treated mice exhibited improved cardiovascular performance, enhanced exercise endurance, increased bone strength, and a 36% extension in their remaining lifespan compared to untreated controls.⁵ These results indicate that the clearance of senescent cells may extend lifespan and reduce morbidity in these models.

Research in disease specific models further supports the potential of senolytic drugs. In studies on atherosclerosis, removal of senescent foam cells resulted in smaller and more stable plaques that may reduce the risk of heart attack. In Alzheimer's disease models, elimination of senescent glial cells led to decreased tau protein accumulation and neuroinflammation, thereby improving cognitive performance.⁶ Similarly, in a mouse model of idiopathic pulmonary fibrosis, senolytic treatment alleviated lung fibrosis and enhanced lung function. Early human trials have reported improvements in physical function after short term senolytic therapy, supporting the potential application of these drugs in treating age related conditions.

Potential Benefits

● Senolytic therapies offer promising benefits by selectively clearing toxic senescent cells, which accumulate with age and contribute to chronic diseases. Studies in animal models show that eliminating these cells extends lifespan, preserves physical function, and improves metabolic health. For instance, in mice, senolytics reduced senescent cell accumulation in fat tissue, lowering inflammation and enhancing insulin sensitivity, which could help prevent type II diabetes and metabolic disorders. In Alzheimer’s disease models, removing senescent brain cells reduced tau tangles and neuroinflammation, preserving cognitive function, while early human trials suggest potential benefits in slowing cognitive decline. These findings indicate that senolytics may improve overall healthspan rather than just prolonging life.⁷

● Senolytics represent a promising anti-aging therapy by selectively eliminating senescent cells, thereby reducing chronic inflammation and promoting healthy longevity. By targeting the underlying mechanisms of aging, senolytic drugs hold the potential to revolutionize anti-aging therapy, extending both lifespan and healthspan to support healthy longevity.

● Senolytics also show therapeutic potential in multiple age-related diseases. By clearing senescent cells from blood vessels, they help stabilize atherosclerotic plaques, potentially reducing heart attack and stroke risks. In osteoarthritis and osteoporosis models, senolytic treatment preserved cartilage and improved bone strength, suggesting benefits for mobility and joint health.² Furthermore, clinical studies in idiopathic pulmonary fibrosis (IPF) indicate improved lung function, while early kidney disease research suggests senolytics may help protect renal function by reducing inflammatory factors.⁸

● Additionally, senolytics could serve as adjunct cancer therapies by eliminating therapy-induced senescent cells that promote tumor growth and relapse. If these benefits are confirmed in human trials, senolytic therapy could revolutionize preventive medicine by addressing aging as the underlying cause of multiple diseases.

Challenges and Future Prospects of Senolytic Therapy

Senolytics face significant challenges before widespread clinical use. Safety concerns remain a primary issue, as some senolytic agents, like Dasatinib and Navitoclax, are repurposed chemotherapy drugs with known toxicities, including fluid retention, immunosuppression, and severe thrombocytopenia. Developing more selective and minimally toxic compounds is crucial. Additionally, senescent cells play beneficial roles in wound healing and cancer suppression, raising concerns about indiscriminate clearance disrupting essential biological processes.⁹ Targeting senescent cells precisely and timing senolytic therapy appropriately will be key to minimizing unintended consequences. Another challenge is the heterogeneity of senescent cells across tissues, requiring a combination of drugs to effectively eliminate all harmful populations. Reliable, non-invasive biomarkers are also needed to identify and track senescent cells in patients.

Despite these hurdles, advancements in senotherapeutics are accelerating. Researchers are developing next-generation senolytics with improved specificity, including prodrugs activated only within senescent cells and senomorphics that suppress harmful secretions without eliminating cells. Innovative approaches, such as senolytic CAR T cells and gene therapies targeting senescence markers like p16^INK4A, show promise in preclinical models.

If clinical trials continue to demonstrate safety and efficacy, senolytics could soon be integrated into mainstream medicine, initially targeting specific diseases like osteoarthritis and macular degeneration before expanding to broader applications in aging prevention. As research progresses, senolytics may play a transformative role in extending healthspan and reducing the burden of age-related diseases.

Conclusion

Senolytics represent a groundbreaking advancement in the pursuit of healthy longevity and anti-aging therapy by targeting and eliminating harmful senescent cells. By reducing inflammation, restoring tissue function, and slowing the aging process, these therapies offer immense potential to combat a wide range of age-related diseases, from cardiovascular conditions to neurodegeneration. While challenges such as safety concerns and precise targeting remain, ongoing research and clinical trials continue to refine these treatments. If successfully integrated into mainstream medicine, senolytics could revolutionize preventive healthcare, enhancing both lifespan and healthspan for future generations.

References:

1. Ellison-Hughes, Georgina M. ‘First Evidence That Senolytics Are Effective at Decreasing Senescent Cells in Humans’. EBioMedicine, vol. 56, May 2020, p. 102473. PubMed Central, https://doi.org/10.1016/j.ebiom.2019.09.053.

2. Kirkland, J. L., and T. Tchkonia. ‘Senolytic Drugs: From Discovery to Translation’. Journal of Internal Medicine, vol. 288, no. 5, Nov. 2020, pp. 518–36. DOI.org (Crossref), https://doi.org/10.1111/joim.13141.

3. Park, Jooho, and Dong Wook Shin. ‘Senotherapeutics and Their Molecular Mechanism for Improving Aging’. Biomolecules & Therapeutics, vol. 30, no. 6, Nov. 2022, pp. 490–500. PubMed Central, https://doi.org/10.4062/biomolther.2022.114.

4. Pipeline | Unity Biotechnology. 12 Mar. 2022, https://unitybiotechnology.com/pipeline/.

5. Xu, Ming, et al. ‘Senolytics Improve Physical Function and Increase Lifespan in Old Age’. Nature Medicine, vol. 24, no. 8, Aug. 2018, pp. 1246–56. www.nature.com, https://doi.org/10.1038/s41591-018-0092-9.

6. Gonzales, Mitzi M., et al. ‘Senolytic Therapy in Mild Alzheimer’s Disease: A Phase 1 Feasibility Trial’. Nature Medicine, vol. 29, no. 10, Oct. 2023, pp. 2481–88. www.nature.com, https://doi.org/10.1038/s41591-023-02543-w.

7. Zhu, Yi, et al. ‘Identification of a Novel Senolytic Agent, Navitoclax, Targeting the Bcl‐2 Family of Anti‐apoptotic Factors’. Aging Cell, vol. 15, no. 3, June 2016, pp. 428–35. DOI.org (Crossref), https://doi.org/10.1111/acel.12445.

8. Childs, Bennett G., et al. ‘Senescent Cells: An Emerging Target for Diseases of Ageing’. Nature Reviews Drug Discovery, vol. 16, no. 10, Oct. 2017, pp. 718–35. www.nature.com, https://doi.org/10.1038/nrd.2017.116.

9. Lorenzo, Erica C., et al. ‘Impact of Senolytic Treatment on Immunity, Aging, and Disease’. Frontiers in Aging, vol. 4, Oct. 2023. Frontiers, https://doi.org/10.3389/fragi.2023.1161799.