- Senolytics are a class of therapeutic agents designed to selectively eliminate senescent cells, which are cells that have permanently exited the cell cycle in response to stress or damage but remain metabolically active.
- Although cellular senescence serves beneficial roles in tumor suppression, wound healing, and tissue remodeling, the long-term accumulation of senescent cells contributes to aging, chronic inflammation, and age-related diseases such as osteoarthritis, atherosclerosis, pulmonary fibrosis, and neurodegenerative disorders. Senolytics target the pro-survival pathways that allow senescent cells to resist apoptosis, effectively inducing their death and clearing them from tissues.
- Senescent cells typically express anti-apoptotic pathways that protect them from immune-mediated clearance. These include members of the BCL-2 family, the PI3K/AKT signaling pathway, and p53/p21 and p16^INK4a regulators. Senolytics exploit these vulnerabilities by disrupting these survival mechanisms, rendering senescent cells susceptible to apoptosis. Some of the most well-studied senolytics include navitoclax (ABT-263), which inhibits BCL-2/BCL-xL; the combination of dasatinib and quercetin (D+Q), which targets tyrosine kinases and multiple anti-apoptotic proteins; and fisetin, a natural flavonoid with senolytic and anti-inflammatory properties.
- Preclinical studies in mouse models of aging and disease have shown that senolytics can improve tissue function, reduce inflammation, and extend healthspan. For example, intermittent treatment with D+Q has been shown to improve cardiovascular and metabolic function, enhance physical endurance, and delay the onset of frailty. In models of neurodegeneration, senolytic treatment has been associated with reduced neuroinflammation, preservation of neuronal function, and improved cognition. These findings suggest that senolytics can alleviate many of the deleterious effects associated with senescent cell accumulation.
- Importantly, senolytic therapies are typically administered intermittently, rather than continuously, to minimize potential side effects and because senescent cells take time to reaccumulate after clearance. This pulsed dosing strategy also helps avoid the disruption of transiently beneficial senescence, such as during tissue repair or after acute injury.
- Despite their promise, senolytics face several challenges in clinical translation. One major hurdle is specificity: identifying and targeting senescent cells without harming normal, non-senescent cells. Additionally, senescent cell heterogeneity—variations in senescence markers and survival mechanisms across cell types and tissues—means that a single senolytic agent may not be universally effective. Moreover, concerns remain about off-target effects, such as hematological toxicity seen with navitoclax due to its impact on platelets.
- Several early-phase clinical trials are underway to evaluate the safety and efficacy of senolytics in humans, particularly for conditions like idiopathic pulmonary fibrosis, diabetic kidney disease, and Alzheimer’s disease. Preliminary results have shown favorable safety profiles and potential therapeutic benefits, but larger and longer-term studies are needed to confirm their clinical utility.
