Senescence and Beyond: Exploring Senolytic Strategies for Chronic Disease

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 p16INK4a expression in immune cells, suggesting a senostatic effect. Across studies, adherence was high, and adverse events were generally mild. Conclusion: These early studies establish 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.