This Phase II, randomized, double-blind, placebo-controlled pilot study will evaluate the effects of fisetin, a senolytic flavonoid compound, on lung function and biomarkers of cellular senescence in older adults aged 60 years and older. Participants will include individuals with a history of at least 10 pack-years of smoking as well as age-matched never-smokers. Forty participants will be randomized to receive either fisetin or placebo using a short-course "hit-and-run" dosing strategy (approximately 20 mg/kg/day orally for 2 consecutive days on Days 1-2 and Days 8-9).

This Phase II, randomized, double-blind, placebo-controlled study is designed to evaluate the effects of fisetin, a naturally occurring flavonoid with senolytic properties, on pulmonary health in older adults. Aging and cigarette smoke exposure have both been associated with cellular senescence, a biological process characterized by the accumulation of dysfunctional cells that may contribute to progressive decline in organ function. The study investigates whether intermittent administration of fisetin can favorably influence lung physiology and biological markers associated with aging.

Participants will be randomized to receive either fisetin or placebo and will undergo a short-course treatment regimen using a "hit-and-run" approach intended to transiently target senescent cells. The study population includes older adults with and without a history of cigarette smoking to allow assessment across groups with differing risk for accelerated pulmonary aging.

Study procedures include clinical evaluations, pulmonary function testing, exercise-based assessments, electrocardiography, laboratory testing, and collection of blood and urine samples for analysis of biomarkers related to cellular senescence and aging. Participants will be followed over a two-week study period, during which safety, tolerability, and protocol feasibility will be assessed. The results of this pilot study are intended to inform the design of future trials evaluating senolytic therapies as potential interventions for age-related declines in lung function and health.

Inclusion Criteria:

• Adults aged 60 years and older who are physically capable of participating in study procedures;
• Willing to be randomized to fisetin or placebo; weight stable within the previous 2 months (<5-pound change);
• No blood donation within 2 months before screening; absence of unstable chronic disease;
• Willing to maintain baseline activity level throughout the study;
• Body mass index <30 kg/m²;
• Either a history of at least 10 pack-years of cigarette smoking or never-smoking status.

Exclusion Criteria:

• Electrocardiogram (ECG) abnormalities, including prolonged QTc.
• Use of fisetin, other flavonoid supplements, or known senolytic compounds within 6 months prior to screening.
• Resting systolic blood pressure >160 mmHg or diastolic blood pressure >110 mmHg.
• Known allergy or hypersensitivity to fisetin or any component of the study product.
• Active malignancy, except non-melanoma skin cancer.
• Clinically significant hepatic, renal, cardiovascular, endocrine, immunologic, metabolic, or other uncontrolled medical conditions that, in the opinion of the investigator, would interfere with study participation or interpretation of results.
• Clinically significant laboratory abnormalities, including severe anemia, leukopenia, thrombocytopenia, uncontrolled diabetes, advanced kidney disease, significant liver dysfunction, or evidence of systemic inflammation.
• Human immunodeficiency virus (HIV) infection, active hepatitis B or hepatitis C infection, or invasive fungal infection.
• History of diverticulitis or diverticulosis with gastrointestinal bleeding.
• Current use of systemic corticosteroids.
• Current use of warfarin.
• Current use of medications with significant interaction potential with fisetin, including selected CYP450 or transporter substrates, inhibitors, or inducers, unless such medications can be safely withheld according to protocol requirements.
• Recent medication, supplement, or lifestyle changes that may affect study outcomes, in the opinion of the investigator.
• Inability to perform required study procedures, including pulmonary function testing, exercise testing, or other protocol assessments.
• Unwillingness or inability to provide informed consent.
• Pregnancy or breastfeeding.
• Any other condition that, in the opinion of the investigator, would make participation unsafe or compromise study integrity.

Individual participant data collected during this study will not be made publicly available. De-identified aggregate study results may be reported in publications and presentations. Requests for additional data may be considered by the Principal Investigator on a case-by-case basis and in accordance with applicable institutional policies, participant consent, privacy regulations, and IRB requirements.

This is a quadruple-masked (participant, care provider, investigator, outcomes assessor) study. Participants will be randomized to receive either fisetin or placebo. The investigational product and placebo will be prepared and dispensed by the Research Pharmacy according to a predetermined randomization schedule. Participants, investigators, study staff involved in participant assessments, and outcome assessors will remain blinded to treatment assignment throughout the study. Only designated unblinded pharmacy personnel responsible for investigational product preparation and dispensing will have access to treatment allocation information. Blinding will be maintained until completion of study procedures unless unblinding is required for participant safety.