Ongoing Lung Decline With Age Intensified Response (OLD AIR)

A PHASE II, DOUBLE-BLIND, PLACEBO-CONTROLLED STUDY EVALUATING THE ONGOING LUNG DECLINE WITH AGE INTENSIFIED RESPONSE (OLD AIR)

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).

Study Overview

• Status: Not yet recruiting
• Conditions: Age-Related Lung Function Decline
• Intervention / Treatment: Drug: Fisetin; Drug: Placebo

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Estimated): 40
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Samuel Cohen, MD; Phone Number: 310-423-1725; Email: samuel.cohen@csmc.edu
• Study Contact Backup: Name: Yunhee Choi-Kuaea; Email: Yunhee.Choi-Kuaea@cshs.org

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: Yes

Description

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; and 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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Single Group Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Fisetin; Participants receive oral fisetin at approximately 20 mg/kg/day for 2 consecutive days on Days 1-2 and again on Days 8-9 using a senolytic "hit-and-run" dosing strategy.	Drug: Fisetin; Participants randomized to the experimental arm will receive oral fisetin capsules administered at a target dose of approximately 20 mg/kg/day for 2 consecutive days on Days 1-2 and again on Days 8-9. Fisetin will be supplied as 100 mg capsules and dosed according to body weight using a senolytic "hit-and-run" treatment approach.
Placebo Comparator: Placebo; Participants receive matching placebo capsules administered on the same schedule as the fisetin arm (Days 1-2 and Days 8-9).	Drug: Placebo; Participants randomized to the control arm will receive matching placebo capsules administered orally on the same schedule as the fisetin arm (Days 1-2 and Days 8-9). Placebo will be used to maintain blinding and permit comparison of efficacy and safety outcomes between treatment groups.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Forced Vital Capacity (FVC)	Forced vital capacity measured by spirometry to assess lung function following treatment with fisetin versus placebo.	Baseline and Day 14
Forced Expiratory Volume in 1 Second (FEV1)	Forced expiratory volume in one second measured by spirometry following treatment with fisetin versus placebo.	Baseline and Day 14
FEV1/FVC Ratio	Ratio of FEV1 to FVC measured by spirometry following treatment with fisetin versus placebo.	Baseline and Day 14

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
6-Minute Walk Distance (6MWD)	Change in distance walked during a standardized 6-minute walk test, with pulse oximetry monitoring before and after the test.	Baseline and Day 14
Peak Oxygen Uptake (VO₂)	Change in peak oxygen uptake measured during cardiopulmonary exercise testing (CPET) as an assessment of exercise capacity and cardiopulmonary fitness.	Baseline and Day 14
Biomarkers of Cellular Senescence	Change in circulating biomarkers associated with cellular senescence measured from blood samples collected before and after treatment.	Baseline and Day 14

Collaborators and Investigators

• Sponsor: Cedars-Sinai Medical Center

Study record dates

Study Major Dates

• Study Start (Estimated): June 17, 2026
• Primary Completion (Estimated): June 16, 2027
• Study Completion (Estimated): July 15, 2027

Study Registration Dates

• First Submitted: June 24, 2026
• First Submitted That Met QC Criteria: June 24, 2026
• First Posted (Actual): June 30, 2026

Study Record Updates

• Last Update Posted (Actual): June 30, 2026
• Last Update Submitted That Met QC Criteria: June 24, 2026
• Last Verified: June 1, 2026

More Information

Terms related to this study

• Keywords: Smoking; Pulmonary Function; Aging; Healthy Aging; Cellular Senescence; Smoking-Related Lung Function Decline
• Additional Relevant MeSH Terms: Behavior; Smoking; fisetin
• Other Study ID Numbers: STUDY00003866

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: 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.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No