ABSTRACT Over 80% of children diagnosed with cancer will survive at least ten years after diagnosis. However, by age 50 years each survivor, on average experiences >4 severe or life-threatening (CTCAE grades 3-4) health chronic conditions (rates typically seen in persons decades older) raising concern for early onset of physiologic frailty. Frailty is a loss of physiologic capacity that interferes with normal function, most commonly described in older adults and characterized (Fried Criteria) by three or more of: 1) low lean muscle mass, 2) reduced strength, 3) slow walking speed, 4) low energy expenditure, and 5) fatigue. In the general population frailty is seen in the elderly. However, at a median age of only 33 years (range 18-50), 8% of survivors are frail, an additional 22.2% meet the definition of pre-frail (two of five criteria), rates similar to adults >65 years of age. Cellular senescence, a quiescent state representing the loss of a cell's ability to replicate or grow, is an important and established mechanism in the aging process. Senescence is strongly associated with frailty and aging biomarkers in the elderly population. There is now evidence that p16INK4A is elevated in survivors treated with chemotherapy and radiotherapy, and the magnitude of elevation is associated with measures of frailty. Thus, cellular senescence may provide a targetable pathway to improve measures of aging. Agents such as Dasatinib and flavonoids (Quercetin; Fisetin, available as nutritional supplements) interfere with this pathway and thus are ?senolytic?. Six clinical trials of efficacy are now underway in chronic disease states associated with senescence (e.g. idiopathic pulmonary fibrosis) and frail populations, including adult bone marrow transplant recipients demonstrating initial evidence for safety and tolerability and that senolytics alleviate physical dysfunction. However, to date, no trial has evaluated senolytic agents in adult survivors of childhood cancer. In order to address this gap in knowledge, we utilize the well-phenotyped population of the St. Jude Life Cohort Study to propose a two arm, randomized, open-label pilot intervention trial in frail survivors (Fried Criteria) of childhood cancer who have diminished walking speed and increased cellular senescence (increased p16INK4a mRNA expression level in peripheral blood T lymphocytes). We aim to test the efficacy of two senolytic regimens: 1) combination of Dasatinib plus Quercetin, and 2) Fisetin alone, to reduce senescent cell abundance in blood and improve walking speed (1° Aim). Secondary endpoints include: additional measures of frailty beyond walking speed (i.e. additional Fried Frailty Criteria), markers of inflammation, insulin resistance, bone resorption and cognitive function. We hypothesize that senolytic therapy will reduce biological markers and clinical measures of aging. Additionally, we will test the safety and tolerability of these senolytic therapies. If successful, this single-institution pilot study will: 1) provide first-in-survivor evidence that targeting cellular senescence pathways can modify frailty and biological markers of aging using brief (two days per month) exposure to senolytic regimens, and 2) provide strong scientific premise for a large-scale clinical trial of efficacy.