Inclusion Criteria:

• Normal postmenopausal women.
• Aged ≥ 60 years.
• Able and willing to provide informed consent.

Exclusion Criteria:

• Subjects who are Type II diabetic and on insulin due to a risk of hypoglycemia.
• Hemoglobin A1c ≥ 8.0% at screening
• Abnormal screening labs (see below):
  • Calcium > 10.1 mg/dL;
  • Phosphorus > 4.7 mg/dL;
  • Thyroid stimulating hormone (TSH) level < 0.3mU/L;
  • Fasting blood glucose > 200 mg/dL.
• Presence of significant liver (with total bilirubin > 2 x upper normal limit, AST > 2 x upper normal limit, alkaline phosphatase >2 x upper normal limit) or kidney disease (see eGFR below).
• Presence of a clinical diagnosis of heart failure.
• Known active malignancy (including myeloma).
• Current diagnosis of malabsorption or currently undergoing treatment for malabsorption disease.
• Gastric bypass / reduction.
• Hyperthyroidism.
• Acromegaly.
• Cushing’s syndrome.
• Hypopituitarism.
• Subjects with a fracture within the past six months.
• Undergoing treatment with any medications that affect bone turnover, including the following:
  • adrenocorticosteroids (> 3 months at any time or > 10 days within the previous yr., except for use of topical steroid creams or gels or inhaled steroids), anticonvulsant therapy (within the previous year, include only those taking Carbamazepine, Phenobarbital and Phenytoin);
  • bisphosphonates (within the past 3 yrs., including injections or infusions); oral use permitted if taken for less than 1 month;
  • denosumab;
  • estrogen (E) therapy or treatment with a selective E receptor modulator, except for vaginal estrogen cream use, or teriparatide, abaloparatide, romosozumab (>1 month within the past yr.).
• QTc > 470 msec.
• Current diagnosis of hypo- or hyperparathyroidism or currently undergoing treatment for the disease.
• Inability to provide consent.
• Inability to tolerate oral medication.
• eGFR<30 ml/min/1.73 m^2 (using the cystatin C blood levels for analysis).
• Subjects on therapeutic doses of anti-coagulants (e.g., warfarin, heparin, low molecular weight heparin, factor Xa inhibitors, etc.).
• Subjects with hypovitaminosis D (25-hydroxyvitamin D [25(OH)D] < 20 ng/ml, whose level does not improve above 20 ng/ml after two courses of 8-week treatment of 1000 IU/d of Vitamin D.  They will be referred to their primary provider should this occur.
• Subjects taking anti-arrhythmic medications known to cause QTc prolongation.
• Subjects taking potentially senolytic agents within the last 6 months: Fisetin, Quercetin, Luteolin, Dasatinib, Piperlongumine, or Navitoclax.
• Subjects currently taking drugs that induce cellular senescence: alkylating agents, anthracyclines, platins, other chemotherapy.
• Subjects taking H2 antagonists.
• Tyrosine kinase inhibitor therapy.
• Subjects not having a PBTL p16INK4a mRNA expression level > 95 percentile of young female controls.
• Known hypersensitivity or allergy to Dasatinib, Quercetin, or Fisetin.
• Subjects taking the following antimicrobial agents: Aminoglycosides, Azole antifungals (fluconazole, miconazole, voriconazole, itraconazole), Macrolides (clarithromycin, erythromycin), Antivirals (nelfinavir, indinavir, saquinavir, ritonavir, elbasvir/grazoprevir), Rifampin.
• Subjects taking the following other drugs if they cannot be held for at least 2 days before and during administration of Fisetin: digoxin, lithium, all statins, repaglidine, bosentan, gemfibrozil, olmesartan, enalapril, valsartan, methotrexate, corticosteroids, eluxadoline, eltrombopag, nitroglycerin, pioglitazone, glyburide, enzalutamide, ezetimibe, colchicine, imatinib, cyclosporine, tacolimus, sirolimus, carbamazepine, flecainide, phenytoin, phenobarbital, rifampicin, theophylline, warfarin, heparin, full dose ASA, clopidogrel, celecoxib, desipramine, thioridazine, venlafaxine, tizanidine, atomoxetine, voriconazole, citalopram, diazepam, escitalopram, propranolol, clozapine, cyclobenzaprine, mexiletine, olanzapine, ondansetron, riluzole.
• Subjects taking medications that are sensitive to substrates or substrates with a narrow therapeutic range for CYP3A4, CYP2C8, CYP2C9, or CYP2D6 or strong inhibitors or inducers of CYP3A4 (e.g., cyclosporine, tacrolimus or sirolimus). If antifungals are absolutely necessary from an infectious disease perspective, then they will be allowed only if the levels are therapeutic.
• Subjects taking strong inhibitors of CYP3A4.
• Subjects on antiplatelet agents (Clopidogrel [Plavix]; Dipyridamole + Aspirin [Aggrenox]; Ticagrelor [Brilinta]; Prasugrel [Effient]; Ticlopidine [Ticlid] or Other) who are unable or unwilling to reduce or hold therapy prior to and during the study drug dosing periods. Subjects may continue their previous regimen between study drug dosing periods.
• Subjects on quinolone antibiotic therapy for treatment or for prevention of infections within ten days.
• Subjects taking proton pump inhibitors and unwilling to discontinue therapy for one week before and two weeks following dosing.
• Subjects with clinically evident fluid retention.
• Subjects with evidence of right heart strain on ECG.
• Subjects with a history of pulmonary hypertension.
• Subjects with an abnormal Complete Blood Count (clinically insignificant changes would be acceptable based on the judgement of the investigators).
• Presence of any condition the Investigator believes would place the subject at risk or would preclude the subject from successfully completing all aspects of the trial.
• If the DXA assessment reveals a spine or femur neck T-score < -2.5, the participant will be advised of this. She would then be given the option of withdrawing from the study to immediately start an osteoporosis drug through her primary care physician or continue in the study and defer osteoporosis drug treatment for the duration of the study (20 weeks). Given that osteoporosis is a chronic, long term disease, the 20week deferral would pose a minimal risk to the participant and she would be free to make this choice.

• Behavioral Modification: Participants will be educated about the risk of excessive caffeine usage. Participants will be encouraged to reduce use by 50% prior to and during the drug dosing periods. Due to drug-drug interaction, subjects may not clear the caffeine from their system properly/as usual.  Because of possible effects on the metabolism of dasatinib, subjects will also be advised not to consume grapefruits or grapefruit juice during their participation in the study. Patients will be asked to contact the study coordinator by phone if prescribed any new medication during the trial.

  Involvement of special vulnerable populations: We will not involve special vulnerable populations, such as fetuses, neonates, pregnant women, children, prisoners, institutionalized individuals, or others who may be considered vulnerable populations.

Note: Other protocol defined Inclusion/Exclusion Criteria may apply.

Eligibility last updated 1/16/24. Questions regarding updates should be directed to the study team contact.