Alleviation by Fisetin of Frailty, Inflammation, and Related Measures in Older Women

Exclusion Criteria

• •Abnormality in any of the screening laboratory studies (see below)
• •Presence of significant liver or renal disease
• •Malignancy (including myeloma)
• •Malabsorption
• •Hypoparathyroidism
• •Hyperparathyroidism
• •Acromegaly
• •Cushing's syndrome
• •Hypopituitarism
• •Gastric bypass/reduction
• •Malabsorption issues
• •Crohn's
• •Myopathies (increased or low calcium, vitamin D deficiency, elevated creatine kinase or ESR)
• •If diabetic AND on sulfonylureas (like glipizide, glimepiride, glyburide), SGLT2 inhibitors (like dapagliflozin and empagliflozin), or insulin
• •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), anticonvulsant therapy (within the previous year),
• •* pharmacological doses of thyroid hormone (causing decline of thyroid stimulating hormone below normal),
• •* calcium supplementation of \> 1200 mg/d (within the preceding 3 months),
• •* bisphosphonates (within the past 3 yrs),
• •* denosumab,
• •* estrogen (E) therapy or treatment with a selective E receptor modulator, or teriparatide (within the past yr).
• •Subjects with a fracture within the past year
• •Subjects taking potentially senolytic agents within the last year: Fisetin, Quercetin, Luteolin, Dasatinib, Piperlongumine, or Navitoclax
• •Subjects currently taking drugs that induce cellular senescence: alkylating agents, anthracyclines, platins, other chemotherapy
• •QTc \>450 msec
• •Inability to provide informed consent
• •Total bilirubin \>2X upper limit
• •Inability to tolerate oral medication
• •eGFR \< 15 ml/ min/ 1.73 m2
• •Subjects on therapeutic doses of anticoagulants (e.g., warfarin, heparin, low molecular weight heparin, factor Xa inhibitors, etc.)
• •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 proton pump inhibitors who are unable or unwilling to reduce or hold therapy prior to and during the 2-day Fisetin dosing
• •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, thyroid hormones, 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
• •In order to ensure vitamin D sufficiency, we will also exclude subjects with serum 25-hydroxyvitamin D levels of \< 20 ng/ml.