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

To the researchers' knowledge, there are no published studies utilizing Fisetin in alteration
of frailty markers. Several studies involve use of Fisetin for its anti-oxidative and
anti-apoptotic effects in animal models. Fisetin may reduce oxidative stress, alleviate
hyperglycemia, and improve kidney function. No one has evaluated the biologic markers of
inflammation and frailty in older adults. The researchers plan to evaluate markers of frailty
and markers of inflammation, insulin resistance, and bone resorption while maintaining bone
formation in older adults.

Inclusion Criteria

• Age ≥ 70 years

Exclusion Criteria

- Unable or unwilling to give informed consent

- Pregnant

- Body weight >150 kg or body mass index (BMI) > 50

- QTc>450 msec

- Total bilirubin >2X upper limit of normal

- Inability to tolerate oral medication

- Abnormality in any of the screening laboratory studies (see below)

- Human immunodeficiency virus infection

- Known active hepatitis B or C infection

- Invasive fungal or viral infection

- Known hypersensitivity or allergy to fisetin

- Uncontrolled pleural/pericardial effusions or ascites

- New/active invasive cancer except non-melanoma skin cancers

- 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.

- Strong inhibitors of CYP3A4. See Appendices 1-3.

- Tyrosine kinase inhibitor therapy

- Known hypersensitivity or allergy to dasatinib or quercetin

- Subjects on quinolone antibiotic therapy for treatment or for prevention of infections
within 10 days.

- Subjects taking H2-antagonists or proton pump inhibitors and unwilling to discontinue
therapy for 1 week before and 2 weeks following enrollment.

- 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

- 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.

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 2-day drug dosing period. Due to drug-drug interaction, subjects may not clear the
caffeine from their system properly/as usual.