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

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 postmenopausal women. The researchers plan to evaluate
markers of frailty and markers of inflammation, insulin resistance, and bone resorption while
maintaining bone formation in older postmenopausal women.

Inclusion Criteria

- Healthy postmenopausal women

- Age ≥ 70 years

Exclusion Criteria

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

- Presence of significant liver or renal disease

- Malignancy (including myeloma)

- Malabsorption

- Diabetes

- Hypoparathyroidism

- Hyperparathyroidism

- Acromegaly

- Cushing's syndrome

- Hypopituitarism

- Myopathies (increased or low calcium, vitamin D deficiency, elevated creatine kinase
or ESR)

- Undergoing treatment with medications that affect insulin sensitivity, including the
following:

- Metformin (within the previous week),

- Glucocorticoids (within the previous month),

- Acarbose (within the previous week)

- 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 anti-inflammatory drugs within the last year, such as
Fisetin

- Subjects currently taking drugs that induce inflammation: alkylating agents,
anthracyclines, platins, other chemotherapy

- QTc >450 msec

- Tobacco use (smoking or chewing)

- Inability to provide informed consent

- Total bilirubin > twice the upper limit of normal

- 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,
tacrolimus, sirolimus, carbamazepine, flecainide, phenytoin, phenobarbital,
rifampicin, theophylline, warfarin, heparin, full dose acetylsalicylic acid (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 periods. Due to drug-drug interaction, subjects may not clear the
caffeine from their system properly/as usual.