Targeting Cellular Senescence With Senolytics to Improve Skeletal Health in Older Humans

Inclusion criteria

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

Exclusion criteria

• Hemoglobin A1c ≥8.0% at screening
• Subjects who are type II diabetic and on insulin
• Abnormal screening labs: 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 (total bilirubin, AST, ALT, or alkaline phosphatase >2x upper normal limit) or kidney disease (eGFR<30 ml/min/1.73 m2 (using the cystatin C blood levels for analysis). If any elevation were to be noted (2x the normal limit), the study participant would stop treatment and have levels re-drawn in a month, per the clinical judgement of the investigator
• Presence of a clinical diagnosis of heart failure
• Known active malignancy (including myeloma)
• Current diagnosis of malabsorption or undergoing treatment for malabsorption disease
• If any of the laboratory blood work drawn at the study visits return with lab values outside of the "normal limits" or show a significant change from a previous value, a repeat blood draw would be done before the subject is excluded.
• 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),
• denosumab,
• estrogen (E) therapy or treatment with a selective E receptor modulator, or teriparatide (within the past yr)
• QTc >450 msec
• Inability to provide consent
• Inability to tolerate oral medication
• Current diagnosis of hypo- or hyperparathyroidism or currently undergoing treatment for the disease
• 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 4-week treatment of 50,000 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: Quercetin, Luteolin, Dasatinib, Piperlongumine, or Navitoclax
• Subjects currently taking drugs that induce cellular senescence: alkylating agents, anthracyclines, platins, other chemotherapy
• Subjects taking H2 antagonists, unless randomized to the control group
• Tyrosine kinase inhibitor therapy
• Subjects not having a PBTL p16INK4a mRNA expression level >95 percentile of young female controls (this cut-off is depicted by the dotted line in Fig. 6)
• Known hypersensitivity or allergy to Dasatinib orQuercetin
• Subjects taking the following antimicrobial agents: Aminoglycosides, Azole antifungals (fluconazole, miconazole, voriconazole, itraconazole), Macrolides (clarithromycin, erythromycin), Antivirals (nelfinavir, indinavir, saquinavir, ritonavir, elbasvir/grazoprevir), Rifampin
• 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 20-week deferral would pose a minimal risk to the participant and she would be free to make this choice.
• 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 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 + Asprin [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 two days before and during the study drug dosing periods.
• 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.