Single Nuclei RNA-sequencing to Map Adipose Cellular Populations and Senescent Cells in Older Subjects
试验速览
- 阶段
- 2 期
- 状态
- 招募中
- 入组人数
- 160
- 试验地点
- 1
- 主要终点
- Glucose tolerance
研究概览
简要总结
All participants will undergo baseline biopsies of subcutaneous abdominal adipose tissue for cellular/molecular profiling via snRNA-seq and metabolic/physiological assessments (insulin sensitivity, glucose tolerance, and β-cell function). Older obese participants will be randomized into three arms: lifestyle intervention (n=24), senolytics (n=24), or placebo (n=24).
详细描述
All participants after consent and enrollment will undergo adipose tissue single nuclei RNA sequencing and metabolic phenotyping. Subjects will undergo glucose tolerance testing to document glucose tolerance status. Each subject will be provided an accelerometer to be worn on their dominant wrist for 7 days for assessment of habitual activity.
A dietitian will teach them to utilize the SmartIntake3 smartphone food picture application (app) for a 7-day food record. The app will be used to record amount of each meal consumed in order to determine daily food and beverage and supplement intake and quantity for dietary composition analysis. DEXA analysis will be performed to measure lean and fat body mass.
Subjects will undergo evaluation of physical function/performance, including the Short Physical Performance Battery (SPPB) and VO2 peak testing for assessment of aerobic capacity. The SPPB will be done in older adults only.
The NIH Patient-Reported Outcomes Measurement System (PROMIS) will be used to measure participants' self-report of symptoms, function, and health-related quality of life in the domains of physical, mental and social health.
All subjects will undergo a two-step euglycemic insulin clamp and indirect calorimetry.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Double (Participant, Investigator)
盲法说明
Investigators and subjects randomized to study drug/placebo will be blinded to which intervention they receive.
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •Age: younger lean group 18-30 years with BMI 18.5-24.9 kg/m2; younger obese group 18-30 with BMI 30.0 -39.9; older obese group ≥ 65 years with BMI 30.0-39.9
- •All races and ethnic groups
- •Community dwelling
- •Sedentary (≤1.5 h of exercise per week)
- •Nondiabetic (fasting plasma glucose < 126 mg/dl, 2-h glucose during oral glucose tolerance test (OGTT) < 140mg/dl, and A1c < 6.5%
- •For all female participants who are women of childbearing potential (WOCBP), who are not pregnant or breast feeding, at least one of the following conditions must apply:
- •A documented hysterectomy, bilateral salpingectomy, or bilateral oophorectomy Use of a contraceptive method that is highly effective (with a failure rate of <1% per year), preferably with low user dependency (implantable progesterone-only hormone contraception, intrauterine hormone releasing system, bilateral tubal occlusion, vasectomized partner) during the intervention period of the study and for at least 30 days after the last dose of study intervention to eliminate any reproductive safety risk of the study drug.
- •Use of a contraceptive method that is highly effective (with a failure rate of <1% per year), with high user dependency, (oral/intravaginal/injectable combined estrogen and progesterone contraception, oral/injectable progesterone only hormone contraception, sexual abstinence) during the intervention period and for at least 30 days after the last dose of study intervention to eliminate any reproductive safety risk of the study drug. In addition to the highly effective methods: male or female condom with or without spermicide; cervical cap, diaphragm, or sponge with spermicide; a combination of male condom with either cervical cap, diaphragm, or sponge with spermicide.
- •ECG value after 10 minutes of resting in the supine position in the following ranges:
- •120ms<PR<220ms: QRS<120ms; QTc<430ms for males and QTc<450ms for females and normal ECG tracing, unless the investigator considers the ECG abnormality to be not clinically relevant.
排除标准
- •Diabetes, clinically diagnosed or HbA1c > 6.5% and/or fasting plasma glucose > 126 mg/dl and/or use of anti-diabetic medications.
- •Participating in > 1.5 h of structured exercise/week
- •Unstable weight (>3% change in last 3 months)
- •Neurological, musculoskeletal, or other conditions that may limit subject's ability to complete study physical assessment and training
- •Active autoimmune/inflammatory disease including: rheumatoid arthritis, multiple sclerosis, systemic lupus erythematous, inflammatory bowel disease
- •Laboratory parameters outside the normal range:
- •impaired kidney function (eGFR < 30ml/min/1.73m² as calculated by the CKD-EPI equation);
- •impaired liver function (AST or ALT level > 2 times upper limit of normal (ULN);
- •total Bilirubin level > 1.5 times ULN;
- •TSH > 1.5 times ULN or < lower limit of normal (LLN);
- •Hemoglobin <10.0 g/dl; Platelets <125,000 cell/mm³;
- •Platelets < 125,000 cell/mm³
- •Prothrombin time (PT) > 1.0 times ULN
- •Partial prothrombin time (PTT) > 1.0 times ULN.
- •Active gastrointestinal disease; coagulopathy; GI bleed within 6 months
- •Clinically significant heart disease (e.g. NYH Classification >II; ischemia)
- •Peripheral vascular disease (claudication)
- •QTc prolongation >45 msec
- •Use of anti-arrhythmic medications known to cause QTc prolongation, anti-platelet or anti-coagulant medication (see section 5.3)
- •Use of quinolone antibiotics or any other drugs that may prolong the QTc interval (see section 5.3)
- •Pulmonary disease (COPD), severe asthma or exercise-induced asthma
- •Recent systemic or pulmonary embolus
- •Uncontrolled blood pressure (systolic BP>170, diastolic BP>95 mmHg)
- •Smoking, alcohol use (history of regular alcohol consumption exceeding 7 drinks/week for female participants or 14 drinks/week for male participants. 1 drink = 5 ounces [150ml] of wine or 12 ounces [360ml] of beer or 1.5 ounces [45ml] of hard liquor) or recreational drug use (other than marijuana)
- •Pregnant or breastfeeding
- •Postmenopausal women new (within 6 months) to systemic hormone replacement therapy
- •Previous bariatric surgery
- •History of stroke with motor disability
- •Recent (3 years) treated cancer other than basal cell carcinoma
- •Acute or chronic infection
- •Medication that might interfere with metabolic studies (weight loss medication, systemic steroids, immunosuppressants) within 6 months (see section 5.3)
- •Potentially senolytic agents within the last 6 months: fisetin, quercetin, luteolin, dasatinib, piperlongumine, or navitoclax (see section 5.3)
- •History of allergy to dasatinib, quercetin and/or lidocaine.
- •Concurrent enrollment in another interventional trial.
研究组 & 干预措施
Younger Lean Group
Participants will be aged 18-30 years and have a BMI of 18.5 - 24.9 kg/m2
干预措施: Abdominal adipose tissue biopsy (Procedure)
Older Lean Group
Participants will be over 65 years of age with a BMI of 18.5 to 24.9 kg/m2
干预措施: Abdominal adipose tissue biopsy (Procedure)
Older Obese Group
Participants will be over 65 years of age with a BMI of 30-39.9 kg/m2.
干预措施: Lifestyle Intervention (Other)
Older Obese Group
Participants will be over 65 years of age with a BMI of 30-39.9 kg/m2.
干预措施: Placebo (Drug)
Older Obese Group
Participants will be over 65 years of age with a BMI of 30-39.9 kg/m2.
干预措施: Abdominal adipose tissue biopsy (Procedure)
Younger Obese Group
Participants will be ages 18-30 years and have a BMI OF 30.0-39.9 kg/m2
干预措施: Abdominal adipose tissue biopsy (Procedure)
Older Obese Group
Participants will be over 65 years of age with a BMI of 30-39.9 kg/m2.
干预措施: Dasatinib 100 MG (Drug)
Older Obese Group
Participants will be over 65 years of age with a BMI of 30-39.9 kg/m2.
干预措施: Quercetin 1000mg (Drug)
结局指标
主要结局
Glucose tolerance
时间窗: Baseline to Week 14
Measurement of change in glucose tolerance using a glucose tolerance test
Insulin sensitivity
时间窗: Week 4 and Week 15
Change in skeletal muscle insulin sensitivity
次要结局
- Senescence-associated secretory phenotype (SASP)(Baseline to Week 16)
研究者
Nicolas Musi, MD
Staff Physician IV
Cedars-Sinai Medical Center