Heterogeneity of Vascular Adaptations to Exercise With Aging in Women and Men

This is a single-blind (investigator and outcomes assessor), parallel-design clinical trial to determine whether heterogeneity in the biology of aging and molecular transducers with acute and chronic AE mediates AE response variation in peripheral endothelial function (brachial artery flow-mediated dilation [FMD]; primary outcome) and cerebrovascular function (cerebrovascular reactivity to a hypercapnic stimulus [CVRCO2]; primary outcome) with age and between sexes. Biospecimens (blood, vascular endothelial cells) obtained: (a) before, during (blood only), and 0.25, 0.5 and 2 h (blood only) after acute treadmill AE (60-80% VO2max, 40 minutes); (b) before and after a 12-week AE intervention (3 d/week, 60-80% heart rate reserve, ~1 h duration); (c) or non-exercise control will be assayed for transcriptomic (mRNA transcripts), proteomic, metabolomic (small metabolites) and EMVs and their cargo (e.g., microRNA) in sex balanced groups of young (18-39 years), middle-aged (40-59 years) and older (≥60 years) adults. There is also collection of cardiorespiratory fitness, blood pressure, body composition (measured by dual-energy x-ray absorptiometry), physical activity and sleep using wearable devices, and health status questionnaires.

Inclusion criteria

• Ability to provide consent;
• Man or woman >= 18 years;
• Willing to be randomized to an exercise or control intervention;
• No orthopedic limitations that would prevent the volunteer from performing treadmill or cycling exercise;
• No use of hormone therapy in postmenopausal women or in men (note, hormonal contraceptives in premenopausal women will be allowed);
• Healthy, as determined by medical history, physical examination, standard blood chemistries and ECG at rest and during a physician monitored graded exercise treadmill test;
• Sedentary or recreationally active (<2 days/wk vigorous activity);
• No use of medications that might influence cardiovascular function (e.g., blood pressure and lipid lowering medications, metformin, insulin, sulfonylureas, etc.);
• No use of vitamins, supplements or anti-inflammatory medications, or willing to stop 1 month prior to enrollment and for the duration of the study;

Exclusion criteria

• Contraindications to aerobic exercise;
• Diabetic or fasted glucose >126 mg/dL;
• Resting blood pressure >= 140/90 mmHg;
• Current or past history of cancer other than skin cancer;
• Preexisting or active cardiac, renal or hepatic disease;
• History of stomach ulcer or bleeding or epilepsy or nervous system and/or seizure disorder;
• Active or chronic infection;
• An abnormal resting ECG, angina and/or ECG evidence of acute myocardial ischemia during the exercise test (development of ST-segment depression of more than 0.3 mV that is either horizontal, downsloping, or slowly upsloping- less than 1 mvolt/sec and lasts more than 0.08 sec; ST elevation; chest pain or discomfort), bundle branch block, AV block greater than first degree, arrhythmias;
• Thyroid dysfunction, defined as ultrasensitive TSH <0.5 or >5 mU/L. Participants with abnormal TSH values will be reconsidered for participation after follow-up with their PCP and initiation of thyroid replacement medications for at least 3 months;
• Smoking or tobacco use;
• Alcohol consumption > 14 drinks/week;
• Body mass index > 39kg/m2;