The purposes of this study are to: 1) compare baseline muscle and cardiovascular health in older individuals (>60 years old) diagnosed with MS to age-matched people without MS, 2) determine muscle and whole body changes to an exercise training program, 3) determine if the muscle in a more affected leg in individuals diagnosed with MS is different from the muscle of a less affected leg, and 4) if or how individuals diagnosed with MS adapt differently than age-matched people without MS to exercise training. Participation in this study will average 1.5 hours per visit, 3 visits per week, for approximately 4 months.

Disease-modifying therapies (DMT) are effective in reducing the risk of developing additional debilitating symptoms of multiple sclerosis (MS) and slowing disease progression, leading to better functional mobility outcomes and quality of life. As a result, people with MS (PwMS) are now more likely to maintain independence into their later years. Since older PwMS maintaining independence is a relatively recent phenomenon, there is virtually nothing known about how MS exacerbates the age-related loss of muscle mass and function (i.e., sarcopenia) or how PwMS adapt to interventions, such as exercise, that slow age-related declines. In addition, PwMS are known to be highly heterogeneous in functional ability, fatigue, and other physical factors. The investigators do not yet understand the aging trajectory in PwMS and if current treatment guidelines for aged individuals for overall health, including maintaining muscle mass and function, are effective in aged PwMS.

Aging-related functional declines are thought to be caused by hallmark biological processes that ultimately manifest in physical, mental, and metabolic impairments, which compromise healthspan and quality of life. Exercise is a multipotent treatment with promise to mitigate most aging hallmarks. However, there is substantial variability in how individuals respond to exercise training, which is termed inter-individual response heterogeneity (IRH). Low cardiorespiratory fitness (CRF, VO2max) and low functional muscle quality (fMQ; strength/muscle mass) are multi-system manifestations of the deterioration of the cellular hallmarks of aging, but both CRF and fMQ are modifiable with endurance exercise training (ET) and resistance exercise training (RT). It is yet to be determined how the hallmarks of aging influence IRH. For example, poor responder status could be caused by hallmark deterioration of mitochondrial function, ability to maintain proteostasis, or systemic inflammation.

The investigators are conducting an NIH funded clinical trial that hypothesizes that factors central to aging itself, such as proteostasis, mitochondrial energetics, and inflammation, are contributors to the multidimensional circuitry that determines whether an individual achieves the minimum clinically important difference (MCID) in CRF and/or fMQ with exercise training. The goal of the funded trial is to disentangle the complicated relationships between endogenous and exogenous factors that drive response variation to exercise. To accomplish this goal, investigators will use tissue (muscle and blood) sampling, multi-omics, extensive phenotyping, and multidimensional modeling. For the PHF proposal, investigators will leverage this ongoing clinical trial and enroll aged PwMS into the study. The overall goal of the current proposal is to establish baseline muscle and overall health characteristics, responsiveness to exercise training, and factors that give rise to heterogeneity of symptomology in aged PwMS.

Inclusion Criteria:

• 1. Male or female aged 60 or above 2. Free of unmanaged chronic diseases other than multiple sclerosis 3. No structured exercise program (2 or more bouts/wk) within previous 6 months 4. Cognitively capable of providing informed consent 5. Must meet EDSS score between 2 to 5.5 during screening

Exclusion Criteria:

• 1. Neuromuscular or musculoskeletal disorder, other than multiple sclerosis, that would limit the ability to perform the exercise and/or testing bouts.

  2. Cardiopulmonary disorders or reduced breathing capacity

  3. Metabolic diseases including markers of liver disease (ALT > 52 U/dl) and type 2 diabetes (HbA1C ≥ 6.5, fasting blood glucose ≥ 126 mg/dl)

  4. Taking any dose of metformin

  5. Any other disease or disorder that would influence exercise response (e.g., chronic kidney disease, Alzheimer's, current cancer diagnosis or within 2 yr remission, cerebrovascular)

  6. History of Chemotherapy within 5 years

  7. Unchangeable anticoagulant (Coumadin, Pradaxa, etc.) use. To be determined by clinical staff.

  8. Insulin sensitizing/blood glucose lowering (e.g., metformin) or metabolic (GLP1 agonists) drugs.

  9. High dose statin (40 mg and above)

  10. Have a non-correctable visual impairment

  11. Score less than 29 on the Symbol Digit Test

  12. Received Botox for spasticity within the prior 3 months of study participation.

  13. Cannot have any adjustments to Baclofen during study participation.

  13. Unable to commit to ~4 months required to complete the study.

  14. Lidocaine allergy

  15. Tobacco use

  16. Excessive alcohol consumption (3 drinks/d or 7 drinks/wk for females; 4 drinks/day or drinks/wk for males)

  17. BMI greater than 35.0 kg/m2

The data will be partially de-identified. IHMC will only have access to the participant's Subject ID, year of birth (and therefore age), and height/weight, which is necessary for normalization of outcomes such as cardiorespiratory fitness (VO2max testing).