This study will test the central hypothesis that fat within the muscle, or intramuscular adipose tissue (IMAT), exhibits elevated damage and pro-inflammatory signaling with aging, both of which are reduced by progressive resistance exercise (PRE). Sixteen older adults 65-80 years old will be recruited and complete a 12 week calf PRE intervention. Calf muscle strength, composition (measured by computed tomography) and muscle biopsies will be collected before and after the intervention. Histology, transcriptomic and secretomic tests will be completed to assess signs of damage and inflammation.

Sixteen older adult (65-80 years) will be recruited from existing databases and screened for potential participation by phone. The Rapid Assessment of Physical Activity (RAPA) will be completed, to include those who are underactive (scores 3-5). Individuals who meet the inclusion criteria will attend an in-person screening where their calf muscle strength, physical performance and safety for muscle biopsy (via complete blood count with differential and prothrombin time/international normalized raio on blood draw) will be assessed. Individuals deemed safe to participate and who give informed consent will attend a second visit which will include a computed tomography (CT) scan of the lower leg and ultrasound-guided gastrocnemius muscle+IMAT biopsy. One week later, participants will begin the ankle plantarflexor-targeted progressive resistance exercise (PRE) program which will be delivered in a group Zoom format with a trained therapist 3 times per week for 12 weeks. One week following completion of the PRE program, participants will return for follow-up strength measures, CT, and biopsy. This will complete their participation. In the lab, biopsies will be subdivided for bulk ribonucleic acid sequencing (RNAseq), explant culture and histology. Bulk RNAseq will be used to identify age- and exercise-responsive genes that encode secreted proteins. These putative secreted signals will be validated by protein quantification in explant culture. The cellular origin of validated signals will then be mapped by RNA in situ hybridization (RNAscope) on the portion of the biopsy allocated to histology. Sections will also used to identify senescent cells, inflammatory macrophages and beige adipocytes.

Inclusion Criteria:

• Rapid Assessment of Physical Activity scores between 3 and 5
• Able to don and doff the weighted vest
• Access to a smart phone and ability to navigate the phone to enter and manage a zoom intervention
• Commitment and availability to attend a virtual 40-minute intervention 3x per week for 12 weeks

Exclusion Criteria:

• Contraindications to radiation exposure (e.g. Women who are pregnant, previous high radiation exposure)
• Bleeding disorders
• Lower extremity trauma/surgery/injury or neuropathy that would impact muscle structure and function or ability to complete exercise intervention
• Diabetes mellitus, cardiovascular disease, peripheral vascular disease, cancer, stage 4 hypertension, anemia, connective tissue disorder
• Neurological disorder (e.g. stroke, Parkinson's disease, multiple sclerosis, spinal cord injury)
• Medications: insulin, glucagon-like peptide-1 (GLP1) agonists, sex hormone replacement therapy, chronic NSAIDs, anticoagulation therapy, cholesterol lowering medications such as statins
• Unable to safely perform the progressive resistance exercise (e.g. Vestibular or balance issues that make performing the intervention unsafe, severe osteoporosis or general fragility that limits weighted vest tolerance)

The following for participants at baseline

1. Demographics (Self-report responses to questionnaires for sex, age, race/ethnicity, socioeconomic status, medical history)

   The following for participants at baseline and post-treatment

2. Clinical measures (Data collected during laboratory examination. De-identified, aggregate summary data per time point will be shared in csv file format)

3. Strength measures (Ankle plantarflexor peak torque measurements. De-identified, aggregate summary data per time point will be shared in csv file format.)

4. Computed tomography measures (Measurements of muscle and adipose volumes. De-identified, aggregate summary data will be shared in csv file format.)

5. RNA sequencing, luminex secretome, histological imagines and RNA scope image

Data will be shared as soon as possible and no later than the time of publication or at the end of the funding period, whichever comes first

All shared data will be de-identified and accessible in a controlled manner according to the guidance of Washington University's Human Research Protection Office (HRPO).