CALM-AF-AI: Counteracting Age-related Loss of Muscle With AAV-Follistatin Combined With Angiogenesis-Inducing VEGF Plasmid Gene Therapy

Inclusion Criteria: * Voluntary written informed consent obtained prior to any study-related procedures * Ability to read, understand, and sign the Informed Consent Form and reliably complete required study documents * Willingness to undergo medical intervention, including genetic therapy, and to comply with the visit schedule and all study procedures * Commitment to maintain a stable medication and supplement regimen throughout the study, with no initiation of new medications, supplements, or performance-enhancing substances unless approved by the Investigator * Men and women aged 45-75 years * Body mass index (BMI) between 17.0 and 30.0 kg/m² at screening * Evidence of age-related physical decline or sedentary lifestyle defined as: * \<150 minutes/week of moderate-intensity activity, or * \<75 minutes/week of vigorous activity, or * \<600 MET-minutes/week, or * Clinical Frailty Scale (CFS) score 3-6 * Active Prospera ZEDE eResidency or Physical Residency * Stable comorbid conditions for at least 3 months prior to screening * Postmenopausal status (women) * Willingness to use reliable contraception for 6 months following therapy * Low or undetectable antibody titers to AAV9 (≤1:100 by ELISA) Exclusion Criteria: * Pregnancy, breastfeeding, or intent to become pregnant; premenopausal status (unless ≥12 months amenorrhea or FSH ≥30 IU/L) * Subjects who have a history of alcohol or drug abuse within 1 year of study entry * Initiation of prohibited medications, supplements, or interventions during the study period that may confound efficacy or safety assessments * Active malignancy * History of malignancy * Strong family history of cancer in first-degree relatives (≥2 relatives with cancer diagnosed \<60 years) * Known hereditary cancer syndrome (BRCA1/2, Lynch syndrome, Li-Fraumeni, FAP, HNPCC) without genetic counseling and enhanced surveillance clearance * History of stroke or transient ischemic attack (TIA) * History of myocardial infarction (MI) or unstable angina (regardless of time since event) * Diagnosed coronary artery disease (CAD) documented by coronary angiography or stress testing * Significant atherosclerotic disease at any location (stenosis ≥50% in carotid, femoral, or other major arteries) * Prior coronary revascularization (percutaneous coronary intervention \[PCI\] or coronary artery bypass grafting \[CABG\]) * Prior valvular repair or replacement * History or current diagnosis of heart failure * Uncontrolled hypertension (SBP \>140 mmHg or DBP \>85 mmHg despite treatment) * Left ventricular ejection fraction (LVEF) \<50%, QTc ≥480 ms, or severe valvular heart disease * Ventricular arrhythmias requiring chronic drug treatment or implantable cardioverter-defibrillator * Presence of pacemaker or persistent left bundle branch block * Known diagnosed cardiomyopathy of any etiology * Significant left ventricular hypertrophy, defined as maximal left ventricular wall thickness ≥15 mm in any segment at end-diastole (by echocardiography or cardiac MRI) * History of venous thromboembolism (DVT, PE, or thrombosis at any site), particularly if unprovoked, or associated with only minor provoking factors (e.g., minor surgery, combined oral contraceptives, short-term immobilization) * Recurrent thrombotic events, including recurrent superficial venous thrombosis * Thrombosis at unusual sites (e.g., mesenteric, portal, or splenic vein thrombosis, Cerebral venous sinus thrombosis, Hepatic vein thrombosis (Budd-Chiari syndrome), Renal vein thrombosis, Retinal vein thrombosis) * Superior vena cava thrombosis not related to central venous catheterization * Strong family history of venous or arterial thrombosis at a young age in first-degree relatives * History of recurrent pregnancy loss or severe obstetric complications suggestive of a hypercoagulable state * High-degree myopia (≥ -6.0 diopters) or pathological myopia without ophthalmologic clearance * History of retinal detachment, vitreous hemorrhage, or retinal vascular disease (diabetic retinopathy, retinal vein occlusion, age-related macular degeneration with neovascularization) * Use of systemic anti-VEGF therapy (e.g., bevacizumab) * Current use of prohibited medications or supplements (see Section 4.3) * Fasting plasma glucose ≥6.0 mmol/L (≥108 mg/dL) at screening * HbA1c ≥6.5% (≥48 mmol/mol) at screening * Known history of diabetes mellitus (any type) * History of peptic ulcer disease within 12 months * Known osteoporosis (DXA T-score ≤ -2.5 at the hip or spine) * Severe pulmonary disease, including COPD or restrictive lung disease (FVC \<49% predicted) * Advanced renal disease (CKD stage 3-5, eGFR \<60 mL/min/1.73 m²) or dialysis dependence * History of cirrhosis or cholestatic liver disease * Chronic viral hepatitis (HBV, HCV) * Autoimmune hepatitis * Active hepatitis or evidence of hepatic decompensation * ALT or AST \>1.5× upper limit of normal (ULN) * Total bilirubin \>1.5× ULN (unless due to Gilbert's syndrome) * Active cholecystitis, symptomatic gallbladder disease (e.g., biliary colic), or any other clinically significant hepatobiliary abnormality * Neurodegenerative disease * Neuromuscular disorder * Psychiatric or movement disorders impairing participation * History of drug-induced myopathy or rhabdomyolysis * Elevated creatine kinase (CK) at screening CK \>1.0× ULN confirmed on two separate occasions at least 48 hours apart * Systemic lupus erythematosus (SLE), including overlap or drug-induced forms * Mixed connective tissue disease (MCTD) * Systemic sclerosis (diffuse, limited, or sine scleroderma) * Inflammatory myopathies (including polymyositis, dermatomyositis, inclusion body myositis, immune-mediated necrotizing myopathy, or overlap myositis) * Primary Sjögren's syndrome requiring systemic immunosuppression * Rheumatoid arthritis requiring biologic therapy or with extra-articular manifestations * Undifferentiated connective tissue disease meeting ≥2 classification criteria * Current or recent use of immunosuppressive agents (within 3 months) * Acute bacterial, fungal, or viral infection, fever, or receipt of live vaccines within 30 days prior to screening * Active hepatitis B infection or reactivation risk (HBsAg positive, HBV DNA detectable, or isolated anti-HBc without anti-HBs) * Hepatitis C infection (detectable HCV RNA or treatment within 6 months) * HIV infection * Active or latent tuberculosis (positive QuantiFERON-TB Gold Plus ≥0.35 IU/mL) * Acute herpesvirus infection, defined as Active HSV-1 or HSV-2 lesions (vesicles, ulcers, crusts) on clinical examination at screening, CMV or EBV IgM positive * Platelet count \<100 × 10⁹/L at screening * Active therapeutic anticoagulation * Known inherited or acquired coagulation disorder * Use of anticoagulants that cannot be safely discontinued prior to study treatment * Severe physical functional limitation (6-Minute Walk Test distance \<150 meters or CFS\>6) * Prior exposure to any AAV gene therapy product (any AAV serotype) * Prior exposure to any investigational drug within 90 days * Participation in another clinical trial within 90 days * Known hypersensitivity to investigational product components or immunosuppressive agents (e.g., prednisone, rapamycin) * Life expectancy \<6 months * Any condition that, in the Investigator's judgment, may pose undue risk, interfere with study outcomes, or impair study participation