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 35-75 years * Body mass index (BMI) between 18.0 and 35.0 kg/m² at screening * 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 or ANY history of cancer * Strong family history of cancer in first-degree relatives (≥2 relatives with cancer diagnosed \<60 years) OR known hereditary cancer syndrome (BRCA1/2, Lynch syndrome, Li-Fraumeni, FAP, HNPCC) without genetic counseling and enhanced surveillance clearance * Clinically significant cardiovascular disease, including: * Any history of stroke, transient ischemic attack (TIA), 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 (LBBB) * 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) * Known or suspected hypercoagulable state/thrombophilia, including any of the following: * Any 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, including but not limited to: * 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 * Any 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 ≥7.0 mmol/L (≥126 mg/dL) at screening * HbA1c ≥6.5% (≥48 mmol/mol) at screening * Current 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 * Chronic liver disease or hepatic impairment: * Any history of cirrhosis, chronic viral hepatitis (HBV, HCV), autoimmune hepatitis, or cholestatic liver disease * 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) * Non-alcoholic steatohepatitis (NASH) and clinically significant liver fibrosis * Active cholecystitis, symptomatic gallbladder disease (e.g., biliary colic), or any other clinically significant hepatobiliary abnormality * Neurodegenerative, neuromuscular, psychiatric, or movement disorders associated with functional or cognitive impairment (e.g., dementia, Parkinson's disease) * 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 * Exception: Transient CK elevation within 72 hours of strenuous exercise, intramuscular injections, or trauma is permitted if CK normalizes (≤1.0× ULN) on repeat testing before baseline visit * Systemic connective tissue diseases (CTDs), including: * Systemic lupus erythematosus (SLE), SLE overlap syndromes, or drug-induced SLE * Mixed connective tissue disease (MCTD) * Systemic sclerosis (SSc, scleroderma): diffuse, limited, or sine scleroderma * Inflammatory myopathies: polymyositis (PM), dermatomyositis (DM), inclusion body myositis (IBM), immune-mediated necrotizing myopathy (IMNM), or overlap myositis * Primary Sjögren's syndrome requiring systemic immunosuppression (corticosteroids \>10 mg/day prednisone equivalent, DMARDs, or biologics) * Rheumatoid arthritis with extra-articular manifestations or requiring biologic DMARDs * Undifferentiated connective tissue disease (UCTD) meeting ≥2 CTD classification criteria * Current or recent (within 3 months) use of immunosuppressive agents, including corticosteroids, cyclosporine, tacrolimus, methotrexate, cyclophosphamide, IVIG, or rituximab * Acute bacterial, fungal, or viral infection, fever, or receipt of live vaccines within 30 days prior to screening * Infectious disease exclusions, including: * 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 * Increased bleeding risk, including platelet count \<100 ×10⁹/L, active anticoagulation (unless washout possible), or known coagulation disorders * Severe physical functional limitation (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