Note. The biological substrates of the Depressed Frail Phenotype are outlined above with their biological and clinical signatures and potential personalized approach to treatment. aAerobic exercise has been shown to improve muscle oxidative capacity and improved skeletal muscle mitochondrial content in older adults; bThe anti-inflammatory medication infliximab was shown to be a more effective antidepressant than placebo in treatment resistant adults with elevated CRP; cDopamine augmentation has been shown to improve cognition and motor and processing speed in both healthy adults and patients with Parkinson’s. PBMC, peripheral blood mononuclear cells; ATP, adenosine triphosphate, NMR, nuclear magnetic resonance; CRP, C-reactive protein; IL-6, Interleukin 6; TNF alpha, Tumor necrosis factor alpha; PET, positron emission tomography