Some of these novel approaches are already under investigation, while others remain to be tested. In Table II, we list mTOR inhibitor certain traditional and nontraditional, but mechanism-based, interventions that may ameliorate the biochemical mediators we have discussed. These interventions range from purely behavioral (eg, exercise and improved fitness, environmental enrichment, yoga and meditation, dietary macronutrient modifications and calorie restriction) (see refs 7,142-144 Inhibitors,research,lifescience,medical for description of these behavioral approaches) to more purely medication-based (see ref 145 for additional descriptions of novel biological mechanism-based therapeutics). For

example, early work suggests the promise, at least in certain patients, Inhibitors,research,lifescience,medical of antiglucocorticoids,67-69 DHEA supplementation,17 insulin receptor sensitizers,99,146 glutamate antagonists,147 calcium blockers,148 anti-inflammatories,149 antioxidants,150 increased BDNF delivery to the brain, 124,151 and, most speculatively, telomerase enhancers.152,153 Inhibitors,research,lifescience,medical Table II. Potential mechanism-based therapeutic interventions. LHPA, limbic-hypothalamic-pituitary-adrenal; GC,

glucocorticoid; GR, glucocorticoid receptor; CRH, corticotrophin-releasing hormone; DHEA, dehydroepiandrosterone; BDNF brain-derived neurotrophic factor; … Summary: is depression accompanied by accelerated aging? We began this review article by noting that depressed individuals are at Inhibitors,research,lifescience,medical increased risk of developing physical illnesses more commonly seen with aging. It

remains unknown whether MDD and these medical conditions are causally related. This determination will be important in considering whether primary treatment of Inhibitors,research,lifescience,medical the depression (eg, with antidepressant medications or psychotherapy) should additionally treat some of the medical comorbidities (and vice versa) or whether the biochemical mediators that are common to both conditions (eg, inflammation and oxidation) should be a primary treatment focus. Phosphoprotein phosphatase We also discussed the potent influence that early-life adversity can have on the subsequent development of depression and medical comorbidities. We noted that many of the biochemical mediators are linked to others, and that there are many examples of bidirectional influence. Finally, we postulated that certain of these mediators have the potential to accelerate cellular aging at the level of DNA. In any event, is important to recognize that MDD may be biologically heterogeneous, and this model may apply only to certain subsets of patients with MDD. This reconceptualization of MDD as a constellation of biochemical features conducive to physical as well as mental distress places MDD firmly in the taxonomy of physical disease and points to new types of treatment.