The Molecular Intersection Between Senescence and Major Depression in the Elderly

Abstract

Major depressive disorder in the elderly-or late-life depression (LLD)-is one of the most common mental illnesses in the aging population. LLD has several negative effects on health and well-being. Individuals with LLD have an elevated risk of chronic and persistent depressive symptoms as well as high rates of treatment resistance. They also have a higher risk of developing cognitive impairment with progression to dementia and higher rates of medical comorbidity, frailty, and mortality. The mechanisms linking LLD to these adverse health outcomes are not well understood. In this article, we review the evidence that individuals with LLD present with, i.e., enhanced molecular and cellular senescent changes, focusing on the senescence-associated secretory phenotype (SASP). We then propose a mechanistic model linking SASP to the greater risk of negative health outcomes in this population. We finally provide evidence that SASP-and cellular senescence in general-can be a therapeutic target for mitigating the risk of these negative outcomes in LLD.