Biological factors influencing depression in later life: role of aging processes and treatment implications

Abstract

Late-life depression occurring in older adults is common, recurrent, and malignant. It is characterized by affective symptoms, but also cognitive decline, medical comorbidity, and physical disability. This behavioral and cognitive presentation results from altered function of discrete functional brain networks and circuits. A wide range of factors across the lifespan contributes to fragility and vulnerability of those networks to dysfunction. In many cases, these factors occur earlier in life and contribute to adolescent or earlier adulthood depressive episodes, where the onset was related to adverse childhood events, maladaptive personality traits, reproductive events, or other factors. Other individuals exhibit a later-life onset characterized by medical comorbidity, pro-inflammatory processes, cerebrovascular disease, or developing neurodegenerative processes. These later-life processes may not only lead to vulnerability to the affective symptoms, but also contribute to the comorbid cognitive and physical symptoms. Importantly, repeated depressive episodes themselves may accelerate the aging process by shifting allostatic processes to dysfunctional states and increasing allostatic load through the hypothalamic-pituitary-adrenal axis and inflammatory processes. Over time, this may accelerate the path of biological aging, leading to greater brain atrophy, cognitive decline, and the development of physical decline and frailty. It is unclear whether successful treatment of depression and avoidance of recurrent episodes would shift biological aging processes back towards a more normative trajectory. However, current antidepressant treatments exhibit good efficacy for older adults, including pharmacotherapy, neuromodulation, and psychotherapy, with recent work in these areas providing new guidance on optimal treatment approaches. Moreover, there is a host of nonpharmacological treatment approaches being examined that take advantage of resiliency factors and decrease vulnerability to depression. Thus, while late-life depression is a recurrent yet highly heterogeneous disorder, better phenotypic characterization provides opportunities to better utilize a range of nonspecific and targeted interventions that can promote recovery, resilience, and maintenance of remission.

Fig. 1. Lifespan model of late-life depression.

Symptoms of depression are the behavioral manifestation of increasingly disrupted brain networks. Multiple influences contribute to network fragility and dysfunction across the lifespan, with some being linked to clear developmental periods. These may be additive and cumulative over time, although other risk and resiliency factors may be modifiable and targeted by specific treatments. Unchecked, repeated depressive episodes and their associated physiological responses may have deleterious effects contributing to accelerated aging.

Fig. 2. Network model of late-life depression.

The model details findings within each intrinsic functional network and between functional networks, specifically the default mode network (DMN), the cognitive control network (CCN), and the anterior salience network (ASN). Disruption in network connectivity influences the cognitive processes, giving risk to the behavioral manifestations of depression. Impaired function of the positive valence system involving the mesolimbic system likely also contributes to depressive behavior [37], although how this system interacts with interacts with intrinsic functional networks in LLD is not entirely clear. The model and figure [34] used with permission. Reprinted from Gunning et al. [34], Copyright 2021, with permission from Elsevier.

Fig. 3. Accelerated aging hypothesis of late-life depression.

Aging processes such as inflammation, vascular disease, or pathological neurodegeneration impair neurotrophic function and contribute to both gray matter atrophy and impairment of white matter microstructure. These changes in turn alter function of key intrinsic networks, leading to the clinical manifestations of late-life depression. In turn, repeated depressive episodes result in altered or sustained physiological responses increasing allostatic load. These effects may then further accelerate biological aging processes, shifting an individual further away from normative aging.