Age-by-disease biological interactions: implications for late-life depression

Abstract

Onset of depressive symptoms after the age of 65, or late-life depression (LLD), is common and poses a significant burden on affected individuals, caretakers, and society. Evidence suggests a unique biological basis for LLD, but current hypotheses do not account for its pathophysiological complexity. Here we propose a novel etiological framework for LLD, the age-by-disease biological interaction hypothesis, based on the observations that the subset of genes that undergoes lifelong progressive changes in expression is restricted to a specific set of biological processes, and that a disproportionate number of these age-dependent genes have been previously and similarly implicated in neurodegenerative and neuropsychiatric disorders, including depression. The age-by-disease biological interaction hypothesis posits that age-dependent biological processes (i) are "pushed" in LLD-promoting directions by changes in gene expression naturally occurring during brain aging, which (ii) directly contribute to pathophysiological mechanisms of LLD, and (iii) that individual variability in rates of age-dependent changes determines risk or resiliency to develop age-related disorders, including LLD. We review observations supporting this hypothesis, including consistent and specific age-dependent changes in brain gene expression and their overlap with neuropsychiatric and neurodegenerative disease pathways. We then review preliminary reports supporting the genetic component of this hypothesis. Other potential biological mediators of age-dependent gene changes are proposed. We speculate that studies examining the relative contribution of these mechanisms to age-dependent changes and related disease mechanisms will not only provide critical information on the biology of normal aging of the human brain, but will inform our understanding of age-dependent diseases, in time fostering the development of new interventions for prevention and treatment of age-dependent diseases, including LLD.

Keywords: depression; epigenetic modifications; gene expression; late-life depression; molecular aging; oxidative stress; telomere.

FIGURE 1

(A) Somatostatin expression decreases with age in control subjects. Individuals with MDD (top panel) and schizophrenia (bottom panel) display lower levels of expression than control subjects at most ages, together prompting the hypothesis that decreased expression of somatostatin in depression and schizophrenia may represent early brain age-related molecular phenotypes in these individuals, which would render these subjects more vulnerable to developing psychiatric diseases. (B) Based on similar age and disease observations for numerous additional genes, we have proposed a model of “age-by-disease biological interaction” (Glorioso et al., 2011). In this model, change in expression of disease-related genes (a decrease is shown) across a threshold (horizontal blue line) marks the onset of disease symptoms. Changes in the trajectory of age-related changes in expression of disease-related genes (Y-axis) determine at what age (X-axis), or even if, an individual develops disease symptoms (vertical red arrows). Modulators (black arrows) may thus place an individual on “at risk” or “protected” trajectory. Per this model, individuals with LLD may have modulators, genetic or environmental, that place them on an “at risk” trajectory for developing mood symptoms. Figures are adapted from Morris et al. (2008), Tripp et al. (2011), Glorioso and Sibille (2011), and McKinney and Sibille (2012).

FIGURE 2

Proposed sequence of biological events and putative mediators for the age-by-disease biological interaction hypothesis. From the top: Although its biological substrates are unknown, a chronological clock drives age-related changes in gene expression. These changes can be exacerbated by psychophysiological stress and/or genetic variants, and placed on accelerated age trajectories. In this model, age-related changes in telomeres, oxidative load and epigenetic landscape, among other putative mechanisms, may represent a first level of biological events, which in turn affect basic cellular processes involved in regulating gene expression (i.e., including DNA damage, altered structure and function of transcription factors (TFs), and associated local cellular signaling). The resulting changes in the global pattern of age-dependent gene expression mediate the next set of deleterious biological events, exemplified here by increased inflammation, oxidative damage-related signaling, and changes in neurotransmission. These two levels of changes are likely to reciprocally interact. At the neural network and brain levels, the emerging properties of those specific cellular events are expressed as senescence in normal aging subjects and, in subjects at risk, as age-related symptom dimensions and diseases, including depression. Notably, the degree of individual vulnerability is thought to be under genetic and environmental control, so decreased vulnerability may mediate resiliency through the same pathways.