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.
Highlights
Introduction1% of individuals over the age of 65 meet criteria for major depressive disorder (MDD), as defined by the diagnostic and statistical manual of mental disorders, fourth edition, text revision (DSMIV-TR; American Psychiatric Association, 2000), a prevalence lower than that in younger adults (Kessler et al, 2003)
Among elderly individuals, depressive symptoms are common and burdensome
In the age-by-disease biological interaction hypothesis we have proposed that those individuals with older predicted molecular ages compared to their chronological age may display greater biological brain aging, but may be at greater risk of age-gated brain diseases, because gene expression of disease-related genes would have proceeded further in disease-promoting directions
Summary
1% of individuals over the age of 65 meet criteria for major depressive disorder (MDD), as defined by the diagnostic and statistical manual of mental disorders, fourth edition, text revision (DSMIV-TR; American Psychiatric Association, 2000), a prevalence lower than that in younger adults (Kessler et al, 2003). Another 15–25%, experience depressive symptoms that, while not meeting criteria for MDD, do cause significant distress and interfere with daily functioning (Koenig and Blazer, 1992). LLD appears to contribute to increased rates of suicide among older individuals (Van Orden and Conwell, 2011)
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