Between destiny and disease: Genetics and molecular pathways of human central nervous system aging

Abstract

Aging of the human brain is associated with "normal" functional, structural, and molecular changes that underlie alterations in cognition, memory, mood and motor function, amongst other processes. Normal aging also imposes a robust constraint on the onset of many neurological diseases, ranging from late onset neurodegenerative diseases, such as Alzheimer's (AD) and Parkinson's diseases (PD), to early onset psychiatric disorders, such as bipolar disorder (BPD) and schizophrenia (SCZ). The molecular mechanisms and genetic underpinnings of age-related changes in the brain are understudied, and, while they share some overlap with peripheral mechanisms of aging, many are unique to the largely non-mitotic brain. Hence, understanding mechanisms of brain aging and identifying associated modulators may have profound consequences for the prevention and treatment of age-related impairments and diseases. Here we review current knowledge on age-related functional and structural changes, their molecular and genetic underpinnings, and discuss how these pathways may contribute to the vulnerability to develop age-related neurological diseases. We highlight recent findings from human postmortem brain microarray studies, which we hypothesize, point to a potential genetically-controlled transcriptional program underlying molecular changes and age-gating of neurological diseases. Finally, we discuss the implications of this model for understanding basic mechanisms of brain aging and for the future investigation of therapeutic approaches.

The Age-by-Disease Interaction Hypothesis of Late-Life Depression

“…58 Not only do the genes relevant to these brain diseases show age-related changes, but the direction of the changes that occur with age is almost always in the direction thought to cause or promote diseases 58 (Table 1), as exemplified by SST age- and disease-related changes shown here (Figure 1A). It is important to note that such normal age effects can go unnoticed in age-matched paired sample design, which may incorrectly suggest that changes in gene expression in depression, Alzheimer's disease, or other age-gated diseases are separate from what would be seen in normal aging.…”

“…Conversely, very few (<5%) of the larger pool of genes that do not display age-dependent changes, are otherwise associated with neurodegenerative and neuropsychiatric diseases. 58 Together, these data suggest that, at the single gene level, aging may promote selective changes in gene expression in ways that promote diseases. Collectively, the large number of disease-related genes affected during aging in pro-disease directions also suggest that system-level adaptations occur with age, such an age-by-disease interaction leads towards physiological states that are in fact closer to disease states than at younger ages (See Douillard-Guilloux et al 71 in this issue).…”

“…These observations have led us to propose that biological aging of the brain may in fact promote age-gated diseases, including LLD, by contributing to selective disruptions of specific neuronal and glial processes, each with putative etiological roles in disease-related biological processes, including mood network disruption. 57-58 …”

“…Interestingly, the set of age-dependent genes in our group's study was very similar to those observed in other studies, 57,60-62,64,66-68 and in fact displayed high degree of conservation across cohorts and cortical brain regions. 58 Expression of genes playing a role in glial-mediated inflammation, oxidative stress responses, mitochondrial function, synaptic function and plasticity, and calcium regulation have now consistently been shown across multiple studies to be affected by aging, despite differences in sample size, selection of tissue type or brain region, expression analysis platforms, and analytical methods. 57,60-62,64,66-68 Of note, not only is the identity of the genes and gene classes that are affected with aging consistent among studies but so are the directions of change.…”

“…For instance, we have reported that the variance in depression-related decrease in the neuropeptide somatostatin (SST) can be mostly explained by superimposed age-related changes 58,69 (Figure 1A). Indeed, consistent with prior findings, 66 normal subjects lose ~40-50% of SST expression between the age of 20 and 70 years, while subjects affected with depression appear to be on an early trajectory of age-related decline 69 (Figure 1A, top panel), and similar findings have been reported in schizophrenia 70 (Figure 1A, bottom panel).…”