Microglia and modifiable life factors: Potential contributions to cognitive resilience in aging

Abstract

Given the increasing prevalence of age-related cognitive decline, it is relevant to consider the factors and mechanisms that might facilitate an individual's resiliency to such deficits. Growing evidence suggests a preeminent role of microglia, the prime mediator of innate immunity within the central nervous system. Human and animal investigations suggest aberrant microglial functioning and neuroinflammation are not only characteristic of the aged brain, but also might contribute to age-related dementia and Alzheimer's Disease. Conversely, accumulating data suggest that modifiable lifestyle factors (MLFs), such as healthy diet, exercise and cognitive engagement, can reliably afford cognitive benefits by potentially suppressing inflammation in the aging brain. The present review highlights recent advances in our understanding of the role for microglia in maintaining brain homeostasis and cognitive functioning in aging. Moreover, we propose an integrated, mechanistic model that postulates an individual's resiliency to cognitive decline afforded by MLFs might be mediated by the mitigation of aberrant microglia activation in aging, and subsequent suppression of neuroinflammation.

Keywords: Cognitive aging; Cognitive enrichment; Diet; Exercise; Microglia; Neuroinflammation.

Figure 1:

Illustration depicting the functions of microglia in normal CNS. Under normal physiological conditions, microglia actively surveil their surrounding microenvironment in a homeostatic state. These cells maintain various pattern recognition receptors (e.g. toll-like receptors, scavenger receptors) that are capable of detecting aberrant molecular patterns in their microenvironment, such as those from malformed polypeptides, pathogens or other cellular debris. Following the detection of cytotoxic factors, microglia become reactive (ameboid) to remove and degrade these aberrant materials that might otherwise compromise the CNS microenvironment, while exhibiting a balanced production of both inflammatory and anti-inflammatory messengers, such as cytokines, as well as trophic factors.

Figure 2:

Schematic depicting the composition of different diets and micronutrients used in prospective cohort studies to examine the impact of nutritional patterns on cognitive health in the elderly.

Figure 3:

Schematic summarizing the effects of dietary supplements on microglia and cognitive functioning in rodent models of aging and AD. Exposure to high-fat/high-cholesterol diets produces abnormal activation of microglia and consequent increase in neuroinflammation, thereby impairing attention and memory. Conversely, supplementation with polyphenols/PUFAs blunt this effect, and preserve cognition by suppressing proinflammatory processes as well as oxidative stress.

Figure 4:

Proposed model depicting microglia as a critical determinant of cognitive variation in aging. Normal dynamics between the homeostatic and the reactive state of microglia regulate CNS homeostasis by supporting neurogenesis, synaptic plasticity, reducing inflammation, and fulfilling normal phagocytic role (i.e. removing cellular debris and neurotoxic substrates in response to acute infection or injury that otherwise cause neuronal damage). Together, these processes are critical to maintain the neuronal activity which supports higher cognitive functions. Advancing age produces microglia senescence/dystrophy to some extent and this process could be exacerbated by genetic and environmental factors, systemic inflammation and pathological conditions. Dystrophic microglia result in chronic abnormalities that increase oxidative stress as well as pro-inflammatory cytokines, and compromised ability for optimal phagocytic function. This facilitates sustained neuroinflammation and neurotoxicity, thereby jeopardizing efficient recruitment of neural networks that support cognitive functions, and resulting in increased risk for age-related dementia as well as AD. By controlling oxidative stress (i.e. lowering ROS, boosting antioxidant defense mechanisms), elevating the levels of neurotrophins (such as BDNF), and reducing systemic inflammation, modifiable life factors (healthy diet, physical exercise, and cognitive enrichment) inhibit the transition of stable (homeostatic/reactive) microglia to dystrophic microglia, and induce resiliency to cognitive decline in aging.