Microglia Priming with Aging and Stress

Abstract

The population of aged individuals is increasing worldwide and this has significant health and socio-economic implications. Clinical and experimental studies on aging have discovered myriad changes in the brain, including reduced neurogenesis, increased synaptic aberrations, higher metabolic stress, and augmented inflammation. In rodent models of aging, these alterations are associated with cognitive decline, neurobehavioral deficits, and increased reactivity to immune challenges. In rodents, caloric restriction and young blood-induced revitalization reverses the behavioral effects of aging. The increased inflammation in the aged brain is attributed, in part, to the resident population of microglia. For example, microglia of the aged brain are marked by dystrophic morphology, elevated expression of inflammatory markers, and diminished expression of neuroprotective factors. Importantly, the heightened inflammatory profile of microglia in aging is associated with a 'sensitized' or 'primed' phenotype. Mounting evidence points to a causal link between the primed profile of the aged brain and vulnerability to secondary insults, including infections and psychological stress. Conversely, psychological stress may also induce aging-like sensitization of microglia and increase reactivity to secondary challenges. This review delves into the characteristics of neuroinflammatory signaling and microglial sensitization in aging, its implications in psychological stress, and interventions that reverse aging-associated deficits.

Figure 1

Aging and environmental factors are intertwined in a dynamic, bidirectional relationship. Under homeostatic conditions, microglia are highly dynamic cells, constantly ‘surveying' the brain microenvironment. Clinical and animal studies support findings of microglial priming (or ‘sensitization') with aging. The ‘primed' microglia are characterized by a dystrophic morphology including, de-ramified processes, spherical cell body, and fragmented cytoplasm (Streit et al, 2004). Associated with these morphological alterations are biochemical changes, such as elevated expression of antigen presentation molecules (MHCII), Toll-like receptors, pro-inflammatory cytokines (IL-1β), reduced expression of regulatory molecules (CX3CR1 and CD200R) (Frank et al, 2006; Maher et al, 2004), DNA methylation changes and telomere shortening (Flanary and Streit, 2003; Zannas et al, 2015). Microglia of the aged brain also show deficient phagocytic activity and impaired mobility under baseline (Damani et al, 2011). This primed profile of microglia has been documented in aging and chronic psychological stress. Primed microglia are vulnerable to subsequent immune stimuli, such as immune challenge, stress, and aging. As such, upon exposure to these stimuli, the primed microglia take on a ‘hyperactive' state marked by exaggerated pro-inflammatory response and resistance to regulation (Barrientos et al, 2009; Frank, Barrientos, et al, 2010; Godbout et al, 2005; Kinsey et al, 2008; Willette et al, 2012; Wynne et al, 2010).

Figure 2

Reversal of aging-associated deficits via immune alterations. Aging is associated with reduced neurogenesis, impaired learning and memory, as well as increased pro-inflammatory markers, antigen presentation molecules and oxidative stress. Recent findings from parabiosis models (left) have shown that exposure to young blood restores neurogenesis, learning and memory and neuronal functions in older mice via increase in growth factors and endothelial remodeling in older mice (Baruch et al, 2014; Katsimpardi et al, 2014; Villeda et al, 2011). Caloric restriction (middle) is associated with prolonged life, increased gray matter volume, improved motor function, and reduced chronic pathology (eg, neoplasia) and inflammatory markers (complement proteins, antigen presentation markers, and pro-inflammatory cytokines) in rodents, non-human primates, and humans (Colman et al, 2009; Willette et al, 2012; Witte et al, 2009). Clinical and animal reports show that aerobic exercise (right) in humans and voluntary running in rodents is associated with enhanced neurogenesis, improved learning and memory, increased hippocampal BDNF, and dampened inflammatory response to immune challenge and microglia proliferation (Barrientos et al, 2011; Colcombe et al, 2003; Gebara et al, 2013).