Maintaining brain health by monitoring inflammatory processes: a mechanism to promote successful aging

Abstract

Maintaining brain health promotes successful aging. The main determinants of brain health are the preservation of cognitive function and remaining free from structural and metabolic abnormalities, including loss of neuronal synapses, atrophy, small vessel disease and focal amyloid deposits visible by neuroimaging. Promising studies indicate that these determinants are to some extent modifiable, even among adults seventy years and older. Converging animal and human evidence further suggests that inflammation is a shared mechanism, contributing to both cognitive decline and abnormalities in brain structure and metabolism. Thus, inflammation may provide a target for intervention. Specifically, circulating inflammatory markers have been associated with declines in cognitive function and worsening of brain structural and metabolic characteristics. Additionally, it has been proposed that older brains are characterized by a sensitization to neuroinflammatory responses, even in the absence of overt disease. This increased propensity to central inflammation may contribute to poor brain health and premature brain aging. Still unknown is whether and how peripheral inflammatory factors directly contribute to decline of brain health. Human research is limited by the challenges of directly measuring neuroinflammation in vivo. This review assesses the role that inflammation may play in the brain changes that often accompany aging, focusing on relationships between peripheral inflammatory markers and brain health among well-functioning, community-dwelling adults seventy years and older. We propose that monitoring and maintaining lower levels of systemic and central inflammation among older adults could help preserve brain health and support successful aging. Hence, we also identify plausible ways and novel experimental study designs of maintaining brain health late in age through interventions that target the immune system.

Keywords: Aging; Brain health; Central inflammatory processes.

Figure 1.

Communication between central nervous system and immune system. Triggers (cardiometabolic and lifestyle factors, or injuries of other nature) occurring anywhere in the body are communicated to the CNS via release of proinflammatory factors. An inflammatory response is initiated when monocytes/macrophages are activated by pathogens or tissue damage to release pro-inflammatory cytokines, including interleukin (IL)-6, IL-1β, and tumor necrosis factor (TNF)-α, and chemokines, such as IL-8. These chemical mediators coordinate a local inflammatory response, resulting in the recruitment and activation of leukocytes to the site of invasion/injury. They also enter peripheral circulation to stimulate a systemic response, which includes the synthesis and release of acute phase proteins, such as C-reactive protein and fibrinogen. The CNS responds to this information by initiating behaviors to adapt to such triggers (e.g., fever, reduced activity) and by releasing immune mediators to respond to the peripheral stimulus (green arrow). In normal circumstances, peripheral inflammatory responses are terminated quickly by the action of anti-inflammatory factors released locally and systemically to shut off the inflammatory response, leading to the adaptive restoration of a lower inflammatory state.

Figure 2.

Biological rationale for a relationship between peripheral inflammatory factors and brain health. Proinflammatory cytokines cause greater endothelial permeability and adhesively of the blood brain barrier (BBB) and may reach the CNS through several pathways: 1 = through the post-inflammatory dysfunctional endothelium of the BBB; 2 = through binding to specific receptors on the BBB cell, and subsequently triggering mRNA production of pro-inflammatory factors; 3 = via diffusion through “nude” areas. 4. Via stimulation of the adrenergic system through the vagal nerve. Upon stimulation, the microglia in the CNS is also capable of producing cytokines directly, thus cytokines levels can increases in the CNS and can trigger brain inflammation even if they are not transferred from the peripheral blood into the brain parenchyma.