Immunosenescence and Neurodegeneration

How greatly does the onset of dementia depend on the age-related decline of the immune system? The most evident contributions to neurodegeneration are vascular aging and the accumulation of protein aggregates such as amyloid-β, tau, and α-synuclein. These are only indirectly connected to the aging of the immune system, in the sense that immune function influences in some way near all aspects of tissue function, and its progressive failure tends to make everything at least a little less functional. Chronic inflammation appears to play a direct and important role in the progression of most neurodegenerative conditions, however, and there at least we can point to the immune system as a primary issue.

The immune system is responsible for defending against pathogens such as bacteria, viruses, and fungi to eliminate broken and harmful cells, like senescent cells and toxic or allergenic substances. Immunosenescence is a term that describes a different state of the immune system in aged people, in association with detrimental clinical outcome, due to reduced ability to respond to new antigens. Although immunosenescence is a phenomenon present in the majority of individuals, factors like genetic, environment, lifestyle, and nutrition are responsible for their heterogeneity among individuals and cause a higher susceptibility to develop infections and progression of disease pathology.

The age-related dysregulation of immune responses impacts the resistance to infections, diminishes responses to vaccination, increases the susceptibility to autoimmunity and cancer, and promotes the development of an inflammatory phenotype. Researchers have introduced the term "inflammaging", related to the immunosenescence, to describe a low-grade, asymptomatic, chronic, and systemic inflammation, characterized by increased levels of circulating cytokines and other proinflammatory markers. The relationship between aging and chronic disorders, including atherosclerosis, dementia, neurodegeneration, and many others, has its bases in senescent remodeling of immune system.

The increased proinflammatory environment could be the major contributing factor to the development of aging-associated diseases. Given the well-established communication between the immune system and brain, the age-related immune dysregulation may bring neurodegeneration. Several studies have demonstrated that immunosenescence and inflammaging can induce an overactivation of central nervous system (CNS) immune cells, promoting neuroinflammation. In Alzheimer's disease patients, the microglial aging and dysfunction lead to amyloid-β accumulation and loss of peripheral immune response, contributing to disease pathogenesis. Furthermore, in Parkinson's disease, the interaction between aging and over time decreased immune response suggests a disease predisposition for neurodegeneration.

Recently, several studies have reported the relationship between delayed immunological aging and reduced expansion of senescent late-stage differentiated T cells and active lifestyle and has been suggested that aerobic exercise training might attenuate cognitive impairment and reduce dementia risk. Although it is unknown whether effects of exercise are direct, such as a targeted removal of dysfunctional T cells, or indirect, such as lower inflammatory activity, it may be hypothesized that these changes can provide benefits for health, including mitigate cognitive impairment.

New strategies to combat immunosenescence and neurodegeneration are focused on cellular and genetic therapies, such as genetic reprogramming and bone marrow transplantation, but cell reprogramming has still poor efficiency, and clinical translation shows several ethical and safety questions that may be answered. Thus, a better understanding of immunosenescence mechanisms will be necessary to develop new, unconventional, or pharmacological therapy strategies, for peripheral and CNS immunosenescence delay. Additional studies are required to determine the effectiveness and optimal conditions to improve the function of the aged immune system and undertake the challenges of immunosenescence.