Age-related changes in the immune system and the consequences of immunosenescence

ABSTRACT

The cellular and molecular hallmarks of aging include genomic instability, telomere attrition, epigenetic alterations, changes in intracellular signaling, cellular senescence, and mitochondrial dysfunction. These lead to complex remodeling and changes involving both the innate and adaptive immune systems. Besides age related changes in immune cells, the microenvironment in the lymphoid and non-lymphoid organs, as well as circulating factors interacting with the immune system also contribute to immunosenescence. Overall, immunosenescence is characterized by reduction of immune response, an increase in inflammatory and oxidation background (inflamm-aging), and production of autoantibodies. One of the most prominent age-related changes in the adaptive immune system is the decline in regenerative thymic capacity. Similar aging related defects have also been observed in stroma of the bone marrow. While lymphocytes in infants show a naive phenotype, memory phenotype predominates after midlife. Though immune responses against recall antigens may still be conserved, the ability to mount primary response against novel antigens declines with age. As a result, increased susceptibility to infections, and suboptimal vaccine response is observed in the elderly. Apart from functional alternation in immune cells, there is a low-grade persistent elevation in inflammatory molecules. Inflamm-aging may result from the accumulation of misfold proteins, compromised gut barrier function, chronic infection, obesity, etc. Furthermore, aging is associated with immune dysregulation, with defective resolution of immune response after activation, and impaired clearance of dead cells with sustained inflammation. Excessive inflammation not only impairs antigen specific immunity, but also leads to tissue damage. In fact, this may partly account for the increased mortality of COVID infection in the elderly. Apart from vulnerability to infection and weakened vaccine response, immunosenescence also plays an important role in cancer and autoimmunity in the elderly. Because of increased tissue damage and apoptosis, coupled with inflamm-aging, increased autoantibodies production is observed in the elderly. Nevertheless, there is an age-related increase in peripheral regulatory T cells. While there is an increase in autoimmunity with aging, this does not always translate into an increase in autoimmune disease. On the other hand, the increase in regulatory T cells, along with other immunosuppressive cells and the senescence associated proinflammatory environment, promotes tumor development and progression in the elderly. As immunosenescence has a significant impact on health and disease, better understanding on this process is crucial for research and development in the future geriatric health care.