Summarizing the Current Understanding of Immunosenescence

The open access review paper here provides a summary of the present scientific understanding of immunosenescence, the name given to the declining function of the immune system with advancing age. Some researchers consider this a separate phenomenon from inflammaging, the increased levels of inappropriate inflammatory activation of the immune system found in older individuals, and also distinct from some other kinds of immune cell failure found in old people, such as cellular senescence or immune cell exhaustion. Others consider all of these line items to be aspects of immunosenescence. Further, when it comes to the roots of age-related immune failure, the degree to which various potential causes are responsible is open to debate, and there will likely remain considerable uncertainty until such time as the research community can reverse those causes one by one to observe the results.

In our era of rapidly improving biotechnology, it is frequently the case that building therapies to address the causes of age-related dysfunction is the fastest path to an understanding of which of those causes are important. In the case of immunosenescence, there are a number of obvious paths forward, some of which should also help to treat autoimmune conditions: reversing atrophy of the thymus to increase the supply of new immune cells; destroying damaged or overspecialized immune cells to free up space for effective replacements; using cell therapies to deliver a large number of new immune cells; restoring function of the hematopoietic stem cells that generate immune cells.

Immunosenescence correlates with the linear extension of average life span that began in the nineteenth century and is still in progress. The aging phenotype, including immunosenescence, is the result of an imbalance between inflammatory and anti-inflammatory mechanisms with the consequence of a state defined by some authors as inflammaging. The most important feature of immunosenescence is the accumulation in the "immunological space" of memory and effector cells as a result of the stimulation caused by repeated clinical and subclinical infections and by continuous exposure to antigens. This state of chronic inflammation that characterizes senescence has a significant impact on survival and fragility. In fact, the condition of frail elderly occurs less frequently in situations characterized by low contact with viral infections and parasitic diseases. Furthermore immunosenescence is characterized by a particular remodelling of the immune system, induced by oxidative stress.

Apoptosis, a complex mechanism of programmed cell death, allows the maintenance of a physiological homeostasis mechanisms between survival and removal of damaged cells. Apoptosis is a strategic mechanism for the manifestation of the clonotypic diversity during lymphocyte selection, permitting to control the clonal expansion after antigenic stimulation. Changes in apoptosis, together with inflammaging and the up-regulation of the immune response with the consequent secretion of pro-inflammatory lymphokines, represents the major determinant of the rate of aging and longevity, as well as of the most common diseases related with age and with tumors. Other changes occur in innate immunity, the first line of defence providing rapid, but unspecific and incomplete protection, consisting mostly of monocytes, natural killer cells, and dendritic cells, acting up to the establishment of an adaptive immune response, which is slower, but highly specific, which cellular substrate consists of T and B lymphocytes.

The markers of inflammaging in adaptive immunity in centenarians are characterized by a decrease in naive T cells. The reduction of CD8- cells may be related to the risk of morbidity and death, as well as the combination of the increase of CD8+ cells and reduction of CD4+ T cells and the reduction of CD19+ B cells. The immune function of the elderly is weakened to due to the exhaustion of CD95 T cells, which are replaced with the clonal expansion of CD28- T cells. The increase of pro-inflammatory cytokines is associated with dementia, Parkinson's disease, atherosclerosis, type 2 diabetes, sarcopenia, and a high risk of morbidity and mortality. A correct modulation of immune responses and apoptotic phenomena can be useful to reduce age-related degenerative diseases, as well as inflammatory and neoplastic diseases.


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