The immune system influences the function of tissues throughout the body. Immune cells are involved in tissue maintenance and wound healing, in the necessary day to day clearance of senescent cells, in the removal of cell debris and molecular waste. In some organs they have even more vital functions, such as assisting in the maintenance of synaptic connections in the brain. Further, immune cells produce inflammatory and anti-inflammatory signals that influence the behavior of other cells in numerous ways. Thus when the immune system runs awry and falters with age, the downstream consequences are pervasive and consequential.

The most obvious issue in immune system aging is a failing capacity to defend against pathogens. When all infections become more serious, causing more harm, this combines poorly with the diminished resilience of an older individual. But there is far more to immune aging than just this. A poor defense against infection is just one slice of the consequences. Arguably the most problematic issue is chronic inflammation, the continual inappropriate activation of immune cells and inflammatory signaling, normally beneficial and useful in the short term, but very harmful when maintained over the long term. Chronic inflammation accelerates the onset and progression of near all of the common fatal age-related conditions. It makes atherosclerosis worse, it drives the pathology of neurodegenerative conditions, it disrupts tissue maintenance.

All of this makes rejuvenation of the aged immune system a very desirable goal. Numerous possible approaches to this challenge are at various stages of development. Regrowth of the atrophied thymus in older individuals would restore the failing supply of new T cells of the adaptive immune system. Replacing damaged hematopoietic stem cell populations would boost the production of all types of immune cell. Selectively destroying damaged or misconfigured immune cells would prevent them from causing further harm. There are many different problem populations: age-associated B cells; senescent immune cells; exhausted T-cells; cells that have become reactive to proteins in ways that lead to autoimmunity; overly inflammatory microglia; and so forth.

The interplay between immunosenescence and age-related diseases

Aging is a major risk factor for the higher incidence and prevalence of chronic conditions, such as cardiovascular diseases, metabolic diseases, and neurodegenerative diseases. Chronic systemic sterile inflammation is crucially involved with the etiology and progression of these conditions. In the elderly, these conditions are often presented with multimorbidity and may finally lead to organ failure and death. With the advance of immunosenescence (aging of the immune system), older adults also become more susceptible to infectious diseases and cancer. Of note, T cell aging and low-grade inflammation (inflammaging) are implicated with several age-related conditions. The expansion of late-differentiated T cells (CD28-), regulatory T cells, increased serum levels of autoantibodies, and pro-inflammatory cytokines were implicated with morbidities during aging. Features of accelerated immunosenescence can be identified in adults with chronic inflammatory conditions, such as rheumatoid arthritis, and are predictive of poor clinical outcomes. Therefore, there is an interplay between immunosenescence and age-related diseases.

First of all, it is important to differentiate acute from chronic inflammatory processes. Acute inflammation is a transient and useful process aiming the elimination of pathogens and tissue regeneration, orchestrated by cells of the innate immunity. It is a self-regulated process with alarm, leukocyte mobilization, and resolution phases. But aging starts a chronic inflammatory process, known as “inflammaging”, with persistent and non-resolved production of pro-inflammatory mediators (cytokines, chemokines, and acute phase proteins) that increases the risk for age-related morbidity and mortality.

Although there are many sources of inflammaging, some evidence indicates the presence of overt infections during life to fuel inflammaging. Age-related intrinsic factors may also contribute to the inflammaging. When cells reach senescence, they produce cytokines, chemokines, growth factors, proteases, and angiogenic factors that characterize a senescence-associated secretory phenotype (SASP). As senescent cells accumulate during aging, SASP may also contribute to inflammaging. Inflammaging can be therefore interpreted as the complex result of the interplay between SASP, lifestyle factors, and of dysregulated innate immune cell functions with aging.

Not surprisingly, immunosenescence and SASP have been observed in older adults and during the developmental course of many immune-mediated conditions. Age-related diseases such as neurodegenerative diseases, rheumatoid arthritis, cardiovascular diseases, metabolic disorders, and cancer share common features of immunosenescence. Adverse effects of chronic low-grade inflammation increase the risk for the early appearance of diseases associated with age, suggesting that both aging and chronic (immune-mediated) diseases are interconnected states with common characteristics.