A Bidirectional Relationship Between Cellular Senescence and Immune System Aging

The pace of age-related loss of function and consequent mortality accelerates over time, picking up particularly rapidly in later life. This is characteristic of systems in which multiple processes feed into each other. A causes B, but B also makes A worse. In the biology of aging there are many more than two processes at work, but the authors of today's open access paper picked two areas of aging in order to examine their bidirectional relationship. Firstly the accumulation of senescent cells, and secondly immunosenescence, the age-related decline of immune system function.

Cells become senescent constantly in the body, largely as a result of somatic cells reaching the Hayflick limit on replication. Wound healing, potentially cancerous molecular damage, and the signaling of other senescent cells are also relevant causes of cellular senescence. Some senescent cells self-destruct, while others are destroyed by the immune system. That immune surveillance of senescent cells becomes slower and less effective as the immune system falls into immunosenescence in later life, allowing for senescent cell accumulation.

Equally, senescent cells secrete inflammatory, disruptive signaling that causes chronic inflammation as well as harmful changes in cell behavior in the hematopoietic system responsible for generating new immune cells. Inflammation also contributes to the involution of the thymus, where T cells mature, accelerating the decline of adaptive immune function by reducing the supply of new T cells. Further, immune cells themselves become senescent in increasing numbers, a response to the burden of too much cell replication and too few replacement cells.

It is plausible that these mechanisms indicate that the progression towards immunosenescence leads the accumulation of senescent cells in the early dance of cause and effect in mid-life, before everything in the body becomes so broken that it is hard to say what is most responsible. It is very hard to assign appropriate blame to interacting mechanisms of aging without a way to eliminate one of them at a time and observe the results, however. Intuition is rarely useful. With the advent of senolytic therapies to clear senescent cells, it should be possible to say with certainty at some point as to whether immunosenescence is upstream of cellular senescence in aging. Few researchers are looking at the details of cellular senescence or immune system decline at early stages in the aging process, however.

Cellular senescence in lymphoid organs and immunosenescence

The immune system is a complex network of cells and tissues working in coalition to maintain the health of an organism. It not only clears foreign pathogens, but also helps to maintain the integrity of the organism by clearing away dead or dysfunctional cells. Like any other system, the immune system changes with age and experiences gradual deterioration. Improving our understanding of this phenomenon is of great significance. Aging of the immune system is also one of the major factors that accelerates the deterioration of an organism, as its dysfunction not only fails to elicit a strong immune response against invading pathogens but also drives the accumulation of undesirable and malfunctioning cells.

From an evolutionary perspective, cellular senescence is widely considered to be a protective mechanism to prevent stressed and damaged cells from becoming deleterious to the body. Like most things optimized by evolution, cellular senescence is not of much concern to the younger body capable of reproduction while the older body, past its reproductive prime, is adversely affected by it. The fitness benefits that cellular senescence provides to younger, reproductively active animals, such as preventing cancer, mitigating the progression of fibrosis, and promoting optimal wound healing, have helped the phenomenon survive the arduous tests of natural selection over the millennia. Unfortunately, in almost an antagonistically pleiotropic manner, accumulation of senesent cells (SnCs) is very detrimental to the older body. Specifically, SnCs secrete various factors classified together as the senescence-associated secretory phenotype (SASP) which cause instability and dysfunction in their surrounding environment.

The interactions between SnCs and the immune system run in both directions, with the immune system surveilling and clearing the SnCs; while the SnCs frequently impede the function, and in some contexts, generation of immune cells. In young and healthy individuals, the immune system can rapidly clear SnCs after their induction, which prevents them from significantly accumulating and causing adverse effects. In older individuals, this turnover is slow and leads to the accumulation of SnCs. It has been demonstrated that accumulation of SnCs is accelerated upon impaired immune surveillance. Since advancing age is associated with impairment in immune function, the decline in the turnover of SnCs with age can, at least partially, be attributed to this impediment. Despite multiple studies demonstrating various mechanisms via which SnCs could evade immune clearance, the impact of aging on immune evasion of SnCs is not yet completely understood.

Of note, SnCs have been shown to cause stem cell exhaustion, and dysfunction. This is of great relevance and importance to the topic of immunosenescence because senescence, exhaustion, and dysfunction of hematopoietic stem cells (HSCs) causes myeloid skewing and a decrease in the production of immune cells which may be one of the underlying causes of age-related immunosenescence. However, even at an organ level, the age-associated changes that contribute to immunosenescence are multifaceted with a wide variety of undesirable phenotypic manifestations. Thus, it would be ill-advised to address each of these problems individually. A more feasible and effective way to deal with immunosenescence would be to tackle the fundamental aspects of aging that drive immunosenescence. With studies showing that clearing SnCs can rejuvenate entire tissues and organs of the aged immune system, cellular senescence is certainly one such fundamental aspect, which has the potential to address immunosenescence.

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