Immunosenescence is the age-dependent deficiency in the immune system functioning. This is one of the most important components of the aging of the whole organism, and it is based on the deregulation of a complicated protein system. One of the key proteins is interleukin 7 (IL-7), which is the subject of this review.
Authors: Vanloan Nguyen, Andrew Mendelsohn, and James W. Larrick
One's chronological age is an important, independent risk factor for many of the most common diseases afflicting the aging population of the world. Thus, understanding the central mechanisms driving senescence may have global impact to improve healthspan and reduce healthcare costs. A diverse group of degenerative pathological processes contribute to the decline and dysfunction of multicellular organisms. Among these are fibrosis, calcification, stem cell drop-out, nonenzymatic glycation, degradation of extracellular matrix (ECM), compromised mitochondrial biogenesis, loss of tissue homeostasis, and uncontrolled inflammation. Immunosenescence is the lifelong reduction in immunological reserve and homeostasis. This process contributes to reduced resistance to infectious diseases (e.g., pneumonia, influenza, meningitis, and urinary tract infections), increased propensity to develop cancer, and increased autoimmune disease (e.g., rheumatoid arthritis, thyroiditis, systemic lupus erythematosus, and multiple sclerosis) observed in aged individuals. Furthermore, immunosenescence limits the success of medical interventions such as vaccination and efforts to augment antitumor immunity. Attempts to pinpoint a single "cause" of senescence in general and immunosenescence in particular have met with limited success. However, recent studies support a critical role for IL-7 in the maintenance of a vigorous healthspan and have identified IL-7 and its receptor and associated proteins, "the IL-7 network," as a useful biomarker of successful aging [1].
To understand the IL-7 network, we begin with a description of IL-7, the IL-7 receptor, and downstream signal transduction. We document how aging affects various parts of the immune system, B cells, T cells, and so forth, in an effort to understand which aspects of the elegant immune mechanism are most vulnerable and connected to IL-7. Next, we examine mechanisms of immunosenescence through the prism of the "molecular and cellular hallmarks of aging" as defined by Lopez-Otin et al. [2]. Among these hallmarks are as follows: (a) increasing damage to DNA, (b) genomic instability and epigenetic changes, (c) telomere shortening, (d) stem cell exhaustion, (e) limited capacity for regeneration, (f) loss of proteostasis, (g) senescence of cells (e.g., Hayflick limit), and (h) altered communication between cells, tissues, and organs. Each of these mechanisms (and probably more!) contributes to the development of immunosenescence. Finally, we describe efforts to utilize the IL-7 axis for therapeutic purposes. While initial attempts to develop therapeutics based on the IL-7 network have met with limited success, efforts are ongoing to harness the pleiotropic activities of this "lympho-homeostatic" cytokine.
... To optimize health and lifespan, it may be useful to "thread the needle," lowering IL-7R enough to preserve peripheral T cells and help maintain low mTOR levels, while maintaining enough to maintain immune function. Transient modulation of IL-7R is one potentially effective strategy to reach this goal. Another possible conclusion is "correlation is not causation" and that the genes of IL-7/IL-7R complex are only part of the answer.
The remarkable plasticity of the adaptive immune system over many decades is a testament to several intrinsic features of its design. Despite attacks on its integrity from multiple angles, the size and diversity of the naive lymphocyte repertoire is maintained well into the 9th decade of life. While IL-7 is a necessary contributor to this "lympho-homeostasis" and its action is required for successful aging, wholesale augmentation of IL-7 above "normal" levels may disrupt this delicate balance. Numerous animal and several human studies suggest much promise remains for the utilization of IL-7 as a specific "immune tonic" or adjuvant. To this end, we look forward to the next generation of improved IL-7-based therapeutics.
