Interleukin-7 and Immunosenescence
Researchers here examine what is known of the role of interleukin-7 (IL-7) in the gradual decline and malfunction of the aging immune system. In the old, the immune system is both more active, producing chronic inflammation that drives the progression many of the most common age-related diseases, and at the same time less effective at carrying out its tasks. This is a major component of the frailty of old age. In the bigger picture, this is a story of molecular damage, misconfiguration of immune cells, and resulting disarray in the regulation of the immune response, but the low-level details of this progressive functional decay are still largely unmapped, such as how exactly the regulatory processes governing the immune system run off the rails.
Immunosenescence is the lifelong reduction in immunological reserve and homeostasis. This process contributes to reduced resistance to infectious diseases, increased propensity to develop cancer, and increased autoimmune disease 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.
IL-7 is a member of the common γ chain family of cytokines. The signaling cascade(s) initiated by these interleukins and their receptors (IL-7R in the case of IL-7) regulates homeostasis of B, T, and natural killer (NK) cells of the immune system. Immunosenescence affects multiple cells within the hematopoietic lineage. The result is a gradual deterioration of immune function with age. Disruption of the IL-7 signaling pathway plays a central role in this process. In the Leiden Longevity Study, survival analysis was carried out for low versus high IL-7R gene expression in 81 nonagenarians versus the combined group of 619 of their middle-aged offspring and controls. Among nonagenarians, high IL-7R gene expression is associated with reduced mortality over 10 years; that is, higher gene expression levels of IL-7R in blood predict better survival in both age groups. Seemingly, high levels of IL-7R are beneficial. It is as if there is a limited total supply of lymphocytes that can be induced by IL-7 over a lifetime. Consuming the lymphocytes in youth and middle age provides better health, with the caveat that it may limit the possibility of living to old age. Fewer/less active lymphocytes during middle age may increase the chance of disease somewhat but result in a large enough pool of lymphocytes in old age to promote viability. Perhaps IL-7R represents a case of antagonistic pleiotropy.
The notion that low IL-7R expression levels are beneficial for reaching healthy old age corresponds with previous observations that patients suffering from autoimmune disease express increased levels of the IL-7 receptor/ligand complex genes and that antagonizing IL-7 or IL-7R may offer possible treatments. However, the results of the Leiden Longevity Study found that gene expression levels of IL-7R decrease with chronological age. On the other hand, the Leiden study also found that higher levels of IL-7R correlate with reduced 10-year mortality and that effect was pronounced in the nonagenarian population in which individuals at the high end of the overall lower IL-7R expression lived longer. 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.