Increased immunosuppression impairs tissue homeostasis with aging and age-related diseases

Chronic low-grade inflammation is a common hallmark of the aging process and many age-related diseases. There is substantial evidence that persistent inflammation is associated with a compensatory anti-inflammatory response which prevents excessive tissue damage. Interestingly, the inflammatory state encountered with aging, called inflammaging, is associated with the anti-inflammaging process. The age-related activation of immunosuppressive network includes an increase in the numbers of myeloid-derived suppressor cells (MDSC), regulatory T cells (Treg), and macrophages (Mreg/M2c). Immunosuppressive cells secrete several anti-inflammatory cytokines, e.g., TGF-beta and IL-10, as well as reactive oxygen and nitrogen species (ROS/RNS). Moreover, immunosuppressive cells suppress the function of effector immune cells by catabolizingl-arginine and tryptophan through the activation of arginase 1 (ARG1) and indoleamine 2,3-dioxygenase (IDO), respectively. Unfortunately, the immunosuppressive armament also induces harmful bystander effects in neighboring cells by impairing host tissue homeostasis. For instance, TGF-beta signaling can trigger many age-related degenerative changes, e.g., cellular senescence, fibrosis, osteoporosis, muscle atrophy, and the degeneration of the extracellular matrix. In addition, changes in the levels of ROS, RNS, and the metabolites of the kynurenine pathway can impair tissue homeostasis. This review will examine in detail the harmful effects of the immunosuppressive cells on host tissues. It seems that this age-related immunosuppression prevents inflammatory damage but promotes the tissue degeneration associated with aging and age-related diseases. Key messages center dot Low-grade inflammation is associated with the aging process and age-related diseases. center dot Persistent inflammation activates compensatory immunosuppression with aging. center dot The numbers of immunosuppressive cells increase with aging and age-related diseases. center dot Immunosuppressive mechanisms evoke harmful bystander effects in host tissues. center dot Immunosuppression promotes tissue degeneration with aging and age-related diseases.

Automated summary

1. Low-grade inflammation is associated with aging and age-related diseases. 2. Persistent inflammation activates compensatory immunosuppression with aging. 3. The numbers of immunosuppressive cells increase with aging and age-related diseases. 4. Immunosuppressive mechanisms evoke harmful bystander effects in host tissues. 5. Immunosuppression promotes tissue degeneration with aging and age-related diseases.