Here, researchers discuss data that sheds light on the way in which age-related declines in autophagy, related mitochondrial dysfunction due to impairment of mitochondrial autophagy, and decline of the immune system might interact with one another. With advancing age, the immune system becomes less capable but ever more overactive, constantly in a state of inflammation without resolution. The evidence here suggests a progressive failure to remove damaged mitochondria to be a contributing cause of that chronic inflammation, at least in a subset of T cells of the adaptive immune system. It isn't completely settled that mitochondrial autophagy is involved, however.
The aging organism develops a chronic state of initially smoldering and then progressively overt inflammation that contributes to the aging process and thus has been nicknamed "inflammaging". A recent paper reveals that purified CD4+ T lymphocytes from healthy, lean, older (57-68 years) donors produce more TH17-associated/supportive cytokines (IL-6, IL-17A, IL-17F, IL-21, and IL-23) than cells from younger (28-38 years) subjects - a TH17-linked cytokine hyperproducer phenotype (TH17-CHP).
The overarching cause of TH17-CHP appears to be reduced autophagy of mitochondria, which compromises mitochondrial turnover and quality control, as indicated by an increase in mitochondrial mass, an increase in the proton leak, and a reduction in the mitochondrial inner transmembrane potential. In addition, mitochondria contained in CD4+ T cells from older donors exhibited an enhanced basic and maximal oxygen consumption, correlating with reduced glycolytic lactate production, enhanced production of reactive oxygen species (ROS). Conversely, knockdown of the essential autophagy gene ATG3 (but not that of PINK1, a gene specifically involved in mitophagy) inhibited autophagy in CD4+ T cells from younger subjects, inducing TH17-CHP similar to the one spontaneously found in CD4+ T cells from older donors.
Altogether, these results have important conceptual and clinical implications at several levels. They suggest yet another causal link between "normal" aging and deficient autophagy involving a vicious cycle in which aging causes an autophagy defect that then aggravates the aging phenotype. Here, it appears that aging compromises autophagy in CD4+ T lymphocytes to stimulate the secretion of several pro-inflammatory interleukins, thus contributing to inflammaging. However, it remains to be determined in preclinical experiments, in mouse models, whether a selective autophagy (or mitophagy) defect solely affecting CD4+ cells would be sufficient to cause TH17-CHP in vivo and accelerate the aging process. As it stands, it appears that autophagy has rather broad anti-inflammatory effects, notably by avoiding the spill of mitochondrial or nuclear DNA into the cytoplasm (to avoid activation of the cGAS/STING pathway) or by inhibiting excessive activation of the NLRP3 inflammasome.