Age-Impaired Autophagy Makes CD4+ T Cells Inflammatory

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.

Link: https://doi.org/10.1016/j.cmet.2020.04.016

Comments

off topic but I fear the shutdown of economy may reduce our, we who are young chance to reach LEV. We should not close down whole society. Labs working on other then cover vaccine have been shut down. Many more lives of the young are at risk of dying decades ahead if we don't open economy. We can't have it this way. Ive already had covid. It lasted 7 weeks. I felt like a moderate influenza. Im 45 yo.

Posted by: Gekki at May 26th, 2020 9:53 AM

@gekki
While for sure there's a some slowdown don't forget that a lot of scientific research is done by processing information alone (can be done from home)
And a lot of laboratories are rarely crowded with people and require sanitary measures anyway.

Therefore, the showdown might not be that severe after the initial shock and adjustments.

Besides , the economy starts to reopen slowly in a lot of places.

Posted by: Cuberat at May 26th, 2020 10:37 AM

Why does autophagy decline in the first place?

Posted by: Jimofoz at May 26th, 2020 11:51 AM

@Jimofoz
Some of this decline is induced, or at least aggravated, by the ROS and other damage.

Now the question might be why the repair mechanisms don't work well enough...

Posted by: Cuberat at May 26th, 2020 2:22 PM

Autophagy require the lysosomes to be working well, and with age the lysosomes get filled up with gunk which they don't know how to break down. This not only gets in the way, but also causes the pH in the lysosome to rise, causing digestive enzymes in it to stop working. Once this happens, the lysosomes just aren't going to be very good a breaking down damaged organelles.

Posted by: Arcanyn at May 29th, 2020 7:08 AM

Post a comment; thoughtful, considered opinions are valued. New comments can be edited for a few minutes following submission. Comments incorporating ad hominem attacks, advertising, and other forms of inappropriate behavior are likely to be deleted.

Note that there is a comment feed for those who like to keep up with conversations.