ADAR1 in Immunity and Aging
This short overview skims recent work on the role of ADAR1 expression in aging. Levels of ADAR1 are reduced with age in many tissues, and this may affect a number of processes relevant to aging, such as cellular senescence. ADAR1 edits RNA, affecting the behavior of gene expression at a very low level. It is a good example of a protein that is thus involved in many, many processes in the cell, and which has indirect effects on any number of cell behaviors. It is exceptionally challenging to pin down specific important roles for such proteins. There is such a large space of possibilities to cover that decades of work may or may not arrive at the crucial realizations and studies that turn out to demonstrate a possible way forward to intervene in aging.
Researchers recently published five papers on the function and molecular mechanism of ADAR1 (adenosine deaminases acting on RNA) in aging, cancer, and autoimmune diseases. Four of the papers revealed that ADAR1 regulates autoimmune disease and cancer immunotherapy through canonical adenosine-to-inosine (A-to-I) RNA editing. Using a different approach, the fifth paper discovered that ADAR1 could suppress cellular senescence by regulating p16INK4a expression through an RNA editing independent pathway.
Researchers found that ADAR1 could promote the interaction between human antigen R (HuR) and SIRT1 mRNA, thereby increasing the stability of SIRT1 mRNA. The elevated SIRT1 expression, in turn, suppresses the translation of p16INK4a mRNA, thus inhibiting the occurrence of senescence. However, in aging cells, ADAR1 is degraded by lysosomal-mediated autophagy. Researchers found that the protein level of ADAR1 in the brain, ovary, and other tissues of aging mice was significantly lower than that of young mice. Because the ADAR1 mRNA expression level did not change significantly, this result indicates that the down-regulation of ADAR1 expression during aging mainly happened at the post-transcriptional level.
The researchers also found that applying small molecule inhibitors targeting the lysosomal autophagy pathway in aging cells could inhibit the loss of ADAR1 expression due to aging. Overall, the study revealed a novel mechanism of autophagy in promoting aging and indicated that the altered ADAR1 expression might be a biomarker of aging. Importantly, modulating ADAR1 expression levels may be potent in treating aging-related diseases.