The likelihood of developing chronic inflammatory and autoimmune diseases, such as rheumatoid arthritis and inflammatory bowel disease, rises sharply among people over 50. This is due, in part, to the declining effectiveness of the specialized cells that suppress overactive immune responses. Researchers at Albert Einstein College of Medicine have discovered the mechanism underlying this decline.

The Einstein scientists, led by the late Fernando Macian-Juan M.D., Ph.D., and  Ana Maria Cuervo, M.D., Ph.D., found that regulatory T cells, or Tregs, which normally tamp down an overactive immune system, become less effective with age due to the loss of chaperone-mediated autophagy (CMA). This cellular recycling process, which slows with age, eliminates old or defective proteins that otherwise accumulate and interfere with normal cell function. The findings, published on May 22 in Nature Communications, stemmed from the work of Ranee Harrison, Ph.D., and Floralba Gjergjova, M.S., co-mentored by Drs. Macian-Juan and Cuervo.

Using mouse models for inflammatory bowel disease, the researchers showed that mice deficient in CMA in Tregs developed inflammation in multiple organs, had shorter lifespans, and experienced a rapid worsening of the disease. They also found that pharmacologically activating CMA in aged mice restored the suppressive activity of Tregs and reduced inflammatory changes associated with aging, suggesting that CMA could represent a promising therapeutic target.

Using proteomic analysis, the investigators found that, in addition to regulating proteins important for Treg function, CMA also regulates protein synthesis by directly mediating the levels of FTO, an enzyme that modulates the stability and translation into proteins of many mRNAs. These findings uncover a new link between cellular protein degradation and RNA methylation pathways that help control immune function.

The study was initiated by Dr. Macian-Juan and completed through a collaboration among the Macian and Cuervo laboratories and Simone Sidoli, Ph.D., associate professor of biochemistry. Dr. Cuervo, the study’s senior author, is a distinguished professor of developmental & molecular biology and of medicine, the Robert and Renee Belfer Chair for the Study of Neurodegenerative Diseases, and co-director of the Institute for Geroscience at Einstein.