Getting older can affect the heart, kidneys, and other important organs, leading to health problems and a decreased quality of life. Although aging is a natural process that every living person goes through, little is known about what causes our bodies to age.
Daniel Jane-Wit, MD, PhD, associate professor of medicine (cardiovascular medicine) and immunobiology, is investigating how a group of proteins may impact the aging process.
With new grant funding from the American Federation for Aging Research (AFAR) and collaboration with Yale faculty from Y-AGE Institute and the Yale Pepper Older Americans Independence Center, Jane-Wit hopes to understand more about what causes our bodies to age and how we might be able to one day block or slow this process.
1. Tell me about your research.
Each person has a set of nine immune proteins called complement proteins, which are made in the liver and circulate in the bloodstream around our bodies.
When complement proteins become activated, they form pores called membrane attack complexes or MACs. Past research on MACs has mainly focused on their roles in bacterial infection. Researchers observed that MACs formed pores to kill bacteria. Thus, it has been long thought that MACs cause inflammation during aging by killing cells.
Our research found that the MAC proteins can become internalized into aging cells, and this overwhelms the cell’s ability to effectively cope with these proteins. This causes MAC proteins to form aggregates inside cells. Protein aggregates can compromise cell function and are associated with Alzheimer’s and Parkinson’s disease. So, rather than killing cells, MAC proteins may form aggregates that might accelerate the aging process.
2. What prompted you to investigate this topic?
This is a new area of research for me. Our lab typically studies solid organ transplants. Complement protein activity is a significant component of transplant rejection and has diagnostic, prognostic, and therapeutic value in transplant patients. I was able to use my knowledge of complement protein activity in transplant rejection to study the aging process.
As a cardiologist who primarily sees older adults at the VA, many of my patients have exposures to ischemic injury, trauma, and toxins that cause cell injury. Many of these exposures may cause complement proteins to become active, leading to advanced aging. It is my hope that the research that I do may help us understand how aging occurs in these patients.
All of us are getting a little older, and as we age, we start to realize that we are becoming closer to the end than to the beginning. This research into the processes of longevity will likely apply to all of us.
3. What is next for your research on aging?
We recently published a paper in Kidney International showing that a protein activated by complement aggregates called ZFYVE21 also accelerates aging and causes a significant decline in renal function. We are in the process of trying to understand how exactly the complement aggregates cause inflammation. More specifically, we are searching for how cells can detect the presence of complement aggregates. Once we understand this more deeply, we might be able to exploit these findings to block or slow protein aggregation.
Moving forward, I hope to form collaborations with others at Yale and at the VA who study aging. There are many patient-related resources and experimental tools that are related to aging that are far beyond the current capabilities of the lab.
4. What do you hope people take away from your research?
I would really like for other researchers to reproduce what we found and to show that our discoveries are relevant to aging. I feel that complement is an underappreciated area of research and I hope that begins to change. I really believe that complement is very important to the aging process.
I also hope that this research opens up new diagnostic strategies for patients. The FDA recently approved drug-blocking protein aggregates for Alzheimer’s disease and AL amyloidosis, and orally available complement drugs might be able to block complement aggregates in select older patients.
I wanted to say thank you to my section leaders in the Section of Cardiovascular Medicine, Drs. Eric Velazquez and Steven Pfau who have supported my research by giving me a lot of protected research time.
I also wanted to thank Dr. Thomas Gill and Denise Acampora from the Yale Pepper Center, and Dr. Vishwa Deep Dixit who leads the Y-AGE initiative. I hope that I, as well as the other recipients of the Hevolution funding award at Yale, may be able to contribute to the success of these research centers.