Ali Javaheri, M.D., Ph.D.

INTRODUCTION

The overarching goal of the Longer Life Foundation Longevity Research Program (LLF-LRP) at Washington University in St. Louis (WashU) is to conduct and stimulate new leading-edge research that supports LLF’s mission to “identify factors that either predict the mortality and morbidity of selected populations or influence improvements in longevity, health, and wellness.”

During the last few years, LLF-LRP has focused on the mechanisms involved in age-related sarcopenia and cardiometabolic diseases, specifically pre-diabetes/diabetes and atherosclerotic vascular disease, which reduce quality of life and are the leading causes of death, and evaluated how nutrition affects these processes.

The current aims of LLF-LRP are.

• Aim 1: Evaluate the effect of high protein intake and amino acids on factors involved in atherogenesis (mTOR signaling to autophagy/mitophagy in circulating monocytes/macrophages and platelets, endothelial cell biology).
• Aim 2: Strengthen existing and establish new collaborations with the goal of generating preliminary data for grants that support research studies that serve LLF’s mission.

PLANS

During the next year, we will continue to conduct the research we proposed in Aim 1 (evaluate the effect of high protein intake and amino acids on factors involved in atherogenesis) and will continue networking and career development activities. We also plan to apply for an NIH U19 award (PAR-22-213, Complex Multi-Component Projects in Aging Research) to evaluate new putative therapeutic strategies to improve cardiometabolic and physical function in older adults that will use preliminary data from studies that were supported by LLF-LRP. In addition, we plan to design experiments and initiate preliminary studies to evaluate whether increasing dietary protein intake during chemotherapy can mitigate the adverse effects of chemotherapy on heart and skeletal muscle cells. About 10 million people with cancer globally receive chemotherapy every year and that number is projected to increase sharply within the next decade. Although chemotherapy is highly effective in destroying tumor cells, commonly used chemotherapy agents such as anthracyclines can also damage healthy cells, including both cardiac and skeletal myocytes, which can lead to cardiac and skeletal muscle atrophy and dysfunction and increases risk of cardiac events and physical frailty.

It has been demonstrated that transcription factor TFEB is necessary and sufficient to cause anthracycline-related myocyte damage. TFEB is a downstream target of mTOR and becomes inactive when phosphorylated by mTOR. Dietary protein, through the subsequent rise in circulating amino acids, is a potent stimulator of mTOR signaling in myocytes.

Therefore, it stands to reason that high protein intake during chemotherapy will inactivate TFEB and prevent the adverse effects of chemotherapy on cardiac and skeletal myocytes. This research direction represents a logical evolution of the work we have conducted over the past few years and is a direct result of Dr. Mittendorfer’s networking and her vision to broaden the LLF-LRP’s scope and impact as proposed in Specific Aim 2. It also accommodates a change in personnel that occurred during the current funding cycle. First, Dr. Babak Razani, who was a basic science and physician collaborator on the LLF-LRP award, recently moved to the University of Pittsburgh. In the meantime, Dr. Mittendorfer has begun collaborating with Dr. Ali Javaheri, a former LLF P&F awardee, and like Dr. Razani, a cardiologist and a basic science, physician investigator with research focus on heart failure and cardiotoxicity. After Dr. Razani’s departure, Dr. Javaheri has provided expertise in clinical medicine and basic science research. His involvement in the LLF-LRP has stimulated new research ideas concerning the impact of dietary protein on skeletal muscle and cardiometabolic function in selected populations (i.e., patients with cancer).

Second, Dr. Mittendorfer has been recruited to MU in Columbia, Missouri as the NextGen Professor of Nutrition and Exercise Physiology, Director of the Clinical and Translational Science Unit, and Senior Associate Dean for Research at the MU School of Medicine. A major mission of Dr. Mittendorfer’s new position will be to strengthen and expand the already existing partnerships between WashU and MU to help investigators at both institutions to maximally leverage the resources at both locations. It is therefore anticipated that Dr. Mittendorfer will continue as an investigator on the LLF-LRP even after her relocation to MU later this year (without pay; her salary will be covered by funds at MU) and Dr. Javaheri will take on additional responsibilities and transition into the role of Multi-PI of the LLF-LRP. Dr. Javaheri’s involvement in the LLF-LRP will benefit the LLF-LRP, because of his research and clinical expertise and research focus that aligns with the LLF-LRP. In addition, he is well integrated into the WashU research community and has many connections. Furthermore, he has demonstrated great willingness to collaborate, support trainees, and further the mission of the LLF-LRP. Being part of the LLF-LRP leadership team will also serve as a catalyst for Dr. Javaheri’s career progression. These plans have been discussed with the LLF scientific review committee and will ensure a highly productive continuation of the LLF-LRP and will retain the longstanding research focus of the LLF-LRP.