The mysterious, complex and inescapable process of aging often comes with chronic diseases like diabetes, heart disease and cancer. Recently, scientists at The University of New Mexico Comprehensive Cancer Center uncovered new details of the aging process. The team also discovered a new class of drugs that combats an important part of the aging process. Eric Prossnitz, PhD, led the UNM team that published its results in Science Signaling.
Prossnitz studies a receptor on our cells called the G protein-coupled estrogen receptor, or GPER. It determines in part how our cells respond to the hormone estrogen and to estrogen-like substances. GPER plays a role in diseases like breast cancer and diabetes. “GPER mediates many beneficial functions in physiology,” says Prossnitz. In one study, he found that making GPER more active in mice placed on a high fat diet reduced the development of atherosclerosis. Atherosclerosis is a condition in which the blood vessels harden and narrow. But another study’s results with old mice surprised him. That study led his team to the discovery of novel processes of aging and a new way to combat them.
In the surprising study, Prossnitz’s team observed mice that lacked GPER in all their cells as they aged. They tracked the mice over the normal mouse life span of about two years. They expected these mice to show increased levels of aging-related disease in their hearts and blood vessels. Instead, compared with normal aged mice, the GPER-lacking mice had healthier hearts and blood vessels. The team then conducted a series of experiments to learn why. They discovered an altered balance between certain signaling molecules in the smooth muscle cells of blood vessels and the heart.
One of those signaling molecules, superoxide, is a type of reactive oxygen species. Reactive oxygen species react quickly and strongly with nearby cellular proteins and impede those proteins’ ability to perform their tasks. Over time, the cell’s proteins and other components degrade enough to prevent normal cell functions. “Almost every disease of aging is influenced by reactive oxygen species,” says Prossnitz.
Prossnitz and his team next tested whether their patented GPER-blocking drug would improve smooth muscle cell function, as they observed in cells lacking GPER. They discovered that blocking GPER changed how the blood vessels’ smooth muscle cells expressed their genes. One of the genes that the drug affected produces a protein called NOX1. NOX1 produces superoxide, one of the most reactive molecules the body produces.
By blocking GPER, the team’s drug also blocked NOX1 expression, reducing the amount of superoxide the cell produced and reducing cellular aging. “It may not be a cure for aging,” Prossnitz says of the drug, “but it may greatly delay the aging process.”
The blood vessels of people, and mice, with chronic diseases like diabetes, heart disease and cancer show signs of accelerated aging. Several diseases, such as progeria, result from mutations which cause rapid aging. By preventing NOX1 expression to block a cell from producing excess superoxide, Prossnitz hopes to find a treatment for these conditions one day. That day is still a long way off— the drug must first be developed for human use and then thoroughly tested. But Prossnitz and his team hope to create a treatment based on this new GPER-blocking approach to help people live longer and better with chronic conditions.
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Eric Prossnitz, PhD, is a Professor in the Department of Internal Medicine at The University of New Mexico School of Medicine. He is The Victor and Ruby Hansen Surface Endowed Professor in Cancer Chemical Biology. Trained at the University of California at Berkeley and the Scripps Research Institute, Dr. Prossnitz is a world-renowned expert in receptor pharmacology and cancer biology. His laboratory identified a novel estrogen receptor, GPER, which plays an important role in cancers of the breast, ovary, and uterus. Having discovered unique small molecules that regulate GPER activity, his team is now studying GPER at the cellular and physiological levels to advance these drugs to clinical studies. Dr. Prossnitz has received the Excellence in Basic Research Award and the Dean’s Award of Distinction in Recognition of Outstanding Faculty Performance at UNM.
“Obligatory role for GPER in cardiovascular aging and disease” was published in the November 1, 2016 online edition Science Signaling (http://stke.sciencemag.org/). Authors include Matthias R. Meyer, Natalie C. Fredette, Christoph Daniel, Geetanjali Sharma, Kerstin Amann, Jeffrey B. Arterburn, Matthias Barton, and Eric R. Prossnitz.
The University of New Mexico Comprehensive Cancer Center is the Official Cancer Center of New Mexico and the only National Cancer Institute-designated Cancer Center in a 500-mile radius. Its 125 board-certified oncology specialty physicians include cancer surgeons in every specialty (abdominal, thoracic, bone and soft tissue, neurosurgery, genitourinary, gynecology, and head and neck cancers), adult and pediatric hematologists/medical oncologists, gynecologic oncologists, and radiation oncologists. They, along with more than 500 other cancer healthcare professionals (nurses, pharmacists, nutritionists, navigators, psychologists and social workers), provided cancer care for nearly 60 percent of the adults and children in New Mexico affected by cancer. They treated 11,249 patients in 84,875 ambulatory clinic visits in addition to in-patient hospitalizations at UNM Hospital. These patients came from every county in the State. More than 12 percent of these patients participated in cancer clinical trials testing new cancer treatments and 35 percent of patients participated in other clinical research studies, including tests of novel cancer prevention strategies and cancer genome sequencing. The 130 cancer research scientists affiliated with the UNMCCC were awarded almost $60 million in federal and private grants and contracts for cancer research projects and published 301 high quality publications. Promoting economic development, they filed more than 30 new patents in FY16, and since 2010, have launched 11 new biotechnology start-up companies. Scientists associated with the UNMCCC Cancer Control & Disparities have conducted more than 60 statewide community-based cancer education, prevention, screening, and behavioral intervention studies involving more than 10,000 New Mexicans. Finally, the physicians, scientists and staff have provided education and training experiences to more than 230 high school, undergraduate, graduate, and postdoctoral fellowship students in cancer research and cancer health care delivery. Learn more at www.cancer.unm.edu.
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