The Future of Discovery in Aging
Barshop Institute Leads Revolution in Geroscience
Most of us consider aging inevitable, and there is nothing we can do to stop it. Research at the Sam and Ann Barshop Institute for Longevity and Aging Studies has demonstrated that there are several interventions that can slow or even reverse the aging process. The most renowned example of this is research by Z. Dave Sharp, Ph.D., and Randy Strong, Ph.D., at the Barshop Institute, in conjunction with scientists from the University of Michigan and The Jackson Laboratory, demonstrating the first anti-aging compound ever described, rapamycin, provides hope that age does not have to result in permanent organ dysfunction.
Healthy aging is crucial for the nation, since the 65 and over population will nearly double from 43 million in 2012 to almost 84 million by 2050, according to the U.S. Census Bureau. This will have enormous implications for families, health care, the workplace, the marketplace, and our culture. It’s time to redefine what exactly we mean by “healthy aging,” in order to keep these individuals active and contributing to their families and their communities. The alternative, where older individuals are crippled by chronic disease, means that there will be an enormous health care price to pay in the next few decades, which will compromise many other medical efforts.
The Barshop is leading the discovery of the scientific mechanisms of aging and the enormous potential for aging well. The impact of our aging population on health care motivates Nicolas Musi, M.D., director of the Barshop Institute. “UT Health San Antonio, the state, philanthropic organizations, and the National Institutes of Health (NIH) have invested heavily in aging research knowing the importance of maintaining good health as we age,” Dr. Musi says. “The idea of the Barshop Institute is to help people age in a healthier, happier and more productive way by expanding the knowledge frontier on aging biology while training the next generation of researchers. Our objective is to better understand the mechanisms that control aging in order to develop novel ways for promoting healthy aging and for the prevention and treatment of the diseases of aging.”
Research at the Barshop has shown that aging is a relative term, where older age does not necessarily have to mean frailty and chronic disease. “It has become clear that aging, in terms of how long and how healthy we can live, is something that is modulated and regulated through our genes and through our interactions with the environment,” Dr. Musi says. “If we understand aging at the molecular level, we can target it and promote healthier life extension.”
Growing evidence demonstrates that aging can be regulated through both exercise and therapeutics. “We are at the forefront in doing research on the emerging concept of translational geroscience,” Dr. Musi says. The field of geroscience recognizes that as we grow older we often accumulate multiple small insults to our organs that result not just in chronic fatigue and frailty which decrease our quality of life but also generate life-threatening heart disease, diabetes and cancer. Geroscience seeks to illuminate the molecular mechanisms behind the aging process that makes it a major risk factor for many chronic, debilitating diseases. For example, the single worst prognostic factor in most types of cancer is the age of the patient, regardless of the overall health of the patient.
“It’s a very novel concept in understanding the biology of aging and targeting it to achieve maximum healthy lifespan,” says Dr. Musi. “We’re using drugs like senolytics, rapamycin and metformin, for example, to target age-related diseases like Alzheimer’s, diabetes and cancer.”
The concept of senolysis, the killing of senescent cells, is revolutionizing aging research, because it provides hope that aging can be reversed, Dr. Musi said. Senolytics are drugs that target senescent cells, which are alive but cannot divide anymore and no longer perform their function. These “zombie” cells continually release inflammatory cytokines into the healthy tissues that surround them, causing oxidative damage in these healthy cells. This damage results in further senescent cells and increases the rate of organ dysfunction.
Rapamycin is the most powerful anti-aging drug yet described. It may decrease the damage of aging by decreasing the response to the inflammation caused by the senescent cells. Researchers at the Barshop have also shown the Abl kinase inhibitor dasatinib may be senolytic. In addition, drugs such as navitoclax that target BCL-XL, a protein that senescent cells use to stay alive, can induce senescent cells to commit suicide. There is some evidence that these senolytics can reverse the aging process and prolong the function of many types of organs. Combining these drugs may be even more effective, and there could be a time when everyone is on these types of drugs.
Prescriptive exercise may be at least as powerful a therapy as rapamycin. The NIH-funded Molecular Transducers of Physical Activity Consortium (MoTrPAC) is one of seven core research centers under the Barshop Institute’s umbrella, and it is the largest clinical trial of its kind to explore the biological effects of exercise on both young and old, exercisers and non-exercisers. “Exercise controls thousands of molecular pathways, but we don’t really have a good catalog or map of these pathways,” Dr. Musi explains. Once these pathways are better understood, exercise could be tailored to better suit individual needs, or, in cases where a person is unable to exercise for medical reasons, researchers could intervene with compounds that work via similar mechanisms as exercise. Defining the molecular pathways triggered by aging is important because it can lead to treatments that mimic exercise for those whose activity is limited.
“We’re just at the tip of the iceberg in our understanding how muscles during exercise release substances to other tissues. For example, exercise is probably the most potent activator of stem cells in the brain. So, you can envision a future where these substances produced by exercise are administered to patients to treat certain brain diseases. We also know that people who exercise have lower rates of cancer, so knowing what substances are playing a role in that is another area of interest.”
Key discoveries include:
Anoop Nambiar, M.D., proposed and led a multi-site study (with Wake Forest and the Mayo Clinic) that first showed senolytics can be safely used against age-related pathologies. They were well tolerated and improved physical function in older adults with idiopathic pulmonary fibrosis, a lethal age-related pathology.
Miranda Orr, Ph.D., and Nicolas Musi, M.D., demonstrated for the first time a direct role of cellular senescence on tauopathies such as Alzheimer’s disease (AD), and improved brain function with the senolytic dasatinib in rodents. Phase 2 trials in human patients with early AD are underway.
Ellen Kraig, Ph.D., and Dean Kellogg, M.D., Ph.D., examined the feasibility of rapamycin administration in healthy older people (mean age 80 years). Rapamycin was well tolerated and did not impair immunologic, physical performance, or cognitive function. This work has laid the foundation for larger clinical trials of rapamycin for prostate cancer and Alzheimer’s disease.
Bess Frost, Ph.D., demonstrated that transposable elements in DNA (called “jumping genes”) are involved in the pathophysiology of Alzheimer’s disease. This discovery has led to Phase 1 human trials using anti-retrovirals (3TC) in patients with early Alzheimer’s disease.
Adam B. Salmon, Ph.D., and Corinna Ross, Ph.D., are leading a clinical trial in marmosets testing rapamycin’s effects on lifespan, health and pathology.
Sara Espinoza, M.D., M.Sc., is conducting a clinical trial of metformin vs. placebo for the prevention of physical frailty in older adults.
Grace Lee, Pharm.D., Ph.D., is leading a clinical trial testing whether metformin improves pneumococcal vaccine responses in older adults.
The Barshop Institute’s comprehensive approach to aging includes three National Institute on Aging-funded core centers including: the San Antonio Nathan Shock Center (basic biology), the San Antonio Claude D. Pepper Center (translational research), and the San Antonio Aging Interventions Testing Program (with a goal of testing four to five new compounds a year). The Barshop is the only institute in the nation to host all three of these centers. The Barshop Institute also hosts a National Institute on Aging-funded Training Program on the Biology of Aging that trains graduate students and post-doctoral fellows. Another source of funding is the Department of Veterans Affairs, since Barshop Institute investigators are members of the San Antonio Geriatric Research, Education and Clinical Center (GRECC) of the South Texas Veterans Health Care System.
“What makes us very unique,” says Dr. Musi, “is we’re the only institution that has this breadth of programs under one roof in which there is high-impact interaction and synergy. We work with very talented scientists and staff that are making new discoveries every day and with an institution that accelerates the pace of these discoveries so we can bring them to the clinical research arena in a much faster way.”