Examining the role of growth differentiation factors, senescence-related proteins and physical activity intervention in clinical outcomes

Feb. 05, 2019

The identification of proteins that both accelerate and delay the emergence of aging-related phenotypes, at least in preclinical models, is a significant recent development in the field of geroscience. Translation of this work to humans is critical to answer key questions about the role of these proteins: Do they associate with or predict important clinical outcomes and, if so, do they represent targets for novel and transformative therapeutic interventions to extend health span?

To address these questions, Nathan K. LeBrasseur, Ph.D., M.S., and colleagues at Mayo Clinic recently began a clinical study funded by the National Institutes of Health. The study involves 1,500 older adults with mobility limitations and is examining whether growth differentiation factors (GDFs) and the senescence-associated secretory phenotype (SASP), or their associated components, serve as indicators of biological age and age-related conditions in humans.

Dr. LeBrasseur is co-chair of research, Physical Medicine and Rehabilitation, at Mayo Clinic's campus in Rochester, Minnesota. His research team studies the genes and signaling pathways influencing skeletal muscle growth and metabolism and how their manipulation — by genetic alteration, diet, drugs or exercise — affects these physiological processes.

Research hypothesis, study methods and related work

The team's central hypothesis is that circulating concentrations of GDFs and several SASP proteins are associated with, and predictive of, clinically important health outcomes and can be altered by physical activity. The team is testing this hypothesis using samples from the Lifestyle Interventions and Independence for Elders (LIFE) Study. The LIFE Study is the largest and longest randomized trial of a physical activity intervention in older adults. The team will validate findings through analyses of approximately 1,000 samples from the Health, Aging and Body Composition (HABC) Study.

"Our approach is founded on the considerable evidence that impaired tissue regeneration and cellular senescence are hallmarks of aging," explains Dr. LeBrasseur. Myostatin (GDF8) and GDF11 are circulating factors that influence muscle rejuvenation, vascular remodeling and neurogenesis in mice. Dr. LeBrasseur notes that in prior research study results published in Cell Metabolism in 2016, Mayo Clinic researchers reported inverse correlations between GDF11 levels and measures of physical function in older adults. And they also obtained preliminary data about the role that these GDFs may play in cognitive health.

"Senescent cells can also impact a tissue's regenerative potential, and the SASP has been implicated in multiple chronic diseases," explains Dr. LeBrasseur. "Our recent studies have shown that removal of senescent cells and suppression of the SASP in mice delay the onset of aging-related phenotypes and extend life span. Additionally, biomarkers of senescence are inversely correlated with physical activity levels in humans, and we have shown that exercise intervention prevents senescence in mice," says Dr. LeBrasseur. Results for these studies were published in Nature Medicine in 2017 and 2018, and in Diabetes in 2016.

Diverse components of the SASP, including cytokines, chemokines, matrix remodeling proteins and growth factors, can be reliably measured in human plasma using standard antibody-based methods. However, GDF8 and GDF11 are 90 percent identical in amino acid sequence and circulate in very low concentrations, so they require an analytical method with far greater specificity and sensitivity. To address this challenge, Dr. LeBrasseur notes that the team has developed a novel assay to accurately quantify GDFs in small volumes of human plasma.

Specific aims

According to Dr. LeBrasseur, the current study leverages two unique yet complementary study cohorts, state-of-the-art methods and a multidisciplinary team to pursue three specific aims:

To determine the extent to which baseline concentrations of GDFs and SASP proteins are associated with baseline measures of the following:
- Physical function, including gait speed and Short Physical Performance Battery (SPPB) scores
- Cardiopulmonary function, including blood pressure and forced expiratory volume (FEV)
- Cognitive function, including processing speed and memory
- Combinations of chronic conditions, such as multimorbidity, documented in the LIFE and HABC studies
To establish the degree to which baseline concentrations of GDFs and SASP proteins predict longitudinal changes (over two to four years) in the following:
- Gait speed and SPPB scores
- Major mobility disability (such as the inability to walk 400 meters)
- Combined cardiovascular events (including myocardial infarction, heart failure, stroke, peripheral artery disease)
- Adjudicated falls and injurious falls
- Cognitive function
- Number of chronic conditions documented in the LIFE and HABC studies
To measure the impact of a structured physical activity intervention on longitudinal changes in GDFs and SASP, compared with that of a health education control intervention, and to assess the degree to which changes in the concentrations of these proteins parallel changes in the health outcomes described in specific aim 2.

Dr. LeBrasseur and colleagues are hopeful that the study findings will have a direct and far-reaching impact on clinical practice. "Overall, we expect this work to fill a critical translational gap in our understanding of how evidence-based modifiers of biological aging — GDFs and senescence-related proteins — predict and potentially mediate chronic disease and disability in humans. We hope to advance basic science discoveries toward truly innovative and transformative clinical interventions to extend human health span."