Islets of Langerhans cells, the source of numerous hormones, express the glucagon-like peptide 1 (GLP-1) receptor
“Many neurological disorders—Huntington’s, Parkinson’s, Alzheimer’s disease, even autism spectrum disorders—are often paired with metabolic and endocrine alterations,” explained Bronwen Martin, Ph.D. Type 2 diabetes, for example, is associated with an increased risk for developing Alzheimer’s disease. “My belief is that if we can understand this dysfunction and correct it, we can ultimately improve brain health.”
Martin is not alone in her conviction. As a postdoctoral fellow with Mark Mattson, Ph.D., at the National Institute on Aging (NIA), Martin was funded by the Huntington’s Disease Society of America to investigate novel endocrine-related strategies for the treatment of Huntington’s Disease. In collaboration with Josephine Egan, M.D., Martin was able to show improvements in a mouse model of Huntington’s Disease by administering a long-acting form of the gut hormone, glucagon-like peptide-1 (GLP-1). GLP-1 causes the release of insulin by the pancreas and also reaches the brain to exert neuroprotective effects. Martin subsequently extended her findings to mouse models of other neurological disorders.
Amyloid plaques are a hallmark of the Alzheimer’s brain
The GLP-1 receptor agonist that Martin used, exendin-4, is already prescribed as Byetta, an FDA-approved drug for type 2 diabetes. As a result of basic studies carried out within the NIA Intramural Research Program, including work by Nigel Greig's group (see J Alzheimers Dis. 2010;19(4):1205-19), the NIA is beginning a clinical trial testing the safety and efficacy of daily exendin-4 treatment in patients with early-stage Alzheimer’s disease or mild cognitive impairment in participants aged 65 and over.
Bronwen Martin and her team discuss new data
Now a Principal Investigator, Martin remains interested in identifying novel metabolic and endocrine approaches to improve the quality of life for people with aging-related cognitive decline. But she is most excited about making a difference before problems arise by detecting and acting on the earliest signs of metabolic dysfunction.
Martin considers herself fortunate to have access to a unique NIA-funded study, the Baltimore Longitudinal Study of Aging (BLSA). Begun in 1958, the BLSA is America’s longest running scientific study of aging. “Hundreds of patients come back every two to four years. Some of our subjects are now in their nineties.” Volunteers are evaluated for physical and cognitive health through a variety of tests ranging from questionnaires and brain imaging to blood work-ups.
A systems biology approach to metabolism and aging includes many components
Using samples from the BLSA, Martin and her team are searching for patterns of biomarkers correlated with neurological and metabolic dysfunction. “We can do a whole range of -omics analyses: genomics, proteomics, metabolomics…,” cited Martin. Her laboratory has the technology at hand to look at literally tens of thousands of molecules that cut across all the organs and systems involved in maintaining metabolic function during aging. “With 50-100 patients, we should have enough data to start seeing patterns.”
“One challenge we came across fairly early was how to put all this information together,” said Martin. She pointed out that, for example, in genome-wide association studies (GWAS), investigators are often faced with large data sets containing thousands of different genes. “You end up with these enormous spreadsheets with rows and rows of data—how on earth do you look for differences?”
A confocal image shows healthy neurons in the brain
Martin and her NIA collaborator Stuart Maudsley, Ph.D., have developed a potential solution to this problem in the form of a software suite called Omnimorph. Omnimorph takes extremely large experimental data sets like the ones Martin and Maudsley are generating and turns them into 3-dimensional graphical representations. “We can see differences among large data sets just by looking at the different shapes that Omnimorph creates.”
Martin believes that this systems biology approach will offer new insights into both the control of metabolic function and how that control is altered during aging and aging-related disorders. “Some people age well—with good cardiovascular, metabolic, and cognitive health. Others don’t. We’re trying to understand and predict metabolic trajectories across a lifetime. If we can predict, we can try to prevent,” said Martin. “And prevention is better than cure.”
Bronwen Martin, Ph.D., is Head of the Metabolism Unit in the Laboratory of Clinical Investigation at the National Institute on Aging (NIA).