Joseph A. Pignolo Award in Aging Research 2015: “REST and Stress Resistance in Aging and Alzheimer’s Research”

On Tuesday, March 1, 2016, the Institute on Aging presented their annual Joseph A. Pignolo Award in Aging Research. This year’s awardee was Bruce A. Yankner, MD, PhD, professor of Genetics and Neurology and Co-director of the Glenn Center for the Biology of Aging at Harvard Medical School, for his 2014 publication in Nature on “REST and Stress Resistance in Aging and Alzheimer’s Research.

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John Q. Trojanowski, MD, PhD (IOA Director), Bruce A. Yankner, MD, PhD (2016 Pignolo Awardee), and Robert J. Pignolo, MD, PhD (founder of the Pignolo Award in Aging Research).

This paper analyzes the gene expression changes that occur in the aging brain and shows the coherent pattern of changes in genes that turn on or off in the neurons of the brain as it ages. The greatest impact was seen in the REST (RE1 neuron-silencing transcription factor) gene. It was previously thought that this gene only functioned in fetal brain development—keeping neural genes at bay until the brain had a chance to build its underlying architecture—however, Dr. Yankner and his team found that it is also expressed in the adult human brain and is dramatically up-regulated in neurons as the brain ages. The significance of this in neurodegenerative research is that they discovered that in the brains of individuals with Alzheimer’s disease, the protein is actually much less up-regulated, or completely absent.

Using both mouse models and culture dishes in a laboratory, they found that regular stressors encountered by an aging brain such as oxidative stress—a disturbance in the balance between the production of reactive oxygen species and antioxidant defenses—and amyloid stress associated with AD had a significant impact on sustaining the REST gene.

“This was a galvanizing observation for us,” explained Dr. Yankner. “It suggested that some people can resist the onslaught of Alzheimer’s because they’re able to up-regulate this intrinsic defense mechanism [REST]. So, a very important question is why some people can do it and some people can’t…”

Dr. Yankner assumes there is a potential genetic underpinning, but also believes that environmental factors contribute as well.

In terms of future research, and based on their current findings, Dr. Yankner and his lab are interested in understanding exactly how REST accomplishes its different functions and manages to maintain neurons in a functional state for so many years. To do this, they are characterizing all of the genes and protein partners that interact with REST and are looking at them as potential therapeutic targets that may be used to delay the onset of Alzheimer’s disease.

View more photos from the 2016 Joseph A. Pignolo Award in Aging Research.

*This study was funded by the National Institute on Aging, the National Institutes of Health Common Fund (NCF), and the Paul F. Glenn Foundation for Medical Research.

 The main focuses of Dr. Yankner’s lab are to understand 1) the molecular biology of the aging brain and how that intersects with pathological aging in diseases such as Alzheimer’s disease (AD), Parkinson’s disease (PD) and Frontotemporal degeneration (FTD) and 2) using humans as a model system by understanding how they age in the brain, from changes in genes, DNA, and proteins, and modeling this in cells in culture and genetically engineered model systems including C. elegans (Caenorhabditis elegans) nematode worms.

The Joseph A. Pignolo, Sr. Award in Aging Research is given out as part of the Institute on Aging (IOA) Visiting Scholars series to annually recognize an outstanding contribution to the field of biogerontology. It was created by geriatrician and gerontologist Robert J. Pignolo, M.D., Ph.D. in honor of his father.