Every Thursday, Laboratory Equipment features a Scientist of the Week, chosen from the science industry’s latest headlines. This week’s scientist is Stephen Ginsberg of the NYU Langone Medical Center and the Nathan Kline Institute. He and a team found that a low-calorie diet can stop the normal rise and fall in activity levels of close to 900 different genes linked to aging and memory formation in the brain.
Q: What made you interested in studying how caloric intake impacts aging?
A: Calorie restriction is a nontoxic intervention known to enhance longevity and mitigate aging phenotypes in many species, including flies, worms, rodents and nonhuman primates. The effects of calorie restriction in humans has received less mechanistic study, but is probably worth intensive evaluation. Based on our growing body of research in wild-type animals as well as animal models of neurodegeneration, we hypothesize that calorie restriction dramatically alters many processes associated with dysfunctional brain aging. Dietary interventions, including calorie restriction, also serve as an essential tool for understanding mechanisms that may underlie the reduction of age-related pathology.
Q: What are the future implications of your research and findings?
A: Our study shows how calorie restriction practically arrests gene expression levels involved in the aging phenotype, which may be beneficial for future drug discovery as well as dietary studies to improve the health-span. While restrictive dietary regimens have been well-known for decades to prolong the lives of rodents, their effects in humans have not been well understood. Benefits of these diets have been touted to include reduced risk of human heart disease, hypertension and stroke, but the widespread genetic impact on the memory and learning regions of aging brains has not before been shown with this number of genes (>10,000) being investigated simultaneously. Although the results of this study does not mean calorie restriction is the “fountain of youth,” it does add evidence for the role of diet in delaying the effects of aging and age-related disease.
Q: What was the most surprising thing you found in your research?
A: Our results indicates that calorie restriction interferes with the expression of the aging phenotype. We predicted that a few genes may be involved in this process, but are results showed that, surprisingly, nearly 900 genes retained a youthful expression following long-term calorie restriction. These findings widen the door to study more in-depth mechanisms underlying positive benefits of calorie restriction on anti-aging genetics. It is possible that a sustained and controlled reduction in calorie intake could help slow brain aging and deter chronic disease.
Q: What is the take home message of your research and results?
A: We tested the hypothesis that long-term calorie restriction positively alters gene expression within the hippocampus, a critical learning and memory area vulnerable in aging and Alzheimer’s disease. To test this hypothesis, we conducted experiments on female wild-type mice that were given food pellets 30 percent lower in calories than what was fed to the control group. The mice ate fewer calories derived from carbohydrates. Analyses were performed on mice in middle and old age to assess any differences in gene expression over time. Our data analysis revealed that the mice that were fed a lower calorie diet had fewer changes in approximately 900 genes that are linked to aging and memory.
Q: What new technologies did you use in your lab during your research?
A: The Ginsberg’s laboratory utilizes state-of-the-art molecular and cellular approaches to study the mechanisms underlying selective vulnerability of specific cell types to neurodegeneration, and includes the assessment of dietary interventions. Our underlying hypothesis is that individual cell types are likely to have unique patterns of gene and protein expression under normative conditions that are altered in pathological states, which drives subsequent neurodegeneration. The present work employed RNA-sequencing technology as well as validation of results using quantitative real-time PCR (qPCR) and a new technology termed NanoString nCounter to determine gene changes in relation to calorie restriction during aging in female wild-type mice.
Q: What is next for you and your research?
A: Our findings strongly support the hypothesis that calorie restriction globally attenuates brain aging through maintenance of youthful expression signatures and activation of neuroprotective expression changes. We plan to assess calorie restriction as a pathology prevention measure in animal models of Alzheimer’s disease, looking at discrete cell types within the hippocampus, which is relevant to learning and memory. We also will pay special attention to see if there are differences between female and male mice in terms of responsiveness to calorie restriction.
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