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Stanford, CA, United States

Brunet A.,Stanford University | Brunet A.,Glenn Laboratories for the Biology of Aging | Berger S.L.,University of Pennsylvania
Journals of Gerontology - Series A Biological Sciences and Medical Sciences | Year: 2014

Aging is associated with a wide range of human disorders, including cancer, diabetes, cardiovascular, and neurodegenerative diseases. Long thought to be an inexorable road toward decline and diseases, aging is in fact remarkably plastic. Such plasticity could be harnessed to approach age-related diseases from a novel perspective. Although many studies have focused on the genes that impact aging, the nongenetic regulation of aging is gaining increasing attention. Specifically, aging is associated with profound epigenetic changes, resulting in alterations of gene expression and disturbances in broad genome architecture and the epigenomic landscape. The potential reversibility of these epigenetic changes that occur as a hallmark of aging offers exciting opportunities to alter the trajectory of age-related diseases. This short review highlights key epigenetic players in the regulation of aging, as well as both future goals and challenges to the utilization of epigenetic strategies to delay and reverse the main diseases of aging. © 2014 The Author.

News Article
Site: www.biosciencetechnology.com

Researchers at the Stanford University School of Medicine have mapped the genome of an unusually short-lived fish, paving the way for scientists to use the organism to study how genes influence longevity. The researchers published the genome map of the African turquoise killifish Dec. 3 in Cell, along with early insights into the genetic determinants of its life span. Using a statistical analysis that looks at mutation rates across different organisms, the scientists found evidence that some of the same rare genes that have persisted in the killifish gene pool over centuries have also persisted in the gene pools of some unusually long-lived animals. The researchers wonder if this means there are certain genes that evolution has “tuned” to create varying life spans. “The range of life spans seen in nature is truly astonishing, and really we have very little insight into how this has evolved or how this works,” said Anne Brunet, PhD, professor of genetics at Stanford and senior author of the study. “By having the genome of this fish and comparing it to other species, we start seeing differences that could underlie life span differences both between species and also within a species.” The study’s lead author is Dario Valenzano, PhD, a former postdoctoral scholar in Brunet’s lab who now directs his own lab at the Max Planck Institute for Biology of Aging. Evolved to both hatch and reproduce within the brief rainy seasons in Mozambique and Zimbabwe, the turquoise killifish has an extremely compressed life cycle. Brunet said she and her team believed that once the fish’s genes were mapped out, they would provide an “exciting new opportunity to use an evolutionary lens to propose ideas about aging.” Brunet and members of her lab have worked for the past nine years to establish a colony of killifish at Stanford and to create online access to killifish gene maps for other researchers who want to study them. They hope that studying the killifish, some strains of which live only four to six months, will help them investigate why some species, like this fish, live less than a year, whereas others, like some whales, can live 200. They also hope the research will provide insights into longevity differences among humans. Using a range of genomic and genetic techniques, team members sequenced small segments of killifish DNA and then used specialized software to string these sequences together until they had assembled a full digital map of the turquoise killifish genome. They repeated this process in different strains of the fish to identify important genetic variations within the species. “Once you have the genome, it really breaks open the possibility of using genetic manipulation experiments and more conceptual comparative genomics studies,” Brunet said. Brunet and her colleagues have already begun to examine genes that are unique to the short-lived killifish, as well as to cross-breed short-lived killifish with a longer-lived strain to look for genes tied to longevity. When they mated long-lived fish with short-lived fish, they observed a cluster of genes shared between the long-lived grandparents and the long-lived grandchildren. They noted that several genes in this cluster are associated with longevity and aging in other species. One of these genes is the killifish equivalent of a human gene whose mutation is associated with frontotemporal dementia, a disease that generally manifests in late adulthood. The researchers see this as another good sign that analyses of killifish genes can set the stage for important health discoveries about human biology. “We don’t know yet exactly how these findings are relevant to humans, but these are questions we are actively pursuing,” Brunet said. Brunet said she and her colleagues were eager to establish the killifish as a model organism not only for their own future studies but for the research community. As they worked to assemble the killifish genome, they also built a user-friendly website that other researchers can access for free. “They can go to our website, enter their favorite gene of interest and then zoom in on the killifish equivalent,” she said. The paper was published alongside another killifish genome paper by a German team in the same issue of Cell. Brunet said she is excited that other researchers have begun working with killifish and hopes the resources published by both teams will usher in a new level of emphasis on the animal as a model for longevity research. “Having the genome transforms a nice, interesting organism into a model organism,” she said.   The research was supported by the National Institutes of Health Pioneer Award and Pathway to Independence Award, the Glenn Laboratories for the Biology of Aging, the Max Planck Institute for Biology of Aging, a Dean’s Fellowship at Stanford, the Life Sciences Research Foundation, the Stanford Center for Computational Evolutionary and Human Genomics, the Damon Runyon Cancer Research Foundation, the Rothschild Fellowship, the Human Frontiers Science Program, and the German Federal Ministry of Education and Research. Stanford’s Department of Genetics also supported the work.

Schaffer B.E.,Stanford University | Levin R.S.,Howard Hughes Medical Institute | Hertz N.T.,Howard Hughes Medical Institute | Maures T.J.,Stanford University | And 8 more authors.
Cell Metabolism | Year: 2015

AMP-activated protein kinase (AMPK) is a central energy gauge that regulates metabolism and has been increasingly involved in non-metabolic processes and diseases. However, AMPK's direct substrates in non-metabolic contexts are largely unknown. To better understand the AMPK network, we use a chemical genetics screen coupled to a peptide capture approach in whole cells, resulting in identification of direct AMPK phosphorylation sites. Interestingly, the high-confidence AMPK substrates contain many proteins involved in cell motility, adhesion, and invasion. AMPK phosphorylation of the RHOA guanine nucleotide exchange factor NET1A inhibits extracellular matrix degradation, an early step in cell invasion. The identification of direct AMPK phosphorylation sites also facilitates large-scale prediction of AMPK substrates. We provide an AMPK motif matrix and a pipeline to predict additional AMPK substrates from quantitative phosphoproteomics datasets. As AMPK is emerging as a critical node in aging and pathological processes, our study identifies potential targets for therapeutic strategies. © 2015 Elsevier Inc.

Rafalski V.A.,Stanford University | Mancini E.,Stanford University | Brunet A.,Stanford University | Brunet A.,Glenn Laboratories for the Biology of Aging
Journal of Cell Science | Year: 2012

Metabolism is influenced by age, food intake, and conditions such as diabetes and obesity. How do physiological or pathological metabolic changes influence stem cells, which are crucial for tissue homeostasis? This Commentary reviews recent evidence that stem cells have different metabolic demands than differentiated cells, and that the molecular mechanisms that control stem cell self-renewal and differentiation are functionally connected to the metabolic state of the cell and the surrounding stem cell niche. Furthermore, we present how energy-sensing signaling molecules and metabolism regulators are implicated in the regulation of stem cell self-renewal and differentiation. Finally, we discuss the emerging literature on the metabolism of induced pluripotent stem cells and how manipulating metabolic pathways might aid cellular reprogramming. Determining how energy metabolism regulates stem cell fate should shed light on the decline in tissue regeneration that occurs during aging and facilitate the development of therapies for degenerative or metabolic diseases. © 2012. Published by The Company of Biologists Ltd.

Lim J.P.,Stanford University | Brunet A.,Stanford University | Brunet A.,Glenn Laboratories for the Biology of Aging
Trends in Genetics | Year: 2013

It is textbook knowledge that inheritance of traits is governed by genetics, and that the epigenetic modifications an organism acquires are largely reset between generations. Recently, however, transgenerational epigenetic inheritance has emerged as a rapidly growing field, providing evidence suggesting that some epigenetic changes result in persistent phenotypes across generations. Here, we survey some of the most recent examples of transgenerational epigenetic inheritance in animals, ranging from Caenorhabditis elegans to humans, and describe approaches and limitations to studying this phenomenon. We also review the current body of evidence implicating chromatin modifications and RNA molecules in mechanisms underlying this unconventional mode of inheritance and discuss its evolutionary implications. © 2013 Elsevier Ltd.

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