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New genetic research suggests that hibernating animals\u2019 superpowers could lie hidden in our own DNA.<\/p>\n
Animals that hibernate are incredibly resilient. They can spend months without food or water, muscles refusing to atrophy, body temperature dropping to near freezing as their metabolism and brain activity slow to a crawl. When they emerge from hibernation, they recover from dangerous health changes<\/a> similar to those seen in type 2 diabetes, Alzheimer\u2019s disease, and stroke.<\/p>\n The new research provides clues on how to unlock these hibernating superpowers, opening the door to someday developing treatments that could reverse neurodegeneration and diabetes.<\/p>\n Two studies describing the results are published in Science (one<\/a>, two<\/a>).<\/p>\n Metabolism and obesity<\/p>\n A gene cluster called the \u201cfat mass and obesity (FTO) locus\u201d plays an important role in hibernators\u2019 abilities, the researchers found. Intriguingly, humans have these genes too.<\/p>\n \u201cWhat\u2019s striking about this region is that it is the strongest genetic risk factor for human obesity,\u201d says Chris Gregg, professor in neurobiology and human genetics at University of Utah Health and senior author on the studies. But hibernators seem able to use genes in the FTO locus in new ways to their advantage.<\/p>\n The team identified hibernator-specific DNA regions that are near the FTO locus and that regulate the activity of neighboring genes, tuning them up or down. The researchers speculate that adjusting the activity of neighboring genes, including those in or near the FTO locus, allows hibernators to pack on the pounds before settling in for the winter, then slowly use their fat reserves for energy throughout hibernation.<\/p>\n Indeed, the hibernator-specific regulatory regions outside of the FTO locus seem crucial for tweaking metabolism. When the researchers mutated those hibernator-specific regions in mice, they saw changes in the mice\u2019s weight and metabolism. Some mutations sped up or slowed down weight gain under specific dietary conditions; others affected the ability to recover body temperature after a hibernation-like state or tuned overall metabolic rate up or down.<\/p>\n Intriguingly, the hibernator-specific DNA regions the researchers identified weren\u2019t genes themselves. Instead, the regions were DNA sequences that contact nearby genes and turn their expression up or down, like an orchestra conductor fine-tuning the volume of many musicians. This means that mutating a single hibernator-specific region has wide-ranging effects extending far beyond the FTO locus, explains Susan Steinwand, research scientist in neurobiology at U of U Health and first author on one of the studies.<\/p>\n \u201cWhen you knock out one of these elements\u2014this one tiny, seemingly insignificant DNA region\u2014the activity of hundreds of genes changes,\u201d she says. \u201cIt\u2019s pretty amazing.\u201d<\/p>\n Understanding hibernators\u2019 metabolic flexibility could lead to better treatments for human metabolic disorders like type 2 diabetes, the researchers say.<\/p>\n \u201cIf we could regulate our genes a bit more like hibernators, maybe we could overcome type 2 diabetes the same way that a hibernator returns from hibernation back to a normal metabolic state,\u201d says Elliott Ferris, bioinformatician at U of U Health and first author on the other study.<\/p>\n Needles in a haystack<\/p>\n Finding the genetic regions that may enable hibernation is a problem akin to excavating needles from a massive DNA haystack. To narrow down the regions involved, the researchers used multiple independent whole-genome technologies to ask which regions might be relevant for hibernation. Then, they started looking for overlap between the results from each technique.<\/p>\n First, they looked for sequences of DNA that most mammals share but that had recently changed in hibernators.<\/p>\n \u201cIf a region doesn\u2019t change much from species to species for over 100 million years but then changes rapidly and dramatically in two hibernating mammals, then we think it points us to something that is important for hibernation, specifically,\u201d Ferris says.<\/p>\n To understand the biological processes that underlie hibernation, the researchers tested for and identified genes that turn up or down during fasting in mice, which triggers metabolic changes similar to hibernation. Next, they found the genes that act as central coordinators, or \u201chubs,\u201d of these fasting-induced changes to gene activity.<\/p>\n Many of the DNA regions that had recently changed in hibernators also appeared to interact with these central coordinating hub genes. Because of this, the researchers expect that the evolution of hibernation requires specific changes to the controls of the hub genes. These controls comprise a shortlist of DNA elements that are avenues for future investigation.<\/p>\n What about humans?<\/p>\n Most of the hibernator-associated changes in the genome appeared to \u201cbreak\u201d the function of specific pieces of DNA, rather than confer a new function. This hints that hibernators may have lost constraints that would otherwise prevent extreme flexibility in the ability to control metabolism. In other words, it\u2019s possible that the human \u201cthermostat\u201d is locked to a narrow range of continuous energy consumption. For hibernators, that lock may be gone.<\/p>\n Hibernators can reverse neurodegeneration, avoid muscle atrophy, stay healthy despite massive weight fluctuations, and show improved aging and longevity. The researchers think their findings show that humans may already have the needed genetic code to have similar hibernator-like superpowers\u2014if we can bypass some of our metabolic switches.<\/p>\n \u201cHumans already have the genetic framework,\u201d Steinwand says. \u201cWe just need to identify the control switches for these hibernator traits.\u201d By learning how, researchers could help confer similar resilience to humans.<\/p>\n \u201cThere\u2019s potentially an opportunity\u2014by understanding these hibernation-linked mechanisms in the genome\u2014to find strategies to intervene and help with age-related diseases,\u201d Gregg says. \u201cIf that\u2019s hidden in the genome that we\u2019ve already got, we could learn from hibernators to improve our own health.\u201d<\/p>\n Support for the research came from the National Institutes of Health, also including the National Institute on Aging , the National Institute of Mental Health, the National Library of Medicine. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.<\/p>\n Conflict of interest statement: Chris Gregg is a cofounder, consultant, and\/or has financial interests in Storyline Health Inc., DepoIQ Inc., Primordial AI Inc., and Rubicon AI Inc.; Elliott Ferris is a consultant with financial interests in Primordial AI Inc.; Jared Emery is an employee with financial interests in Storyline Health Inc.<\/p>\n