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July 27, 2017

Only as Old as the Brain’s Stem Cells Feel

  • What the brain tells the body can accelerate aging and shorten lifespan. That much is already clear from recent studies on neuroendocrine interactions between the central nervous system and the periphery. These studies have even identified a brain region known to regulate growth, development, reproduction, and metabolism—the hypothalamus—as a particularly important communications hub. Yet this brain region’s cell-level contributions to aging regulation have been unclear.

    A new study has listened to the hypothalamus more closely in hopes of picking up cell-level chatter that could influence aging speed. This study, which was completed by scientists based at Albert Einstein College of Medicine, tuned into a tiny population of adult stem cells. Already known to be responsible for forming new brain neurons, these stem cells, the scientists found, also regulate aging speed, partly through the release of exosomal microRNAs (miRNAs).

    "Our research shows that the number of hypothalamic neural stem cells naturally declines over the life of the animal, and this decline accelerates aging," said the study’s leader, Dongsheng Cai, M.D., Ph.D., a professor of molecular pharmacology at Einstein. "But we also found that the effects of this loss are not irreversible."

    Details of the study appeared July 26 in the journal Nature, in an article entitled “Hypothalamic Stem Cells Control Ageing Speed Partly through Exosomal miRNAs.” The article describes how the scientists worked with mouse models in which hypothalamic stem/progenitor cells were evaluated.

    “Each mouse model consistently displayed acceleration of ageing-like physiological changes or a shortened lifespan,” wrote the article’s authors. “Conversely, ageing retardation and lifespan extension were achieved in mid-aged mice that were locally implanted with healthy hypothalamic stem/progenitor cells that had been genetically engineered to survive in the ageing-related hypothalamic inflammatory microenvironment.”

    The researchers first looked at the fate of those cells as healthy mice got older. The number of hypothalamic stem cells began to diminish when the animals reached about 10 months, which is several months before the usual signs of aging start appearing. "By old age—about two years of age in mice—most of those cells were gone," noted Dr. Cai.

    The researchers next wanted to learn whether this progressive loss of stem cells was actually causing aging and was not just associated with it. So they observed what happened when they selectively disrupted the hypothalamic stem cells in middle-aged mice. "This disruption,” pointed out Dr. Cai, “greatly accelerated aging compared with control mice, and those animals with disrupted stem cells died earlier than normal."

    Could adding stem cells to the hypothalamus counteract aging? To answer that question, the researchers injected hypothalamic stem cells into the brains of middle-aged mice whose stem cells had been destroyed as well as into the brains of normal old mice.

    “By replenishing these stem cells or the molecules they produce, it's possible to slow and even reverse various aspects of aging throughout the body,” the authors of the Nature article declared. “Mechanistically, hypothalamic stem/progenitor cells contributed greatly to exosomal miRNAs in the cerebrospinal fluid, and these exosomal miRNAs declined during ageing, whereas central treatment with healthy hypothalamic stem/progenitor cell-secreted exosomes led to the slowing of ageing.”

    The researchers extracted miRNA-containing exosomes from hypothalamic stem cells and injected them into the cerebrospinal fluid of two groups of mice: middle-aged mice whose hypothalamic stem cells had been destroyed and normal middle-aged mice. This treatment significantly slowed aging in both groups of animals as measured by tissue analysis and behavioral testing that involved assessing changes in the animals' muscle endurance, coordination, social behavior, and cognitive ability.

    The researchers are now trying to identify the particular populations of miRNAs and perhaps other factors secreted by these stem cells that are responsible for these antiaging effects—a first step toward possibly slowing the aging process and treating age-related diseases.

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