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April 13, 2017

Hickory Dickory Dock, the Mouse Aged with Its Epigenetic Clock

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    What interventions might help the mouse outrun its epigenetic clock and thus age more slowly? Such interventions may not be limited to changing lifestyle factors, but may also include direct manipulation of the clock’s ticking rate. Should such manipulations be found, analogous interventions might help humans live longer lives. [Wikicommons]

    Lessons in telling time aren’t just the stuff of old nursery rhymes. They’re also the subject of research papers, as Genome Biology recently demonstrated when it published the work of epigenetic scientists. According to these scientists, the human epigenetic clock that was discovered a few years ago now has company: a mouse epigenetic clock.

    The newly discovered clock, a predictor of chronological and biological age, could be amenable to direct manipulation—adjustments of its ticking rate, for example. Maybe it could even be turned back, potentially revealing whether aging is preset, or whether the clock merely reflects underlying aging processes.

    The Genome Biology paper, entitled “Multi-Tissue DNA Methylation Age Predictor in Mouse,” appeared April 11. It was contributed by a team of scientists led by Wolf Reik, M.D., head of the epigenetics program at the Babraham Institute.

    “We have generated a comprehensive set of genome-scale base-resolution methylation maps from multiple mouse tissues spanning a wide range of ages,” wrote the paper’s authors. “Many CpG sites show significant tissue-independent correlations with age which allowed us to develop a multi-tissue predictor of age in the mouse. Our model, which estimates age based on DNA methylation at 329 unique CpG sites, has a median absolute error of 3.33 weeks and has similar properties to the recently described human epigenetic clock.”

    Recent research has shown that DNA methylation, an epigenetic modification that alters how DNA is read and expressed without altering the underlying sequence, can show age-related changes. A subset of these modifications is so accurate that chronological age in humans can be predicted +/– 3.6 years from any tissue or fluid in the body. This is by far the best biomarker of age available and is referred to as the epigenetic clock. Interestingly, analysis of DNA methylation can also provide information on biological age, which is a measure of how well your body functions compared to your chronological age. For instance, people suffering from fatty liver disease have a faster-ticking clock, while centenarians have a slower clock.

    But, how does this epigenetic clock work? And is it possible to change the ticking rate? Researchers at the Babraham Institute and the European Bioinformatics Institute have now identified a mouse epigenetic aging clock. This work shows that changes in DNA methylation at 329 sites in the genome are predictive of age in the mouse with an accuracy of +/– 3.3 weeks. Considering that humans live to approximately 85 years and mice to 3 years, the accuracy of the mouse and human clocks (better than 5%) are surprisingly similar.

    Using the mouse model, researchers also showed that lifestyle interventions known to shorten lifespan sped up the clock. For example, removing the ovaries in female mice accelerates the clock, something that is also observed in early menopause in women. And interestingly, a high-fat diet, which we know is detrimental to human health, also accelerates the aging clock. Remarkably, researchers were able to detect changes to the epigenetic clock as early as 9 weeks of age, bearing in mind that the lifespan of a mouse can easily be more than 3 years, this represents a massive reduction in both time and cost which the researchers believe will accelerate future aging discoveries.

    Tom Stubbs, Ph.D. student in the Reik group at the Babraham Institute and lead author of the paper, said: "The identification of a human epigenetic aging clock has been a major breakthrough in the aging field. However, with this finding came a number of questions about its conservation, its mechanism, and its function. Our discovery of a mouse epigenetic aging clock is exciting because it suggests that this epigenetic clock may be a fundamental and conserved feature of mammalian aging. Importantly, we have shown that we can detect changes to the ticking rate in response to changes, such as diet; therefore in the future we will be able to determine the mechanism and function of this epigenetic clock and use it to improve human health."

    Marc Jan Bonder, Ph.D., postdoctoral researcher at the European Bioinformatics Institute, added: "Dissecting the mechanism of this mouse epigenetic aging clock will yield valuable insights into the aging process and how it can be manipulated in a human setting to improve healthspan."

    With further study, scientists will be able to understand the inner mechanistic workings of such a clock (for example, using knowledge about enzymes that regulate DNA methylation in the genome) and change its ticking rate in the mouse model. This will reveal whether the clock is causally involved in aging, or whether it is a readout of other underlying physiological processes. These studies will also suggest approaches to wind the aging clock back in order to rejuvenate tissues or even a whole organism.

    “It is fascinating to imagine how such a clock could be built from molecular components we know a lot about (the DNA methylation machinery),” noted Prof. Reik. “We can then make subtle changes in these components and see if our mice live shorter, or, more interestingly, longer. Such studies may provide deeper mechanistic insights into the aging process and whether lifespan in a species is in some way programmed."

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