Mouse’s internal clock could reveal the secrets of ageing

Researchers have discovered that mice’s DNA ages in a similar way to humans

Recent research has shown that changes to our DNA are a good indicator of our biological age. These changes – known as DNA methylation – are modifications to the outer structure of the DNA chain, which affect how our genes work. For this reason it is known as our epigenetic clock. However important questions have yet to be answered: Does ageing cause the epigenetic changes or do epigenetic changes cause ageing? Could we wind back our biological age by removing the methyl tags? Research carried out in mice is starting to answer these questions.

Published in Genome Biology, researchers at the Wellcome Trust Sanger Institute, Babraham Institute and the European Bioinformatics Institute reveal that mice have a similar epigenetic ageing clock to humans, providing a great laboratory model to explore how the clock works. The scientists discovered 329 sites in the genome that are predictive of age in the mouse with an accuracy of +/- 3.3 weeks (better than 5 per cent of its three-year average life span). The human clock shows remarkably similar accuracy with +/- 3.6 years of the average 85 years.

It might be possible to use mice as a model of human epigenetic clocks to understand how fast it ticks, what determines the speed of ticking, and whether or not the clock can be turned back.

“Dissecting the mechanism of this mouse epigenetic ageing clock will yield valuable insights into the ageing process and how it can be manipulated in a human setting to improve health span.”

Dr Marc Jan Bonder Postdoctoral Researcher at the European Bioinformatics Institute

The researchers also showed that the mouse’s clock could be sped up by lifestyle interventions known to shorten lifespan. For example, removing the ovaries in female mice increased the rate of DNA methylation, something that is also observed in women who undergo an early menopause. In addition, when mice were fed a high-fat diet (which is well known to damage human health), their epigenetic clock ticked faster.

“The identification of a human epigenetic ageing clock has been a major breakthrough in the ageing field. However, with this finding came a number of questions about its conservation, its mechanism and its function. Our discovery of a mouse epigenetic ageing clock is exciting because it suggests that this epigenetic clock may be a fundamental and conserved feature of mammalian ageing. 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.”

Tom Stubbs PhD student in the Reik group at the Babraham Institute and first author of the paper

It is hoped that this laboratory model will allow researchers to explore whether the clock is causally involved in ageing, or is a consequence of other, underlying, processes that actually cause ageing. For example, researchers will be able to change the ticking rate of the clock by using enzymes that regulate DNA methylation to see if it increases or decreases lifespan. These studies could also suggest approaches to winding back the ageing clock 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. 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 ageing process and whether lifespan in a species is in some way programmed.”

Professor Wolf Reik Head of the Epigenetics Programme at the Babraham Institute and Associate Faculty at the Sanger Institute

More information

Babraham Institute’s Animal research statement:

As a publically funded research institute, the Babraham Institute is committed to engagement and transparency in all aspects of its research. The research presented here used mice kept in a specific ‘ageing colony’ within the Institute’s Animal Facility. Cortex, heart, liver and lung samples were collected from male mice of different ages – soon after birth (< 1 week), 14 weeks, 27 weeks and 41 weeks for analysis of genomic DNA.

All animal work was approved by the Babraham Institute Animal Welfare and Ethical Review Body, and carried out in accordance with the Animals (Scientific Procedures) Act 1986, under a UK Home Office project licence. To test the model developed, the researchers took advantage of four publicly available externally generated datasets stored online by GeneExpressionOmnibus (GEO) database. Such data-sharing is a valuable aid in the Institute’s efforts to apply the principles of the 3Rs (reduction, refinement, replacement) in its animal research, in this case the principle of reduction, since some duplication of animal use was avoided. Details of the animals used in these studies can be found in the methods section of the paper.

Please follow the link for further details of the Babraham Institute’s animal research and its animal welfare practices.

Funding:

This research was funded through grants provided to Prof. Wolf Reik by the Biotechnology and Biological Research Council (BBSRC), the Wellcome Trust and the EpiGeneSys and BLUEPRINT EU Networks of Excellence.