Longevity Briefs: Reversing Ageing In Middle-Aged Mice By Rewinding The Epigenetic Clock

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Longevity briefs provides a short summary of novel research in biology, medicine, or biotechnology that caught the attention of our researchers in Oxford, due to its potential to improve our health, wellbeing, and longevity.

Why is this research important: There’s more to our DNA than the genetic code itself. Chemical compounds can affect gene activity without changing the genetic code. These are known as epigenetic alterations, and are important in determining which genes are switched on or off. In this way, epigenetic alterations can control whether a cell in the developing embryo becomes a neuron, a muscle cell, or any other specialised cell type in the body. However, unwanted epigenetic alterations accumulate throughout life, and this is thought to play a role in the ageing process, for example by turning off important genes. This article provides a more in-depth explanation as to how epigenetic alterations relate to ageing.

By using a cocktail of gene regulators called Yamanaka factors, it is possible to ‘reprogram’ ]cells to a state similar to that of embryonic cells. This process erases all epigenetic changes, representing a reversal of ageing, but also causes cells to lose their identities. Muscle cells, brain cells, kidney cells all lose the ability to perform their specialised functions when reprogrammed. Since the discovery of Yamanaka factors, scientists have succeeded in reversing cellular ageing in living mice using so-called partial reprogramming: cells are exposed to Yamanaka factors for long enough to reverse age-related epigenetic changes, but without returning the cells to an embryonic-like state. However, these experiments were done in mice with progeria, a genetic condition that results in rapid ageing. Does partial reprogramming still work in naturally ageing mice? For how long and at what stage of life should mice receive reprogramming factors?

Reprogramming erases epigenetic changes associated with ageing, but reprogrammed cells lose their identity. Scientists can differentiate reprogrammed cells back into specialised cells, which now have the characteristics of young cells. Partial reprogramming reverses epigenetic ageing without loss of cell identity.
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What did the researchers do: In this study, researchers tested three different partial reprogramming approaches on naturally ageing mice. One group received the treatment for 7 months, starting at 15 months of age. One group received treatment for 10 months, starting at 12 months of age. These two groups were referred to as the long-term treatment groups. The third group (the short-term treatment group) received treatment for just 1 month, starting at 25 months of age. For reference, 12-15 ‘mouse months’ translate to around 35-50 ‘human years’, while a 25 month old mouse is roughly equivalent to an 80 year-old human. Researchers then measured various factors related to biological ageing such as epigenetic changes and wound healing speed.

Key takeaway(s) from this research: Neither reprogramming approach showed significant adverse effects on the mice when compared to the untreated control groups. One major concern in epigenetic reprogramming is the formation of teratoma, which are tumours formed from a mix of different cell types. The results from this study suggest that it is possible to safely expose mice to reprogramming treatments for longer periods of time.

As shown in previous experiments in mutant mice, long-term partial reprogramming was associated with reduced age-related changes and a reversal of epigenetic ageing, particularly in the skin and kidneys, as well as with improved wound healing. Short-term reprogramming, on the other hand, did not seem to elicit such changes. This may be because the mice receiving short-term reprogramming were older, and so age-related changes in these mice were more permanent and harder to reverse.

There’s still much more work to be done before we can consider trying partial reprogramming in humans. Much of this work will involve ironing out the precise timing and dosing of reprogramming factors to achieve maximum benefit for minimum risk.