Epigenetics behind age reversal in mice- what does that mean for humans?

Syed A K Shifat Ahmed

New research findings in mice suggest old cells retain a copy of their young state that can be reactivated to regain phenotypes lost from aging

Let’s admit it- in conscious or subconscious minds we all have been lured to that anti-aging skincare commercial on the roadside billboard or that anti-aging hack post on our social feed.  The desire to look young and stay away from age-related health complications is real. Science for decades have been trying to understand and control aging¹. It is known that specific signatures like methylation markers tags DNA stretches (collectively known as epigenome) that is critical in deciding the functional DNA sites in a biological phenomenon called epigenetics².  A recent article published in Cell by Yang et al. 2023, provides evidence that disrupting this epigenome accelerated molecular, cognitive, and physiological aging in mice³. Alternatively restoring the disrupted areas was able to reset the epigenome to its younger biological state³. This suggest epigenetic information is not completely lost, rather the cell saves the information in a form that can be retrieved upon appropriate activation (Figure 1a). Understanding this age reversal epigenetic mechanism can open novel therapies for a host of age-related disorders.

Aging has largely been associated with mutational or unwanted changes in DNA as the cell responds to DNA damages such as double stranded breaks (DSB)^1,4.  However recent research suggests the aging associated changes are also triggered from loss of epigenetic information^4,5.  A previous study from this research group showed that that when subjected to DNA damage, the cells recruit special chromatin repair proteins to the sites of damage where they are tasked with repairing the errors⁵. These proteins would normally leave after fixing the damage allowing the DNA to return to its usual compactness. But with repeated DNA damage-repairs, these proteins may get displaced inappropriately. Since DNA compactness influences which genes get exposed and expressed, this displacement can result in altered expressions of genes that are critical to aging.

In this study, the researchers investigated if regulating the epigenetic landscape could alter cell aging³. This was experimented through genetically modified mice containing a gene for a scissor-like-enzyme called Ppo1 endonuclease. The enzyme upon induction with drug tamoxifen, which is known to increase oxidative cellular stress, produced cuts in non-protein coding DNA regions mimicking the DSBs as seen in physiological state. The increased DNA damages induced in transgenic mice resulted in rapid modifications of the epigenetic landscape and the system being termed as ICE (Inducible Changes to Epigenome).  Both the transgenic ICE mice (with Ppo1 endonuclease) and non-transgenic control mice (without Ppo1 endonuclease) were treated with tamoxifen for 3 weeks and phenotypes observed for a period. There were not any noticeable differences in the first 4-6 months post-treatment. However, after 10 months the ICE mice started exhibiting features typical of aging like grey hair, reduced body weight, lower activity, and cognitive decline – all these features were absent in the control mice group (Figure 1b). This was reasoned to occur from higher rate of DNA damage and epigenetic reshuffling due to the endonuclease mediated DNA cutting in the ICE mice. ChIP sequencing which is performed to study interactions between epigenetic regulators and DNA confirmed there was increased epigenetic disruption in the ICE mice that resulted in advancement of the epigenetic clock by 50% causing the ICE mice to biologically age faster³.

Having provided evidence of epigenome erosion in accelerated aging, the team decided to test if the epigenome could be reversed to the original landscape in post treated ICE mice. The researchers used a subset of Yamanaka factors called OSK³. The Yamanaka factors are proteins known for their role in reversing adult stem cells to embryolike ones and can alleviate old-age phenotypes and increase lifespan of progeroid mice⁶. In this study, cyclic expression of Yamanaka factors reversed age-associated gene expressions in ICE mice, with the genes associated with chromatin modification showing expression profiles similar to younger mice³ (Fig 1c). The results consolidated earlier findings from this research group where Yamanaka factors was used to cure blindness in mice by restoring the youthful epigenome⁷.

The concept of age reversing has attracted a lot of interest among researchers and investors. While our lifespan has improved considerably, has our health span improved equally? Exploring mechanisms involved in aging and cell rejuvenation could pave the way for novel treatment interventions for conditions like cancer, diabetes, and blindness. This work has shown our perceived idea of cell aging being driven by accumulation of DNA mutations only – is a bit misleading. When DNA from ICE mice and non-ICE mice were sequenced, they did not reveal significant differences despite the former demonstrating higher aging phenotypes³.  This led to the authors conclude that epigenetics holds cues to cell aging and reprograming the epigenome would be a more feasible option than correcting mutations in the DNA as scientists continue to tackle cell aging.

When Steve Horvath first developed the concept of epigenetic clock to measure biological age, based on the epigenetic markers the DNA has accumulated, scientists thought of dialing this clock -up and – down to regulate aging⁸. The current work not only give hope of gaining control to such a dialing meter but also shows promise in reversing age by retrieving the encrypted copy of the “young epigenome” information. At present how and where this information is stored and what signals could authorise the cell to download this epigenetic software permanently are questions for further investigation.

References

1. Melzer, D., Pilling, L.C. & Ferrucci, L. The genetics of human ageing. Nat Rev Genet 21, 88–101 (2020). https://doi.org/10.1038/s41576-019-0183-6
2. Benayoun, B., Pollina, E. & Brunet, A. Epigenetic regulation of ageing: linking environmental inputs to genomic stability. Nat Rev Mol Cell Biol 16, 593–610 (2015). https://doi.org/10.1038/nrm4048  
3. Yang, J.-H. et al. Loss of epigenetic information as a cause of mammalian aging. Cell 186, (2023). https://doi.org/10.1016/j.cell.2022.12.027
4. Tian, X. et al. SIRT6 is responsible for more efficient DNA double-strand break repair in long-lived species. Cell 177, (2019). https://doi.org/10.1016/j.cell.2019.03.043
5. Oberdoerffer, P. et al. SIRT1 redistribution on chromatin promotes genomic stability but alters gene expression during aging. Cell 135, 907–918 (2008). https://doi.org/10.1016/j.cell.2008.10.025
6. Ocampo, A. et al. In vivo amelioration of age-Associated Hallmarks by partial reprogramming. Cell 167, (2016). https://doi.org/10.1016/j.cell.2016.11.052
7. Lu, Y. et al. Reprogramming to recover youthful epigenetic information and restore vision. Nature 588, 124–129 (2020). https://doi.org/10.1038/s41586-020-2975-4
8. Horvath, S. DNA methylation age of human tissues and cell types. Genome Biology 14, (2013). https://doi.org/10.1186/gb-2013-14-10-r115