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To die young – but at an old age

22.5.2023

Translation: Veronica Bielawski

The ageing process is universal. No one can escape it. The underlying biological processes are complex, and we’re still far from understanding how we age. But science has made decisive progress.

Life is a highly complex interaction between our cells and the information stored in our DNA and epigenome. Epigenome refers to chemical changes in DNA. The epigenome regulates the activity of genes and is involved, among other things, in the developmental process and differentiation of tissue. If DNA is the biological hardware, the epigenome is the software. Whether we age because of hardware decay or software decay (or both) is still unknown.

Our DNA is a double-stranded helix. If the DNA is damaged, this can lead to mutations and accelerate the ageing process. In particular, breaks in both DNA strands, so-called double-strand breaks, which occur 10 to 50 times per cell per day, are suspected of causing us to age [1,2]. However, there are doubts about this theory; many old cells have few mutations [3] and cells from mice with high mutation rates show few or no signs of premature ageing [4].

Previous experiments with yeast showed that the loss of epigenetic information could represent an ageing mechanism [5,6]. Such age-associated epigenetic changes can also be also observed in multicellular organisms, such as worms, flies, or naked mole rats. Many of these epigenetic changes are due to the methylation of DNA. This is the chemical modification of DNA that occurs with the transfer of a chemical compound, a methyl group. This modification doesn’t alter the underlying DNA; it regulates the activity of the relevant section of DNA, with methylation typically repressing gene expression. Why the epigenome changes with age remains a mystery. However, here too, experiments with yeast have provided a clue. In particular, double-strand breaks [7] and subsequent repair, which requires epigenetic factors, appeared to be a strong driver of these epigenetic changes.

So, could it be that changes in our software are ageing us? A group of researchers investigated this question. They wanted to test whether epigenetic changes are a cause of ageing in mammals.

The experiments

The researchers were the first to develop a system that generates double-strand breaks in single cells and in multicellular organisms, without inducing mutations. To do this, they fused two genes together. One comes from slime mould and is an endonuclease. Endonucleases recognise specific sites on DNA and cut both strands, causing double-strand breaks. The other gene is a mutated oestrogen receptor that is regulated exclusively by tamoxifen. These fused genes were transferred to a plasmid. Plasmids are small, ring-shaped double-stranded DNA molecules found in bacteria. However, plasmids are also found in unicellular and multicellular organisms. Plasmids can replicate independently and can therefore be transferred from one cell to another. Therefore, the use of plasmids is widespread in genetic engineering, where they’re used as vectors to introduce genetic material into living organisms.

The researchers targeted stem cells from mice and wanted to equip them with the new genetic material. The genetically modified stem cells were then injected into blastocysts, that is, cells in the early developmental stage of mouse embryos. The blastocyst, in turn, was implanted into a mouse that acted as a surrogate mother. The offspring produced in this way now consist of genetically different cells and are called chimera in biological science. The chimeric mice could then pass on the inserted genes to their offspring. To generate only mice with the desired genetic characteristics, they were backcrossed with normal mice. The researchers created a line of mice in which they could induce double-strand breaks by adding tamoxifen. Normal mice served as the control group. The genetically modified mice were additionally fed tamoxifen for 3 weeks at 4 to 6 months of age to induce double-strand breaks.

The researchers named the study system used and the corresponding mice «ICE» (inducible changes to the epigenome). First, the researchers demonstrated that ICE induces double-strand breaks without causing mutations in order to ensure that any DNA mutations induced didn’t contribute to the ageing process.

The next step was the analysis of the ageing process caused by double-strand breaks. Initially, no obvious changes in behaviour, activity, or diet occurred in the ICE mice or the control mice. However, after one month, the researchers noticed small changes. And 10 months after the intervention, the ICE mice showed the classic signs of old age, such as a reduction in body weight, an increase in fat mass independent of diet, and decreased activity during the night. Signs of ageing were also evident in the brain as well as in the muscles in ICE mice. The researchers compared their epigenetic age, a measure of the ageing of the cellular machinery, to the control mice and observed that the rate of cellular ageing was approximately 50% greater than in the control mice. The epigenome also suffered from the ageing process. In ICE mice, the researchers found a loss of epigenetic information. A related problem is that epigenetically aged cells lose their cell identity.

Can we reboot our software?

Sinclair and et al. [8] wanted to know if they could reset the epigenome in vitro and in vivo. This would rule out the possibility that mutations are responsible for ageing. So-called Yamanaka factors (Oct4, Sox2, Klf4 and Myc) [9] alleviate the symptoms of ageing and prolong lifespan in mice [10,11]. Another study also showed that epigenetic age can be reset to cure blind mice – a process that requires DNA methylation [12].

These findings indicate that cells possess a backup of juvenile epigenetic information that can restore cell identity [13]. Therefore, the researchers investigated what happens when the Yamanaka factors Oct4, Sox2, and Klf4 (OSK) are expressed in ICE cells. On average, the epigenetic age of the cells was rejuvenated by 57%. Remarkably, kidneys and muscles rejuvenated to an age equivalent to the negative control group after only five weeks. However, exactly how this rejuvenation occurs is still unknown.

It appears that mammalian cells create a kind of backup of their epigenetic information in a juvenile state. This may allow them to reboot themselves to a younger state if, for example, the epigenome has taken too much damage. The experiments by Sinclair et al. have also shown that the epigenome can be manipulated to either accelerate or reverse the ageing process. The ICE method is promising because it gives us a new way to study the epigenetically associated ageing process.

Perhaps someday we really will be able to rejuvenate with a software reboot.

References

Tian X, Firsanov D, Zhang Z, Cheng Y, Luo L, Tombline G, et al. SIRT6 Is Responsible for More Efficient DNA Double-Strand Break Repair in Long-Lived Species. Cell. Cell Press; 2019;177: 622-638.e22. doi:10.1016/j.cell.2019.03.043

Vilenchik MM, Knudson AG. Endogenous DNA double-strand breaks: Production, fidelity of repair, and induction of cancer. Proc Natl Acad Sci U S A. National Academy of Sciences; 2003;100: 12871–12876. doi:10.1073/PNAS.2135498100/SUPPL_FILE/5498TABLE3.HTML

de Majo F, Martens L, Hegenbarth JC, Rühle F, Hamczyk MR, Nevado RM, et al. Genomic instability in the naturally and prematurely aged myocardium. Proc Natl Acad Sci U S A. National Academy of Sciences; 2021;118: e2022974118. doi:10.1073/PNAS.2022974118/SUPPL_FILE/PNAS.2022974118.SAPP.PDF

Robinson PS, Coorens THH, Palles C, Mitchell E, Abascal F, Olafsson S, et al. Increased somatic mutation burdens in normal human cells due to defective DNA polymerases. Nat Genet 2021 5310. Nature Publishing Group; 2021;53: 1434–1442. doi:10.1038/s41588-021-00930-y

Sinclair DA, Mills K, Guarente L. Accelerated aging and nucleolar fragmentation in yeast SGS1 mutants. Science (80- ). American Association for the Advancement of Science; 1997;277: 1313–1316. doi:10.1126/science.277.5330.1313

Smeal T, Claus J, Kennedy B, Cole F, Guarente L. Loss of Transcriptional Silencing Causes Sterility in Old Mother Cells of S. cerevisiae. Cell. Cell Press; 1996;84: 633–642. doi:10.1016/S0092-8674(00)81038-7

Park PU, Defossez P-A, Guarente L. Effects of Mutations in DNA Repair Genes on Formation of Ribosomal DNA Circles and Life Span in Saccharomyces cerevisiae . Mol Cell Biol. American Society for Microbiology; 1999;19: 3848–3856. doi:10.1128/MCB.19.5.3848/ASSET/D1E72663-9CCB-4583-8D74-8D455B378AFB/ASSETS/GRAPHIC/MB0591949006.JPEG

Yang J-H, Hayano M, Griffin PT, Amorim JA, Bonkowski MS, Apostolides JK, et al. Loss of epigenetic information as a cause of mammalian aging. Cell. Elsevier; 2023;186: 305-326.e27. doi:10.1016/J.CELL.2022.12.027

Takahashi K, Yamanaka S. Induction of Pluripotent Stem Cells from Mouse Embryonic and Adult Fibroblast Cultures by Defined Factors. Cell. Cell Press; 2006;126: 663–676. doi:10.1016/J.CELL.2006.07.024

Ocampo A, Reddy P, Martinez-Redondo P, Platero-Luengo A, Hatanaka F, Hishida T, et al. In Vivo Amelioration of Age-Associated Hallmarks by Partial Reprogramming. Cell. Cell Press; 2016;167: 1719-1733.e12. doi:10.1016/J.CELL.2016.11.052

Sarkar TJ, Quarta M, Mukherjee S, Colville A, Paine P, Doan L, et al. Transient non-integrative expression of nuclear reprogramming factors promotes multifaceted amelioration of aging in human cells. Nat Commun 2020 111. Nature Publishing Group; 2020;11: 1–12. doi:10.1038/s41467-020-15174-3

Lu Y, Brommer B, Tian X, Krishnan A, Meer M, Wang C, et al. Reprogramming to recover youthful epigenetic information and restore vision. Nature. Springer US; 2020;588: 124–129. doi:10.1038/s41586-020-2975-4

Sinclair AD. Lifespan: The Revolutionary Science of Why We Age and Why We Don’t Have To [Internet]. Atria books, Simon and Schuster; 2019. Available: https://www.amazon.com/Lifespan-Why-Age-Dont-Have/dp/0008353743/

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Claudio Viecelli

Biologe

claudio.viecelli@keyoniq.com

Molecular and Muscular Biologist. Researcher at ETH Zurich. Strength athlete.

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To die young – but at an old age

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