It's Only a Matter of Time
Identifying the Cause of Mammalian Age
How do you quantify age? We mark our calendars, ring in the new year, and celebrate our birthdays. But we know that chronological time is not a perfect measure of age.
Discoveries in the field of epigenetics have revealed that we all age differently. Between the uniqueness of each person’s DNA and the life choices that can play a role on epigenetics, no two individuals will have the exact same aging process. But what drives the natural aging process, genetics, epigenetics, or both? Scientists have uncovered so much about the characteristics, causes, and effects of epigenetic age in the last few decades. We know that epigenetic information is changed over time in mammals, but we still have not assessed if that is a cause or consequence of aging.
Looking at the Research
Two publications from the 1950’s independently proposed that loss of genetic information causes aging. [1,2] Yet other, subsequent published studies do not support loss of genetic material as the cause of aging. A primary example challenging the opinion is that cloning from older somatic cells will still produce individuals with normal lifespans. [3] Studies have also been published showing epigenetic information loss as a cause of aging, as opposed to genetic information loss. [4,5] We also know that DNA damage most consistently linked to aging is double stranded DNA break (DSB) and that any defects in DSB repair result in accelerated aging. [6] Other studies support that aging may be caused by dysregulation of transcriptional networks and epigenetics over time. [7,8]
Recent discoveries have found that methylation status of specific CpG sites will predictably change over time. These findings have shown that we can use CpG changes to estimate biological age within a species as well as across species. [9,10,11,12,13] All this research points to a few conclusions. Aging is not random. Instead, it is driven or programmed by predictable and reproducible epigenetic changes.
What's New?
A recent study led by academic leader David Sinclair, Ph.D., professor of genetics at Harvard Medical School and anti-aging researcher at Harvard University, took a deep dive to test the cause of mammalian aging.
A system called ICE (Inducible Changes to the Epigenome) was generated that allowed researchers to accelerate age-related epigenetic changes. The ICE system gave the researchers the ability to create DSBs at more natural levels for both in vitro and in vivo experiments.
Zymo Research scientists Yap Ching Chew, Wei Guo, and Xiaojing Yang were excited to be a part of the expert research team. With their own extensive background in science, they contributed to the research involving mouse muscle age. The aging clock has an assortment of applications in both research and industry, and the team was excited to see how the Zymo Research SWARM system could assist in the project. Zymo Research’s Quick-DNA Universal kit and Genomic DNA Clean & Concentrator-10 were used for Reduced representation bisulfite sequencing. The Epigenetic age samples were preserved in DNA/RNA Shield and DNA was purified using Quick-DNA Plus Kit. Genomic DNA was bisulfite converted using EZ DNA Methylation-Lightning Kit.
They found evidence that changes to the epigenetic landscape accelerated the DNA methylation clock, suggesting that DSB repair alters the epigenome and accelerates aging. Among the results shown, changes to the epigenetic landscape led to loss of cellular identity and caused age-related decline in tissue function. Post-treated ICE cells displayed characteristic physical changes of old age that were not seen in wild types during the same time frame. ICE treated mice also had reduced ability for memory recall as well as significantly less muscle mass, physical endurance, and reduced ATP, all hallmarks of aging in the species. The rate of epigenetic aging was estimated to be ~50% faster in the ICE mice than controls.
All the findings support the hypothesis that loss of epigenetic information over time contributes to aging. As the authors summarize: ‘Repairing DNA causes chromatin reorganization and a loss of cell identity that may in turn contribute to mammalian aging’.
This article is currently in review for publication. You can check out the details and read the full paper through Cell Press Sneak Peak.
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Learn MoreReferences
- Medawar, P.B. (1952). An unsolved problem of biology (Published for the College by H.K. Lewis).
- Szilard, L. (1959). ON THE NATURE OF THE AGING PROCESS. Proceedings of the National Academy of Sciences of the United States of America 45, 30-45.
- Burgstaller, J.P., and Brem, G. (2017). Aging of Cloned Animals: A Mini-Review. Gerontology 63, 417-425.
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- Sinclair, D.A., Mills, K., and Guarente, L. (1997). Accelerated aging and nucleolar fragmentation in yeast sgs1 mutants. Science (New York, NY) 277, 1313-1316.
- Vilenchik, M.M., and Knudson, A.G. (2003). Endogenous DNA double-strand breaks: Production, fidelity of repair, and induction of cancer. Proceedings of the National Academy of Sciences 100, 12871-12876.
- Mills, K.D., Sinclair, D.A., and Guarente, L. (1999). MEC1-dependent redistribution of the Sir3 silencing protein from telomeres to DNA double-strand breaks. Cell 97, 609-620.
- Oberdoerffer, P., Michan, S., McVay, M., Mostoslavsky, R., Vann, J., Park, S.K., Hartlerode, A., Stegmuller, J., Hafner, A., Loerch, P., et al. (2008). SIRT1 redistribution on chromatin promotes genomic stability but alters gene expression during aging. Cell 135, 907-918.
- Hannum, G., Guinney, J., Zhao, L., Zhang, L., Hughes, G., Sadda, S., Klotzle, B., Bibikova, M., Fan, J.B., Gao, Y., et al. (2013). Genome-wide methylation profiles reveal quantitative views of human aging rates. Molecular cell 49, 359-367.
- Horvath, S. (2013). DNA methylation age of human tissues and cell types. Genome biology 14, R115.
- Lu A.T., Fei, Z., Haghani, A., Robeck, T.R., Zoller, J.A., Li, C.Z., Zhang, J., Ablaeva, J., Adams, D.M., Almunia, J., et al. (2021). Universal DNA methylation age across mammalian tissues. bioRxiv, 2021.2001.2018.426733.
- Petkovich, D.A., Podolskiy, D.I., Lobanov, A.V., Lee, S.G., Miller, R.A., and Gladyshev, V.N. (2017). Using DNA Methylation Profiling to Evaluate Biological Age and Longevity Interventions. Cell metabolism 25, 954-960 e956.
- Weidner, C.I., Lin, Q., Koch, C.M., Eisele, L., Beier, F., Ziegler, P., Bauerschlag, D.O., Jockel, K.H., Erbel, R., Muhleisen, T.W., et al. (2014). Aging of blood can be tracked by DNA methylation changes at just three CpG sites. Genome biology 15, R24.
