For decades, popular theory postulated that aging is caused by the accumulation of mutation in one’s DNA over the course of one’s life, resulting in cells losing their identities and causing the failure of tissue and organ. However, in recent years, scientists have noticed that many types of old cells have a paucity of mutations (De Majo et al., 2021; Kaya et al., 2015). Additionally, strains of mice or people that suffer from higher mutation rates show insubstantial evidence of premature aging (Narayanan et al., 1997; Robinson et al., 2021), and mammals cloned from old somatic cells produce organisms with unaffected lifespans (Burgstaller and Brem, 2017).

The first evidence that the loss of epigenetic (relating to the expression of genes) information could be a potential cause of aging emerged from yeast studies in the 1990s. Multiple studies showed that epigenetics changes are not merely a biomarker for aging but a direct cause of it (Dang et al., 2009; Feser et al., 2010; Hu et al., 2014; Kaeberlein et al., 1999).

DNA is packaged into chromosomes in the nucleus for the majority of its lifespan. These chromosomes are made up of proteins and DNA that can loosen and tighten their structure to control their expression. This is essential for all differentiated cells; it would be disastrous if the cells in your eyes suddenly started producing hydrochloric acid. One can think of a cell as being situated someplace on an epigenetic landscape: a model of the developmental pathway that cells undergo.

We can imagine a cell’s journey to be akin to a ball rolling down a hill. At the top, we have a totipotent cell, one that has the potential to divide and reproduce to create a whole new functioning organism: a zygote, for example. Once the ball has rolled a little more down the hill, it becomes a pluripotent cell, one that has the potential to become almost all cell types but cannot evolve into its own organism (stem cells, essentially). From here the cell can go a number of ways, differentiating to achieve several different functions. Cell identity is specified by chromatin structures (the complex that chromosomes are made of) that direct the cells into the valleys of the Waddington landscape until terminal differentiation (Waddington, 1957). The catch is that the metaphorical ball can never roll back uphill after its terminal differentiation. This being said, all cells in an organism have the exact same set of DNA (save for mutations to it) so this begs the question of how permanent differentiation is even possible in the first place.

The answer lies in epigenetics. There are many different ways that gene expression is controlled in eukaryotic cells.

DNA methylation occurs at cytosine bases in DNA strands: they are converted to methylcytosine with DNA methyltransferase enzymes (DNMTs). These methylated cytosines are usually directly adjacent to a guanine nucleotide. This results in another methylcytosine diagonal to the first (due to complementary base pairing rules). This methylation decreases transcription rates in two primary ways: physically impedes the binding of proteins required to translate the DNA into mRNA and attracts proteins to the locus of methylation that repress transcription. Another way in which gene expression is controlled is through the structure of chromatins: the tightness of genes packaged up in a chromatin controls whether they are expressed or not. Proteins that transcript DNA into mRNA cannot get to the genes if they are tightly wound up.

A recently published international study, thirteen years in the making, directly implicates the degradation of the epigenetic information of a cell as a cause of aging rather than changes the cell’s DNA itself and backs this up with empirical evidence. Researchers found that epigenetic changes, changes in DNA methylation patterns, are found in multicellular organisms to cause aging (Sen et al., 2016). This being said, we actually still do not know exactly why mammalian epigenome change over time, however we can draw some conclusions from yeast. A major driver to changes in the epigenome of yeast are double stranded DNA breaks (DSB)—DNA gets completely severed and needs to be repaired by epigenetic factors that usually deal with the regulation of the genome. The leading theory is that aging in eukaryotes is due to the loss of epigenetic information over time, which is driven by a mechanism that initially evolved to regulate responses to damage such as a DSB (Yang et al., 2023). This repair causes chromatin reorganization which results in the flattening of the epigenetic landscape: causes cell identity to be lost (essentially what aging is).

This theory was tested in vivo through induced changes to the epigenome through causing DSBs without mutation (changes were not made to coding sections of genes) in mice. These mimic the cuts in DNA that mammalian cells experience regularly in response to interaction with the environment. After epigenetic factors coordinated repairs of the DSBs, they would return to their previous locations. However, as time went on these factors failed to return to the proper loci, instead drifting away from them. The epigenome became disorganized and the landscape began to flatten: chromatin was unspooled and condensed in the wrong places. When scientists tested how ‘biologically’ old the mice were, based on how many sites had lost methyl groups that should have been there, the treated mice had aged significantly more than the untreated mice in the same amount of time.

After this, researchers delivered three genes that are active in stem cells, named OSK, to the mice. These genes can help to rewind a mature cell back to an earlier state. The treated mice’s organs and tissue resumed a more youthful state and its epigenetic information was restored.

The exact process through which this works still remains unclear to researchers however they think that mammalian cells maintain a ‘backup copy’ of their epigenome that can then be reinstated to restore the cell back to a youthful state.

Regardless, these experiments consolidated the fact that the manipulation of the epigenome can drive aging back and forth at accelerated rates. Researchers are now looking for methods beyond OSK gene therapy to restore lost epigenetic information and investigating other ways that they could manipulate the epigenome to produce desirable results. True medical applications, however, are a long way off and still require extensive testing on larger mammalians such as primates and humans themselves. In the words of Dr. Sinclair, “We’re talking about taking someone who’s old or sick and making their whole body or a specific organ young again, so the disease goes away,” he said. “It is a big idea. It is not how we typically do medicine.”.

This research really opens up a new door for scientists attempting to rejuvenate tissue and cells: a method to potentially delay, prevent or entirely eliminate age-related diseases such as type 2 diabetes, neurodegeneration, and frailty.


  • Kaya, A., Lobanov, A.V., and Gladyshev, V.N. (2015). Evidence that mutation accumulation does not cause aging in Saccharomyces cerevisiae. Aging Cell 14, 366–371.
  • De Majo, F., Martens, L., Hegenbarth, J.C., Ruhle, F., Hamczyk, M.R., Nevado, R.M., Andre ́ s, V., Hilbold, E., Ba ̈ r, C., Thum, T., et al. (2021). Genomic instability in the naturally and prematurely aged myocardium. Proc. Natl. Acad. Sci. USA 118. 
  • Narayanan, L., Fritzell, J.A., Baker, S.M., Liskay, R.M., and Glazer, P.M. (1997). Elevated levels of mutation in multiple tissues of mice deficient in the DNA mismatch repair gene Pms2. Proc. Natl. Acad. Sci. USA 94, 3122–3127.
  • Robinson, P.S., Coorens, T.H.H., Palles, C., Mitchell, E., Abascal, F., Olafsson, S., Lee, B.C.H., Lawson, A.R.J., Lee-Six, H., Moore, L., et al. (2021). Increased somatic mutation burdens in normal human cells due to defective DNA polymerases. Nat. Genet. 53, 1434–1442. 00930-y.
  • Burgstaller, J.P., and Brem, G. (2017). Aging of cloned animals: A mini-review. Gerontology 63, 417–425.
  • Dang, W., Steffen, K.K., Perry, R., Dorsey, J.A., Johnson, F.B., Shilatifard, A., Kaeberlein, M., Kennedy, B.K., and Berger, S.L. (2009). Histone H4 lysine 16 acetylation regulates cellular lifespan. Nature 459, 802–807. 10.1038/nature08085.
  • Feser, J., Truong, D., Das, C., Carson, J.J., Kieft, J., Harkness, T., and Tyler, J.K. (2010). Elevated histone expression promotes life span extension. Mol. Cell 39, 724–735.
  • Kaeberlein, M., McVey, M., and Guarente, L. (1999). The SIR2/3/4 complex and SIR2 alone promote longevity in Saccharomyces cerevisiae by two different mechanisms. Genes Dev. 13, 2570–2580. gad.13.19.2570.
  • Sen, P., Shah, P.P., Nativio, R., and Berger, S.L. (2016). Epigenetic mechanisms of longevity and aging. Cell 166, 822–839. cell.2016.07.050.

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