If changes to the epigenome drive the aging process, might epigenetic manipulation throw things into reverse gear?

Aging is a slow but gradual process that leads to the decline in normal physiological activities of living beings with time. Aging makes people more vulnerable to aging-related diseases and increases the risk of death, but as well as the visible changes aging causes, several changes take place at the DNA and chromatin organisation levels due to aging, as well. This includes changes in histone marks, relocalisation of chromatin modifying factors, nucleosome remodeling and loss, as well as reduced global heterochromatin [1].

Aging is a complicated process that is regulated by several factors [2]. Szilard and Medawar independently proposed in the 1950s that aging results due to a loss of genetic information occurring due to mutations caused by DNA damage. The most common type of DNA damage linked to aging is the double-stranded DNA break (DSB). DSBs occurs at a rate of 10 to 50 per cell each day – that’s a million DNA breaks a minute [3]. As cells repair these breaks, changes to the chromatin structure occur that can lead to the wrong genes being expressed and contributing to aging.

Recent research with yeast has suggested that perhaps it is a loss of epigenetic information (rather than genetic information) that is, in fact, a cause of aging. Studies have reported that alterations in histone modifications, histone occupancy, and gene transcription along with relocalisation of the silent information regulator complex (Sir2/3/4) away from silent mating-type loci to the unstable rDNA to be an indicator of aging in yeast.

Longevity.Technology: Epigenetic changes associated with aging include changes in DNA methylation (DNAme) patterns, but the reason for changes in the mammalian epigenome over time is not yet known. Epigenome changes in yeast can serve as clues for changes that occur in mammals; one important driver in yeast is DSBs whose repair requires many epigenetic regulators. The “Information Theory of Aging” and ‘‘RCM hypothesis” indicates that aging occurs in eukaryotes due to a loss of epigenetic information and transcriptional networks that occurs in response to cellular damage like a crash injury or a DSB.

Now an exciting new paper from a group of scientists including Jae-Hyun Yang, David Sinclair, Michael Bonkowski, Norman Wolf, Carlos Palmeira and Vadim Gladyshev have shown that cellular responses to DSBs erode the epigenetic landscape, and the resulting loss of epigenetic information accelerates the hallmarks of aging. However, these changes are reversible by epigenetic reprogramming, and by manipulating the epigenome, aging can be driven forward – and backward [4].

A new study in Cell analysed whether mammalian aging is brought about by epigenetic changes [4], using transgenic mice that had been engineered to speed up the DNA break and repair process. These mice were termed as “inducible changes to the epigenome” or ICE mice, and the researchers found a DSB marker was observed to be 4-fold above the background after 24 hours in ICE cells, and the age of ICE cells was reported to be about 1.5 times higher than controls [4].

Sinclair reports that the act of repairing DNA breaks accelerates aging at the physiological, cognitive and molecular levels, including erosion of the epigenetic landscape, loss of cell identity, senescence and increased epigenetic age [3].

The post-treated ICE cells were also reported to be more susceptible to DNA-damaging agents as well, as had reduced lamin B1 levels which is an important indicator of aging. The ICE system was observed to cause specific DNA breaks without any evidence of mutations or deleterious effects. ICE mice were observed to show signs of aging, including skin, brain, muscle and kidney aging 10 months post-treatment.

Furthermore, epigenetic aging was observed to occur about 50 percent faster in ICE mice as compared with controls, with overall, ICE treatment reported to corrupt epigenetic information. Also, the effects of DSBs on the expression of homeobox (Hox) developmental transcription factor genes were reported to be independent of where the DSB occurs. DSB breaks were also reported to alter spatial chromatin contacts.

Treated ICE cells were observed to lose their cellular identity and differentiate into other cell types, which is also termed ‘‘exdifferentiation’’. Thus, induction of non-mutagenic DSBs is reported to accelerate the epigenetic clock as well as age-related changes to cellular identity, gene expression, and chromatin.

However, the cyclic expression of Yamanaka factors Oct4, Sox2, Klf4, and Myc (OSKM) was observed to reverse age-associated mRNA changes in post-treated ICE cells [4].

The research suggests mammals retain a backup copy of epigenetic information that is capable of restoring the functions of old tissues. As Sinclair neatly puts it – if our epigenome is our genetic software, and it has become corrupted over time, could rebooting it with virally-delivered Yamanaka factors, reset the clock and reboot youth?

Work with Life Biosciences is ongoing to test this age-reversal tech in Bruce Ksander’s lab using non-human primates, and Sinclair hinted on Twitter that human trials might be underway in as little as a “couple of years” – watch this space!

[1] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6424622/
[2] https://www.nature.com/articles/s41392-022-01211-8
[3] https://twitter.com/davidasinclair/status/1613633454595313674
[4] https://www.sciencedirect.com/science/article/abs/pii/S0092867422015707