An international study demonstrates for the first time that degradation in epigenetic information can drive ageing in an organism, independently of changes to the genetic code itself. Published in the journal Cell, the work shows that a breakdown in epigenetic information causes mice to age and that restoring the integrity of the epigenome reverses those signs of ageing.
“We believe ours is the first study to show epigenetic change as a primary driver of ageing in mammals,” said the paper’s senior author, David Sinclair, professor of genetics at Harvard Medical School.
The team’s extensive series of experiments provide long-awaited confirmation that DNA changes are not the only, or even the main, cause of ageing. Rather, the findings show, chemical and structural changes to chromatin contribute ageing without changing the genome.
“We expect the findings will transform the way we view the process of ageing and the way we approach the treatment of diseases associated with ageing,” said co-first author Jae-Hyun Yang, research fellow in genetics in the Sinclair lab.
Since it is easier to manipulate epigenetics than DNA, this could lead to a whole new avenue of research. Studies in nonhuman primates are currently underway.
“We hope these results are seen as a turning point in our ability to control aging,” said Sinclair. “This is the first study showing that we can have precise control of the biological age of a complex animal; that we can drive it forwards and backwards at will.”
Beyond mutations
A reigning, decades-old theory of ageing was that it arises from an accumulation of changes to DNA, primarily genetic mutations, which over time prevent more and more genes from functioning properly. Over time, researchers began finding contradictory evidence: in some human and mice, high mutation rates was not accompanied by premature ageing, while many types of aged cells lacked mutations. Some researchers believed that epigenetics could be the true culprit.
A component of epigenetics is the physical structures such as histones that bundle DNA into tightly compacted chromatin and unspool portions of that DNA when needed. Bundled up, genes are inaccessible when but are available to be copied and used to produce proteins when they’re unspooled. Thus, epigenetic factors regulate which genes are active or inactive in any given cell at any given time.
By acting as a toggle for gene activity, these epigenetic molecules help define cell type and function. Since each cell in an organism has basically the same DNA, it’s the on-off switching of particular genes that differentiates a nerve cell from a muscle cell from a lung cell.
“Epigenetics is like a cell’s operating system, telling it how to use the same genetic material differently,” said Yang, who is co-first author with Motoshi Hayano, a former postdoctoral fellow in the Sinclair lab who is now at Keio University School of Medicine in Tokyo.
In the late 1990s and early 2000s, Sinclair’s lab and others showed in yeast and mammals that epigenetic changes were associated with ageing but could not determine whether they caused it or were caused by it. At least, this new study let the scientists disentangle epigenetic causes from genetics.
ICE mice
The team’s main experiment involved creating temporary, fast-healing cuts in the DNA of lab mice, which mimicked those breaks chromosomes that mammalian cells receive on a daily basis from things like breathing, exposure to sunlight and cosmic rays, and contact with certain chemicals. This let the researchers simulate a sped-up life.
Most of the breaks did not happen in the DNA’s coding regions, so did not cause mutations. Rather, the breaks altered the way DNA is folded.
Sinclair and colleagues called their system ICE, short for inducible changes to the epigenome.
At first, epigenetic factors paused their normal job of regulating genes and moved to the DNA breaks to coordinate repairs. Afterward, the factors returned to their original locations.
But as time passed, things changed. The researchers noticed that these factors got ‘distracted’ and did not return home after repairing breaks. The epigenome grew disorganised and began to lose its original information. Chromatin got condensed and unspooled in the wrong patterns, a hallmark of epigenetic malfunction.
As the mice lost their youthful epigenetic function, they began to look and act old. The researchers saw a rise in biomarkers that indicate ageing. Cells lost their identities as, for example, muscle or skin cells. Tissue function faltered. Organs failed.
The team used a tool recently developed by Sinclair’s lab to measure how biologically old the mice were, based on how many sites across the genome lost the methyl groups normally attached to them. Compared to untreated mice born at the same time, the ICE mice had aged significantly more.
Young again
Next, the researchers gave the mice a gene therapy that reversed the epigenetic changes they’d caused, which Sinclair likened to rebooting a malfunctioning computer.
The therapy delivered a trio of genes (Oct4, Sox2, and Klf4, together named OSK) that are active in stem cells and can help rewind mature cells to an earlier state. (Sinclair’s lab used OSK to restore sight in blind mice in 2020.)
The ICE mice’s organs and tissues resumed a youthful state.
The therapy “set in motion an epigenetic program that led cells to restore the epigenetic information they had when they were young,” said Sinclair. “It’s a permanent reset.”
How exactly OSK treatment achieved that remains unclear.
At this stage, Sinclair says the discovery supports the hypothesis that mammalian cells maintain a kind of backup copy of epigenetic software that, when accessed, can allow an aged, epigenetically scrambled cell to reboot into a youthful, healthy state.
For now, the extensive experiments led the team to conclude that “by manipulating the epigenome, aging can be driven forwards and backwards,” said Yang.
From here
The ICE method offers researchers a new way to explore the role of epigenetics in ageing and other biological processes.
Because signs of ageing developed in the ICE mice after only six months rather than toward the end of the average mouse life span of two and a half years, the approach also saves time and money for researchers studying aging.
Yang said that researchers can also look beyond OSK gene therapy to other methods such as drugs, to determine how lost epigenetic information might be restored in aged organisms.
Watch the team describe their research in the video below.
Source: Harvard Medical School
