By S. Dutchen, HMS
An international study 13 years in the making shows for the first time that degradation of the organization and regulation of DNA, known as epigenetics, can drive the body to age independently of changes in the genetic code.
The study showed that mice age due to disruption of epigenetic information and that restoring epigenome integrity reverses the signs of aging.
Countless experiments conducted by a team of scientists provide the long-awaited confirmation that DNA changes are not the only or even the main cause of aging. Rather, the findings suggest that chemical and structural changes to chromatin, the complex of DNA and proteins that make up chromosomes, drive aging without changing the genetic code itself.
The authors say that because it is easier to manipulate the molecules that control epigenetic processes than to reverse DNA mutations, new approaches are emerging that target epigenetics, rather than genetics, to prevent or treat age-related damage.
"We hope these results will be considered a turning point in our ability to control aging," Sinclair said. "This is the first study to show that we can precisely control the biological age of an animal; that we can slide it back and forth at will."
The study was published on January 12, 2023 in the journal Cell - Loss of epigenetic information as a cause of mammalian aging
Without Mutations
For decades, the prevailing theory in the field was that aging is caused by changes in DNA, primarily genetic mutations, that prevent genes from functioning properly over time. These disorders cause cells to lose their identity, causing tissues and organs to break down, leading to disease and ultimately death.
Scientists have also studied other factors that cause aging, including epigenetic changes. Epigenetic factors regulate which genes are active or inactive in any given cell at any given time.
Acting as a gene switch, these epigenetic molecules help define cell type and function. Since every cell in the body has essentially the same DNA, what differentiates a nerve cell from a muscle cell or a lung cell is the switching on and/or off of certain genes. "Epigenetics is like a cell's operating system that tells it how to use the same genetic material in different ways," said Yang, one of the authors.
Back in the early 2000s, studies in yeast and mammals from Sinclair's lab showed that epigenetic changes occur with aging, but they couldn't say whether these changes were a cause or a consequence of aging.
Only in the current study were Sinclair's team able to separate epigenetic changes from genetic changes and confirm that the breakdown of epigenetic information actually contributes to aging in mice.
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The team's main experiment was the creation of temporary, fast-healing DNA cuts (made in laboratory mice).
These incisions mimicked the small-scale permanent breaks in chromosomes that mammalian cells undergo every day in response to things like breathing, exposure to sunlight, and exposure to certain chemicals.
To test whether aging is caused by this process, the researchers increased the number of incisions in the study to simulate the accelerated flow of life. The team also ensured that these cuts did not cause gene mutations.
ICE Mice
Sinclair and his colleagues named their system ICE (inducible changes to the epigenome)
At first, epigenetic factors paused their normal work of gene regulation and switched to DNA breaks to coordinate their editing. Later, these factors returned to their original places.
However, over time, things changed. The researchers observed that these factors "dislodged" and did not return to their original locations after repairing the DNA breaks. The epigenome became disorganized and began to lose its original information, signaling signs of epigenetic failure.
After the mice lost their youthful epigenetic function, they began to look and behave like old people. The researchers observed an increase in biomarkers that indicate aging. Cells lost their identity, tissue function was impaired, organ function was impaired.
The team used a new tool developed by Sinclair's lab to measure the mice's age not chronologically, in days or months, but "biologically," based on how many places in the genome have lost the methyl groups normally attached to them. Compared to untreated mice born at the same time, ICE mice were significantly older.
Young again
The researchers then gave the mice gene therapy that was supposed to reverse (reverse) the epigenetic changes they had caused.
"It's like rebooting a malfunctioning computer," Sinclair said.
This therapy consisted of a trio of genes - Oct4, Sox2 and Klf4, collectively named OSK. These genes are active in stem cells and can help restore mature cells to their previous (more youthful) state. (D. Sinclair's lab used this cocktail to restore sight to blind mice in 2020.)
Organs and tissues in ICE mice became youthful again.
The therapy "starts an epigenetic program that prompts cells to restore the epigenetic information they had when they were young," Sinclair said. "It's a full recovery."
Exactly how such results were achieved with OSK remains unclear.
Sinclair says the discovery supports the hypothesis that mammalian cells have a backup copy of epigenetic software. Once it is achieved, an aging, epigenetically messed up cell can be restored to a youthful and healthy state.
Through many experiments, the team concluded that "by manipulating the epigenome, aging can be promoted both forward and backward," Yang said.
What's next
The ICE method provides scientists with a new way to study the role of epigenetics in aging and other biological processes.
Sinclair hopes the work will inspire other researchers to study aging control to prevent and reverse age-related human diseases such as cardiovascular disease, type 2 diabetes and neurodegeneration.
"These are signs of aging that we try to treat with drugs only when they occur, and then it's almost too late," he said.
The therapeutics are still a long way from being applied to medicine and will require countless detailed studies in cell and animal models. But Sinclair says scientists should think big and continue to pursue such dreams.
"We're talking about treating an old or sick person by making their body or a specific organ young again so that the disease goes away," he said. "It's a big idea. This is not how we normally practice medicine.”
This article was originally published by Harvard Medical School