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Restoring Integrity of The Epigenetic Group Reverses Signs of Aging

A 13-year international study has shown for the first time that degradation of the way DNA is assembled and regulated -- so-called epigenetics -- can drive aging in organisms independently of changes in the genetic code itself. The study shows that disruption of epigenetic information causes aging in mice and that restoring the integrity of the epigenome reverses these signs of aging.

"We believe our study is the first to show that epigenetic changes are a major driver of aging in mammals," said co-corresponding author David Sinclair, professor of genetics at the Blavatnik Institute at Harvard Medical School.

An extensive series of experiments by these authors provide long-awaited confirmation that DNA changes are not the sole or even primary cause of aging. Instead, their findings suggest that chemical and structural changes to chromatin -- the complex of DNA and proteins that form chromosomes -- speed up aging without altering the genetic code itself.

"We anticipate that these findings will change the way we view the aging process and the way we treat diseases associated with aging," said co-corresponding author and co-first author Jae-Hyun Yang, a genetics researcher in Sinclair's laboratory.

Given that it is easier to manipulate molecules that control epigenetic processes than to reverse DNA mutations, the new research points to new avenues that focus on epigenetics rather than genetics to prevent or treat age-related damage, the authors said.

First, these results need to be validated in large mammals and humans. Research in non-human primates is currently ongoing. "We hope these results are seen as a turning point in our ability to control aging," Sinclair said. "This is the first study to show that we can precisely control biological age in complex animals; we can drive it forward and backward at will."

Perhaps the most pressing question for those who study aging is what causes it. For decades, a leading theory in the field has been that aging results from a buildup of DNA changes, mostly genetic mutations, that over time make more and more genes fail to function properly. These malfunctions in turn cause cells to lose their identity, causing tissues and organs to collapse, leading to disease and eventual death.

However, in recent years, more and more studies have shown that this is not the case. For example, some scientists have found that some people and mice with high mutation rates do not show signs of premature aging. Others have observed that many types of senescent cells have few or no mutations.

Scientists are beginning to wonder what else causes aging along with or instead of DNA changes. A growing list of possible culprits. Among them are epigenetic changes.

One component of epigenetics is a physical structure, such as histones, that wrap DNA into compact chromatin and unwind parts of the DNA when needed. When genes are wrapped, they are inaccessible, but when they are unwrapped, they can be transcribed and used to make proteins. Thus, epigenetic factors regulate which genes are active or inactive in any given cell at any given time.

By acting as toggle switches for gene activity, these epigenetic molecules help determine cell type and function. Since every cell in an organism has essentially the same DNA, it's the on-off switches of specific genes that differentiate nerve cells from muscle cells and lung cells.

In the late 1990s and early 2000s, the Sinclair lab and others had identified epigenetic changes that accompany aging in yeast and mammals. However, they were unable to tell whether these changes were driving aging or a consequence of aging. It was not until this new study that Sinclair and his research team were able to separate epigenetics from genetic changes and confirm that disruption of epigenetic information actually promotes aging in mice.

Sinclair's team's main experiment involved creating temporary, fast-healing DNA breaks, or nicks, in the DNA of laboratory mice. These breaks mimic the low-level, continuous breakage of chromosomes that mammalian cells experience every day from breathing, exposure to sunlight and cosmic rays, and exposure to certain chemicals.

In the new study, to test whether aging arises from this process, Sinclair and colleagues increased the number of DNA breaks to simulate fast-forwarding life. They also made sure that most of the breaks were not within the coding regions of the mouse DNA -- the segments that make up genes. This prevented the genes from mutating in these mice. Instead, these breaks change the way DNA is folded. They called their system ICE, short for inducible changes to the epigenome.

At first, epigenetic factors suspend their normal task of regulating genes and move to DNA breaks to coordinate repair. Afterwards, the factors returned to their original positions. But over time, things changed. They noticed that the elements became "distracted" and did not return to their original position after repairing the break. The epigenome becomes disorganized and begins to lose its original information. Chromatin condenses and unfolds in the wrong patterns, a hallmark of epigenetic dysfunction.

As these mice lost their youthful epigenetic functions, they began to look and behave old. The authors observed increases in biomarkers indicative of aging. Cells lose their identity. Organizational function is weakened. Organ failure.

The authors used a tool recently developed in the Sinclair lab to measure the age of mice not chronologically (in days or months), but in terms of how many sites in the genome lost the genes normally attached to them. Methyl, to measure "biologically". ICE mice were significantly older compared to untreated mice born at the same time period.

The gene therapy delivered three genes -- Oct4, Sox2 and KLF4, collectively named OSK -- that are active in stem cells and help mature cells return to an earlier state. This ICE approach provides a new way to explore the role of epigenetics in aging and other biological processes. The approach also saves scientists studying aging time and money, as the ICE mice show signs of aging after only six months rather than at the end of the average mouse's two-and-a-half-year lifespan.

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