Making the whole body or a specific organ young again so that disease goes away

Genetics professor David Sinclair explains how changes in DNA organization and regulation can accelerate or reverse signs of aging in mice.Video: Rick Grollo and Bruce Walker

“We believe our study is the first to show that epigenetic changes are a key driver of mammalian aging,” said senior author of the paper, Bravatnik Research, Harvard Medical School. Professor of Genetics, Paul F. Glenn Center for the Biology of Aging Research.

The team’s extensive series of experiments has provided long-awaited confirmation that DNA alterations are not the sole, or even the main, cause of aging. Rather, research results show that chemical and structural changes in chromatin (the complexes of DNA and proteins that make up chromosomes) accelerate aging without altering the genetic code itself.

Co-first author Jae-Hyun Yang, a genetics researcher at the Sinclair Institute, said:

The authors suggested that epigenetics, rather than genetics, would be a better choice to prevent or treat age-related damage because it is easier to manipulate the molecules that control epigenetic processes than to undo DNA mutations. It points to a new path that focuses on

First, the results need to be replicated in larger mammals and humans. Studies in non-human primates are currently underway.

“We hope that these results will be seen as a turning point in our ability to control aging,” said Sinclair. “This is the first study to show that the biological age of a complex animal can be precisely controlled, such that it can move back and forth at will.”

Beyond Mutation

Perhaps the most compelling question for those studying aging is the cause of aging.

For decades, the dominant theory in the field was that aging primarily results from the accumulation of changes in DNA by genetic mutations. Over time, more and more genes stop working properly. These malfunctions lead to cells losing their identity, tissues and organs to disintegrate, disease, and ultimately death.

However, in recent years, a growing body of research suggests there is more to the story.

For example, some researchers have found that some people and mice with high mutation rates show no signs of premature aging. Others have observed that many types of senescent cells have few or no mutations.

Researchers have begun to wonder what works in conjunction with, or instead of, the DNA changes that cause aging. The list of possible culprits has grown. Among them were epigenetic changes.

The building blocks of epigenetics are physical structures such as histones that bundle DNA into tightly packed chromatin and unwind portions of that DNA as needed. Genes are inaccessible when bundled, but can be copied and used to make proteins when unrolled. Thus, epigenetic factors regulate which genes are active or inactive within any cell at any given time.

These epigenetic molecules help define cell types and functions by acting as toggles for gene activity. Since each cell in an organism has essentially the same DNA, switching specific genes on and off differentiates nerve cells from muscle cells and lung cells.

“Epigenetics is like a cell’s operating system, telling you how to use the same genetic material in different ways,” says a former postdoctoral fellow in Sinclair’s lab, now at Keio University’s graduate school. Motoshi Hayano and co-first author Yang said: Medicine in Tokyo.

In the late 1990s and early 2000s, Sinclair’s lab and others demonstrated aging-associated epigenetic changes in yeast and mammals. However, it was not clear whether these changes accelerated aging or were a consequence of it.

It wasn’t until the current study that Sinclair’s team was able to disentangle the epigenetic from genetic alterations and confirm that the disruption of epigenetic information indeed contributes to aging in mice.

ICE mouse

In the team’s main experiment, they created temporary, fast-recovering breaks in the DNA of lab mice.

These breaks mimicked the low-grade, ongoing breaks in chromosomes that mammalian cells experience every day in response to respiration, exposure to sunlight and cosmic rays, and exposure to certain chemicals. .

In this study, to test whether aging is attributable to this process, researchers increased the number of breaks to simulate life in fast-forward.

The team also confirmed that most of the cuts were not made within coding regions (segments that make up genes) of mouse DNA. This prevented the animal’s genes from mutating. Instead, the break altered the way the DNA folded.

Sinclair et al. called their system ICE. It stands for Inducible Changes to the Epigenome.

Initially, epigenetic factors paused their normal job of regulating genes and shifted to DNA breaks to coordinate repair. After that, the factor returned to its original place.

But as time went on, things changed. Researchers found that these factors were “distracted” and did not return after repairing the break. Chromatin condensed and unwound in the wrong patterns that are hallmarks of epigenetic dysfunction.

Mice that lost their youthful epigenetic function looked and behaved older. Researchers saw a rise in biomarkers indicative of aging. Cells have lost their identity as muscle and skin cells, for example. Decreased organizational function. The organ has failed.

The team used a recent tool developed in Sinclair’s lab to measure the age of the mice in days or months rather than chronologically, although the methyl groups normally attached to the mice was measured “biologically” based on the number of genome-wide sites that have lost . Compared with untreated mice born at the same time, ICE mice were significantly aged.

young again

The researchers then treated mice with gene therapy that reversed the epigenetic changes they had caused.

“It’s like restarting a dead computer,” Sinclair says.

This treatment resulted in three genes — October 4, Sox2, When Klf4These are collectively named OSKs and are active in stem cells and help rewind mature cells to their nascent state. (Sinclair’s lab used this cocktail to restore sight in blind mice in 2020.)

Organs and tissues in ICE mice regained their youthful state.

The treatment “started an epigenetic program that restored the epigenetic information that the cells had when they were younger,” Sinclair said. “It’s a permanent reset.”

It remains unclear how exactly OSK treatment was achieved.

At this stage, Sinclair said, the findings support the hypothesis that mammalian cells harbor a sort of backup copy of epigenetic software that, when accessed, becomes scrambled to senescent epigenetics. Sinclair says it supports the hypothesis that it allows cells to reboot into a youthful, healthy state.

So far, large-scale experiments have led the team to conclude that “manipulation of the epigenome can drive aging back and forth.”

from here

The ICE method offers researchers a new way to investigate the role of epigenetics in aging and other biological processes.

This approach saves time and money for researchers studying aging because ICE mice show signs of aging after just six months, rather than toward the end of the average mouse lifespan of two and a half years. will also be

Researchers can also look beyond OSK gene therapy in investigating how lost epigenetic information is restored in aging organisms.

“There are other ways to manipulate the epigenome, such as mild stress-inducing drugs and small-molecule chemicals,” Yang said. “This study opens the door for applying other methods of rejuvenating cells and tissues.”

Sinclair says the research will inspire other scientists to find ways to control aging to prevent and eliminate human aging-related diseases and conditions, such as cardiovascular disease, type 2 diabetes, neurodegeneration, and frailty. I hope to encourage you to study

“These are all signs of aging and I’ve tried to treat them with medication when they occur, but it’s almost too late,” he said.

The goal is to address the root causes of aging and extend the healthy lifespan of humans. That is, the number of years that a person can not only live, but also stay healthy.

Medical applications are still in the future and require large-scale experiments in multiple cell and animal models. But Sinclair said scientists need to think big and keep working hard to make such dreams a reality.

“We’re talking about taking an old or sick person and rejuvenating the whole body or a specific organ to get rid of the disease.” is not the way of

Long time no see

This research is the culmination of Yang’s 10-year career as a postdoctoral researcher. But there were moments along the way that he thought he would never see his work completed.

Projects were often underwhelming as the scope expanded over the years and colleagues and critics encouraged Yang to add experiments and incorporate new technologies. Yang has occasionally heard people ask if it was worth it. At one point, he drafted an email to Sinclair that he wanted to quit the project.

“Fortunately,” said Sinclair.

The problem wasn’t Yang’s skill or dedication. Rather, the research was the most ambitious ever attempted in the lab. Sinclair believes this could represent one of the most difficult projects undertaken in science in recent years.

“There aren’t many opportunities in life to do a project like this,” he said. “It has taken an incredible amount of mental and physical work to get this far. Jae and the team have been very resilient and have been working hard for another 6 years despite being rejected and re-examined. culminating in a body of work that answers one of the most important questions in biology, and I’m really proud of the team.”

Sinclair said that the findings of the finally published survey are not only professionally satisfying, but also poignant on a personal level.

“This project started when I was 39. I’m 53 now,” he said. “A lot has happened in the meantime. We are older. Our family and friends have changed. A member of the project has died. It’s a major part of life.”

“There’s a lot of emotion in this,” he continued. “I feel like a piece of my soul is there.”

Yang wants to become a senior researcher in South Korea, where he grew up.

“I am very pleased to have answered one of the long standing questions in this area,” he said. “I’m looking forward to seeing the results.”

Original: Loss of epigenetic information accelerates aging, recovery can reverse it

Than: Harvard Medical School