Researchers Find What Drives Aging, Reverse It In Mice

In a 13-year study, researchers led by Dr. David Sinclair have finally answered the question of what causes aging.

The study by Harvard University School of Medicine researchers demonstrates that epigenetics, which is the degradation in how DNA is organized and regulated, can drive aging in an organism.

Research published in the journal Cell on January 12 confirmed for the first time that DNA changes are not the only or leading cause of aging, which has been a reigning theory for decades.

The study found that chemical and structural changes to chromatin — the complex of DNA and proteins that form chromosomes — fuel aging without altering the genetic code.

"We believe ours is the first study to show epigenetic change as a primary driver of aging in mammals," Dr. David Sinclair, the paper's senior author, said in a press release.

The study suggests that focusing on epigenetics rather than genetics may be more beneficial in an effort to prevent or treat age-related damage. This is because it is easier to manipulate the molecules that control epigenetic processes than to reverse DNA mutations.

However, the authors say further studies in larger mammals and in humans have to be conducted.

Reversed aging in mice

In the main experiment, researchers tested whether aging results from cuts in the DNA of lab mice. These breaks mimicked the low-grade breaks in chromosomes that mammalian cells experience daily in response to breathing, exposure to sunlight and cosmic rays, and contact with certain chemicals.

The researchers then sped the number of breaks to simulate life on fast-forward. At the same time, the breaks were made outside the coding regions of the mice's DNA, which are segments that make up genes.

This prevented the mice's genes from developing mutations. Instead, the breaks altered the way DNA is folded. The researchers called the system ICE, which is 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, eventually returning to their original locations.

But as time passed, epigenetic factors did not return after repairing DNA breaks. The epigenome grew disorganized and began to lose its original information.

As the mice lost their youthful epigenetic function, they began to look and act old. Moreover, biomarkers indicating aging rose, cells lost their identities, tissue function faltered, and organs failed.

Researchers then gave the mice a gene therapy consisting of a trio of genes — Oct4, Sox2, and Klf4, together named OSK. The therapy reversed the epigenetic changes, but it remains unclear how it achieved that.

Dr. Sinclair says that 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.

"There are other ways to manipulate the epigenome, like drugs and small molecule chemicals that induce gentle stress. This work opens a door for applying those other methods to rejuvenate cells and tissues," said co-first author Jae-Hyun Yang, research fellow in genetics in the Sinclair lab.

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