Aging Molecular Process Unlocks a Piece of the Puzzle

Friday - April 28 2023, 19:27 UTC - 1 year ago

A new study in Nature has found a critical molecular process in five species that powers every single body cell that degrades with age. With two interventions, scientists were able to slow down transcription in multiple species, including mice, thus potentially increasing lifespan.

Our bodies’ molecular machinery breaks down with age.

DNA accumulates mutations. The protective ends of chromosomes erode away. Mitochondria, the cell’s energy factory, falter and break down. The immune system goes haywire. The reserve pool of stem cells dwindles, while some mature cells enter a zombie-like state, spewing toxic chemicals into their environment.

The picture sounds dire, but it’s not all bad news. Aging is a complicated puzzle. By finding individual pieces, scientists can assemble a full picture of how and why we age—and engineer new ways to stave off age-related symptoms.

There’s already been some success. Senolytics—drugs that kill off zombie cells—are already in clinical trials. Partial reprogramming, which erases a cell’s identity and reverts it back to a stem-cell-like state, is gaining steam as a promising alternative treatment, and it’s one of the hottest longevity investments in Silicon Valley.

A new study in Nature hunted down another piece to the aging puzzle. In five species across the evolutionary scale—worms, flies, mice, rats, and humans—the team honed in on a critical molecular process that powers every single cell inside the body and degrades with age.

The process, called transcription, is the first step in turning our genetic material into proteins. Here, DNA letters are reworked into a "messenger" called RNA, which then shuttles the information to other parts of the cell to make proteins.

Scientists have long suspected that transcription may go awry with aging, but the new study offers proof that it doesn’t—with a twist. In all five of the species tested, as the organism grew older the process surprisingly sped up. But like trying to type faster when blindfolded, error rates also shot up.

There’s a fix. Using two interventions known to extend lifespan, the team was able to slow down transcription in multiple species, including mice. Genetic mutations that reversed the sloppy transcription also extended lifespan in worms and fruit flies, and boosted human cells’ ability to divide and grow.

The new hallmark of aging is hardly ready for human testing. But "it opens up a really fundamental new area of understanding how and why we age," said Dr. Lindsay Wu at UNSW Sydney, who was not involved in the study.

--- The Genetic Editor --- .

Turning our genetic blueprint into proteins is a two-step process.

First, DNA’s four letters—A, T, C, and G—are transcribed into RNA. Also made up of four letters, RNA strands are basically molecular notes that can slip past DNA’s confined space to deliver messages to the cell’s protein-making factory. There, RNA is translated into the language of proteins.

The first step—turning DNA into RNA—is harder than it sounds. To conserve space, DNA is tightly wrapped around a group of proteins called histones, like bacon around eight stalks of asparagus. This effectively "hides" the genetic information, making it impossible for the cell to read.

It takes a whole village of protein helpers to unwind DNA and prepare it for transcription. But the star is Pol II (RNA polymerase II), a giant multicomplex that moves along a DNA strand helping it transform into an early version of RNA, aptly called pre-RNA.

Like a wordy sentence, pre-RNA strands are then copyedited into pithier sequences for building proteins, a procress called alternative splicing. And that’s where the new study lands a punch.