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 process called splicing. Pol II oversees the entire process, making sure that hundreds of thousands of RNAs are perfectly made.
Yet as we age, the process degrades. No one has figured out why.
The new study asked: why not hone in on the star of the transcription show?
Spanning Species
Deciphering aging hallmarks comes with a stumbling block: a potential lead may only be relevant for one species.
The new study tackled the problem head-on by examining five species. Using a technique called RNA sequencing, they captured Pol II’s speed as it rolled down the DNA of worm, fruit fly, mouse, rat, and human cells at different ages. Human samples ranged from 21 to 70 years of age, along with two “immortal” cultured cell lines.
For an even more comprehensive view the team tested samples from multiple organs, including the brain, liver, kidneys, and blood.
The results came back as a surprise. Although every species had their own Pol II “speed signature,” the trend was the same: Poll II sped up across species with age in every tissue examined. The exact gene or tissue didn’t matter. The age-related change covered roughly 200 different genes in multiple species. Rather than a local change, the Pol II speed-up seemed to be a universal aging marker.
With speed, however, came errors. Splicing—which edits pre-RNAs—requires Pol II speed to be in a Goldilocks zone. Increasing the speed boosts the risk of bad translations, which in previous studies “has been associated with advanced age and shortened lifespan,” the authors explained.
“Increased speeds of Pol II can lead to more transcriptional errors because the proofreading capacity of Pol II is challenged,” they said.
Turning Back the Clock
If Pol II in overdrive contributes to aging, can we slow it down—and in turn combat aging?
In one test, the team tapped into two well-known treatments for delaying aging: inhibiting insulin signaling and caloric restriction. In worms, flies, and mice, genetically disrupting the insulin-sensing pathway slowed down the pace of Pol II. Putting mice on a diet in early adulthood and middle age—but not old age—also tapped the brakes on Pol II.
Another test honed in on the ultimate question: does Pol II acceleration drive aging? Here, the team tracked a horde of genetically engineered worms and fruit flies harboring mutations that reduce their Pol II speed. Compared to non-mutants, both engineered strains extended their lifespans by 10 to 20 percent.
When the team used CRISPR-Cas9 to reverse the Pol II mutations in worms, however, their lifespan shortened and matched the wild-type peers. It seems like Pol II is a cause for aging, explained the authors.
Why?
Digging deeper into the transcription machinery, the team found one answer. Remember: DNA is wrapped in bacon-asparagus bundles, known scientifically as nucleosomes. By comparing human umbilical vein cells and lung cells, the team found that as cells age, the bundles slowly unwind and fall apart. This makes it far easier for Pol II to slide across a DNA strand, in turn triggering a transcription speed boost.
Further testing their theory, the team genetically inserted two types of histone proteins—the asparagus part of the nucleosome bundle—to form more nucleosomes in human cells in Petri dishes. This in turn created additional speed bumps for Pol II and slowed it down.
It worked. Cells with additional histone proteins had less chance of becoming zombie senescent cells. In fruit flies, a popular model for longevity research, the genetic tweak gave them a notable lifespan bump.
Although it’s still very early, the results are great news for potentially pursuing a novel class of anti-aging drugs. Pol II has been extensively researched in cancer therapy, with multiple medications already tested and approved, providing the chance of repurposing the medications for longevity research.
“Together, the data presented here reveal a molecular mechanism contributing to aging and serve as a means for assessing the fidelity of the cellular machinery during aging and disease,” said the team.
Image Credit: David Bushnell, Ken Westover and Roger Kornberg, Stanford University/NIH Image Gallery
