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Proc Natl Acad Sci U S A
Proc Natl Acad Sci U S A
PNAS
Proceedings of the National Academy of Sciences of the United States of America
0027-8424
1091-6490
National Academy of Sciences

39236237
202416630
10.1073/pnas.2416630121
front-matterFront Matterinner-workInner WorkingsgeneticsGenetics102
419
Inner Workings
Biological Sciences
Genetics
Gene length could be a critical factor in the aging of the genome
Brouillette Monique Science Writer
5 9 2024
10 9 2024
5 9 2024
121 37 e24166301212024
https://creativecommons.org/licenses/by-nc-nd/4.0/ This article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND).

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pmcThe quest to understand aging has long focused on identifying genes responsible for its relentless march. Yet, these efforts have yielded a frustrating lack of genetic clues. Time after time, geneticists have failed to pinpoint aging’s genetic underpinnings.

Some researchers contend that aging’s genetic signature is rooted more in gene length, and the physical properties of aging genes, than in gene function. Image credit: Rothschild.

Multiple groups of researchers have converged upon a new theory with a consistent through line: during aging, longer genes are expressed less often than shorter genes. In March, four groups of scientists published a paper detailing what they call “gene length-dependent transcription decline” (GLTD) (1). Intriguingly, it’s an idea rooted more in gene length, and the physical properties of aging genes, than in gene function. Already, independent lines of research suggest that gene expression decreases in the largest genes. Work based on human, mouse, and fruit fly databases revealed similar findings. Together, the findings may reveal an important principle of aging that could have implications for developing new aging biomarkers and anti-aging strategies—though the notion is not without its critics.

New Clues in Old Data

Over the past several years, Ander Izeta, a stem cell biologist at the Biogipuzkoa Research Institute in San Sebastian, Spain, has examined the transcription patterns in the aging genome. Initially, he failed to find any discernable patterns.

His luck changed when he learned of data from Jan Hoeijmakers, a molecular geneticist at Erasmus University in Rotterdam, the Netherlands. Published in 2016, the work showed a disruption in the expression of long genes in the aging liver (3). At the time, nobody knew whether it was a widespread trend or a one-off finding specific to the liver. Izeta and his team set out to investigate.

They first examined a gene expression database of the aging mouse known as the Tabula Muris Senis. It contains gene expression information from 350,000 cells in mice across their lifespans from the baby to the elderly stage. They found, in multiple organs, that the longest genes were the least active in the oldest individuals. Hoeijmakers’ liver data turned out to be the tip of the iceberg. Izeta’s lab saw the same pattern (2) in the bladder, brain, heart, kidney, liver, lung, muscle, pancreas, skin, spleen, and thymus. Later, they repeated the analysis in other datasets, including the human lung, pancreas, and skin, and even female-mouse-specific data. The results came back the same: an age-associated shutdown of gene expression in long genes across all cell types. “It was amazing—the best correlation I have seen,” Izeta says.

Izeta’s team wasn’t the only one to stumble upon this connection. Computational biologist Thomas Stoeger at Northwestern University in Illinois came to a similar conclusion through a different route (4). Stoeger had been mulling over a puzzling pattern: among the roughly 20,000 protein-coding genes, some have been studied more than others—particularly those of interest before the advent of advanced genomics tools (5). Genes may be overlooked for various reasons—perhaps, for example, the gene is patented, or findings seem only relevant to a particular species or gene. Once Stoeger understood this bias, he developed a tool to apply filters to highlight lesser-known genes. Among his findings: a new gene involved in aging.

The gene, called Splicing factor, proline- and glutamine-rich (Sfpq), has a role in the elongation of RNA during the transcription of long genes. It was a eureka moment for Stoeger, highlighting the relationship between gene length and aging. “I realized that there must be an understudied corner of aging biology hiding behind this gene,” he says.

Later, Stoeger’s team examined eight interventions known to extend the lifespan of mice. His question was simple: if gene expression gets turned down with age, can anti-aging treatments turn it back up again? He found significant evidence that it could. When he gave mice known anti-aging interventions such as rapamycin, resveratrol, and senolytics, there was a significant uptick in the expression of long genes. His research, published in 2022 (6), confirmed Izeta’s.

“It is really cool that this phenomenon is malleable,” says Matthew Yousefzadeh, an aging researcher at Columbia University in New York. Yousefzadeh believes the discovery could point to biomarkers that help track aging and test anti-aging interventions. “I think it is really interesting that they overlaid length with transcription data,” he says. “Someone should have done this years ago.”

According to one study, older mice show decreased gene expression of long genes in various tissues compared to young mice, as this figure shows. Image credit: Reprinted from ref. 2 under CC BY-NC-ND 4.0.

Why Length Matters

Some cells and tissues express more long genes than others. The nervous system has the longest genes in the genome—the human dystrophin gene, widely expressed in human astrocytes, is 2.3 million base pairs long and takes roughly 16 hours to transcribe into RNA. According to Stoeger, such extended transcription time increases the occurrence of transcription errors, such as incorrectly paired nucleotides or a problem with chromatin unwinding.

Transcription errors are the focus of Hoeijmakers’ research. For decades before his pivotal discovery in the mouse liver, he studied rare diseases and the malfunctioning DNA repair mechanisms that cause them. Xeroderma pigmentosum causes extreme ultraviolet (UV)-light sensitivity and a high risk of skin cancer. Cockayne syndrome causes microcephaly, short stature, learning delays, and early death. Trichothiodystrophy entails brittle hair, failure to grow, and developmental delay.

One by one, Hoeijmakers made genetic models of these diseases in mice; he noticed that the symptoms mimicked those of aging. His mice were born able to see, but went blind. They were born able to hear, but the sense diminished over time, starting with high-frequency sounds. Their spines curved, and they developed hypertension, atherosclerosis, frailty, and even incontinence. When he bred different DNA repair mutants to each other, combining their genetic defects, their progeny suffered even worse effects. According to Hoeijmakers, the mouse models were “an eye opener.” Not only did he observe the obvious parallels with aging, but he also discovered hidden molecular effects.

In 2016, he published a paper showing that long genes are less active in the liver and the hippocampus of elderly mice (3), offering a first glimpse at the relationship between aging and downregulation of long genes. In 2023, he and his colleagues confirmed the trend (7). To gauge gene length, they examined RNA transcription in older mice and found that in elderly mice (roughly 2 years of age), there was a significant reduction in RNA transcription compared to 15-week-old mice in many organs. Overall, they found a 1.5-fold reduction in new RNA synthesis in elderly mice that occurred in a gene-length-dependent manner.

Additional work helped determine whether the phenomenon was linked to DNA damage. The researchers cultured cells from mice genetically altered to have nonfunctioning DNA repair mechanisms. They then subjected the cells to increasing doses of UV light, which is known to create DNA lesions. The cells given the highest doses of UV light had the most dramatic decline in transcription in a length-dependent manner.

“All of a sudden, there are many pieces of the puzzle that fold together. You know we have found one main cause of aging.”

—Jan Hoeijmakers

Hoeijmakers says the research backed up his long-held suspicion that the breakdown of DNA repair mechanisms leads to aging. DNA damage happens randomly around the genome, and long genes are disproportionately affected, simply because they make up a higher proportion of the genome. “If we can reduce DNA damage or boost protection mechanisms, it should lead to less damage and delay aging,” he says, “and thereby delay dementia, cardiovascular disease, osteoporosis, and more.”

“All of a sudden, there are many pieces of the puzzle that fold together,” he says. “You know we have found one main cause of aging.”

Physics of Aging

But just how important these long genes are for aging remains a matter of debate. “Everything changes with age,” says Vadim Gladyshev, an aging researcher at Harvard University in Massachusetts. He calls aging a multidimensional process that includes the epigenome, metabolome, transcriptome, and more. “There is no major driver or major contributor to all these changes,” he says. Gladyshev is not discounting the research, but cautions that long genes shouldn’t be given too much credit or blame for aging because it is a multifaceted process. “There's no silver bullet. It's everything that changes,” he adds.

Indeed, Mahdi Moqri, professor of medical genetics at Harvard Medical School, emphasizes that there are many theories of aging; this is just one of them. “Ten years ago, there were 300 different theories of aging, and more and more keep coming every day,” he says.

Still, the work could offer a relatively untrodden path to useful biomarkers and therapeutics. “I think as biologists, we have our own bias,” Izeta says. “We always think of genes and gene expression in terms of function. In my opinion, what we have found—all of us together—is a phenomenon that is just pure physics—three-dimensional physics.”

Prioritizing genome form over function remains an unconventional approach. But it could allow scientists to see new patterns in old data, perhaps unlocking new avenues of therapies and ways to combat aging. “There could be paradigm shifts in interventions,” Stoeger adds, “and a new class of biomarkers and interventions that are conceptually different from what others have done in the past.”
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