Researchers discover previously unknown mechanism that drives aging

Clock aging time old

The discovery could open the door to interventions to slow or even reverse the aging process.

A previously unknown mechanism driving aging has been found to be universal in a range of different animals, including humans.

  • A new study finds that most of the molecular-level changes that occur during aging are related to gene length
  • Organisms balance the activity of short and long genes
  • Aging is accompanied by a shift in gene activity towards short genes, which are associated with accelerated aging
  • Researcher: “Aging is a subtle imbalance away from equilibrium” that makes your cells work harder to function properly
  • Findings could lead to medical interventions that slow or even reverse the biological signatures of aging

A groundbreaking study by researchers at Northwestern University has uncovered a previously unknown mechanism that controls aging.

Using artificial intelligence, the team analyzed data from a wide variety of human, mouse, rat and killifish tissues. They found that gene length plays an important role in the molecular changes that occur during aging.

All cells must balance the activity of long and short genes. The researchers found that longer genes are linked to a longer lifespan and shorter genes are linked to a shorter lifespan. They also found that aging genes change their activity depending on height. More specifically, aging is associated with a shift in activity to short genes. This causes gene activity in cells to become unbalanced.

Surprisingly, this finding was almost universal. The researchers found this pattern in several animals, including humans, and in many tissues (blood, muscles, bones, and organs, including liver, heart, intestines, brain, and lungs) analyzed in the study.

The new finding could potentially lead to interventions designed to slow or even reverse the rate of aging. The study was recently published in the journal Nature aging.

“The changes in gene activity are very, very small, and these small changes involve thousands of genes,” said Northwestern’s Thomas Stoeger, who led the study. “We found that this change was consistent across tissues and across animals. We found it almost everywhere. I think it’s very elegant that a single, relatively succinct principle seems to explain almost all of the changes in gene activity that take place in animals as they get older.”

“The imbalance of genes causes aging because cells and organisms work to maintain balance — what doctors call homeostasis,” said Northwestern’s Luís AN Amaral, a senior author on the study. “Imagine a waiter carrying a large tray. That tray must have everything in balance. If the tray is not balanced, the waiter has to make extra effort to counteract the imbalance. If the balance in the activity of short and long genes shifts in an organism, the same thing happens. It’s like aging is this subtle imbalance away from equilibrium. Small changes in genes don’t seem like a big deal, but these subtle changes affect you and require more effort.”

Amaral, an expert in complex systems, is the Erastus Otis Haven Professor of Chemical and Biological Engineering at Northwestern’s McCormick School of Engineering. Stoeger is a postdoctoral researcher in Amaral’s lab.

Looking across ages

To conduct the study, the researchers used several large datasets, including the Genotype-Tissue Expression Project, a National Institutes of Health-funded tissue bank that archives samples from human donors for research purposes.

The research team first analyzed tissue samples from mice aged 4 months, 9 months, 12 months, 18 months and 24 months. They noticed that the median length of genes shifted between the ages of 4 months and 9 months, a finding that indicated an early-onset process. Next, the team analyzed samples from rats aged 6 months to 24 months and killifish aged 5 weeks to 39 weeks.

“Something seems to happen early in life, but it becomes more pronounced with age,” Stoeger said. “It seems that at a young age our cells are able to counteract disruptions that would lead to an imbalance in gene activity. Then suddenly our cells can’t counteract it.”

After completing this study, the researchers turned their attention to humans. They looked at changes in human genes from ages 30 to 49, 50 to 69, and then 70 and older. Measurable changes in gene activity based on gene length were already taking place by the time people reached middle age.

“The result for humans is very strong because we have more samples for humans than for other animals,” Amaral said. “It was also interesting because all the mice we studied are genetically identical, have the same sex and were raised under the same lab conditions, but the people are all different. They all died of different causes and at different ages. We analyzed samples from men and women separately and found the same pattern.”

Changes at ‘system level’

In all the animals, the researchers noticed subtle changes in thousands of different genes in different samples. This means that not just a small subset of genes contribute to aging. Aging, on the other hand, is characterized by system-level changes.

This view differs from mainstream biological approaches that study the effects of individual genes. Since the dawn of modern genetics in the early 1900s, many researchers have expected to attribute many complex biological phenomena to single genes. And while some diseases, such as hemophilia, result from single gene mutations, the narrow approach of studying single genes has yet to lead to explanations for the myriad changes that occur in neurodegenerative disease and aging.

“We mainly focused on a small number of genes, assuming that a few genes would explain the disease,” Amaral said. “So maybe we weren’t focused on the right thing before. Now that we have this new understanding, it’s like we have a new tool. It’s like Galileo with a telescope looking at space. Looking at gene activity through this new lens allows us to see biological phenomena differently.”

Long insights

After compiling the large datasets, many of which have been used in other studies by researchers at[{” attribute=””>Northwestern University Feinberg School of Medicine and in studies outside Northwestern, Stoeger brainstormed an idea to examine genes, based on their length.

The length of a gene is based on the number of nucleotides within it. Each string of nucleotides translates to an amino

Suspected ties to long COVID-19

This finding also may help explain why bodies take longer to heal from illnesses as they age. Even with a simple injury like a paper cut, an older person’s skin takes a longer time to recover. Because of the imbalance, cells have fewer reserves to counteract the injury.

“Instead of just dealing with the cut, the body also has to deal with this activity imbalance,” Amaral hypothesized. “It could explain why, over time with aging, we don’t handle environmental challenges as well as when we were younger.”

And because thousands of genes change at the system level, it doesn’t matter where the illness starts. This could potentially explain illnesses like long

Hope for medical interventions

The researchers believe their findings could open new venues for the development of therapeutics, designed to reverse or slow aging. Current therapeutics to treat illness, the researchers argue, are merely targeting the symptoms of aging rather than aging itself. Amaral and Stoeger compare it to using Tylenol to reduce a fever instead of treating the illness that caused the fever.

“Fevers can occur for many, many reasons,” Amaral said. “It could be caused by an infection, which requires antibiotics to cure, or caused by appendicitis, which requires surgery. Here, it’s the same thing. The issue is the gene activity imbalance. If you can help correct the imbalance, then you can address the downstream consequences.”

Other Northwestern co-senior authors include Richard Morimoto, a professor of molecular biosciences in the Weinberg College of Arts and Sciences; Dr. Alexander Misharin, an associate professor of medicine at Feinberg; and Dr. G.R. Scott Budinger, the Ernest S. Bazley Professor of Airway Diseases at Feinberg and chief of pulmonary and critical care at Northwestern Medicine.

Reference: “Aging is associated with a systemic length-associated transcriptome imbalance” by Thomas Stoeger, Rogan A. Grant, Alexandra C. McQuattie-Pimentel, Kishore R. Anekalla, Sophia S. Liu, Heliodoro Tejedor-Navarro, Benjamin D. Singer, Hiam Abdala-Valencia, Michael Schwake, Marie-Pier Tetreault, Harris Perlman, William E. Balch, Navdeep S. Chandel, Karen M. Ridge, Jacob I. Sznajder, Richard I. Morimoto, Alexander V. Misharin, G. R. Scott Budinger and Luis A. Nunes Amaral, 9 December 2022, Nature Aging.
DOI: 10.1038/s43587-022-00317-6

The study was funded by the U.S. Department of Defense, the National Institutes of Health, the National Science Foundation, and the Veterans Administration Medical Center. 

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