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

A previously unknown mechanism that drives aging has been found to be universal across a variety of animals, including humans.

• New research shows that many of the molecular-level changes that occur during aging are linked to gene length.
• Microorganisms balance the activity of short and long genes
• Aging is accompanied by a change in gene activity to shorter genes associated with accelerated aging
• Researcher: “Aging is a subtle imbalance away from balance” that requires your cells to work harder to function properly.
• Findings may lead to medical interventions that slow or reverse the biological signs of aging.

Researchers at Northwestern University A previously unknown mechanism that controls aging has been revealed.

Using artificial intelligence, the team analyzed data from a wide range of tissues from humans, mice, rats and killerfish. They found that the length of genes plays a significant 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 were associated with longer lifespans, while shorter genes were associated with shorter lifespans. They also discovered that aging genes change their activity as a function of length. In particular, aging is accompanied by a movement toward shorter genes. This causes the gene activity in the cells to become unbalanced.

Surprisingly, this finding was near universal. The researchers uncovered this pattern in a variety of animals and many tissues (including blood, muscle, bone and organs, liver, heart, intestine, brain, and lung), including the humans analyzed in the study.

The new discovery could lead to interventions designed to slow or reverse the rate of aging. The study was recently published in the journal Natural 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 this change to be consistent across different tissues and across different animals. We found it almost everywhere. I find it fascinating that it seems to point to a single, relatively short principle for the changes in gene activity that occur in animals during aging.”

“Gene imbalances cause aging because cells and organisms work to maintain balance — what physicians refer to as homeostasis,” said senior author of the study, Louis A. Amal of Northwestern. “Imagine a waiter carrying a large tray. This tray should balance everything. If the tray is not balanced, the host will have to make an extra effort to combat the balance. The same thing happens if the balance in the activity of short and long genes is altered in the body. Like aging, this subtle imbalance is far from balanced. Small changes in genes don’t seem like a big deal, but these subtle changes are pushing you, which requires 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 fellow in Amaral’s lab.

Looking back over the ages.

To conduct the study, the researchers used a variety of large datasets, including the Genotype-Tissue Expression Project, a National Institutes of Health-funded project that stores samples from human donors for research.

The research team first analyzed tissue samples from mice – aged 4 months, 9 months, 12 months, 18 months and 24 months. They observed that the median length of genes changed between 4 months and 9 months, a finding that suggests an early onset process. The team then analyzed samples from mice aged 6 months to 24 months and killifish aged 5 weeks to 39 weeks.

“There seems to be something early in life, but it becomes more pronounced with age,” Stoeger said. “When we’re young, our cells seem to be able to cope with problems that lead to imbalances in gene activity. Then suddenly our cells couldn’t handle it.

After completing this study, the researchers turned their attention to humans. They observed changes in human genes from 30 to 49, 50 to 69 and then 70 and above. Measured changes in gene activity based on gene length occurred as people reached middle age.

“The results for humans are stronger because we have more samples for humans than for other animals,” Ameral said. “It was also interesting because all the mice they studied were genetically identical, sexed identically and raised in the same laboratory conditions, but humans are all different. They all died of different causes and at different ages. We analyzed samples from males and females separately and found the same pattern.

‘System-level’ changes

In all the animals, the researchers observed subtle changes in thousands of different genes in the samples. This means that it is not just a small set of genes that contribute to aging. Aging, instead, is characterized by systemic changes.

This perspective differs from biological approaches that study the effects of single genes. Since the beginning of modern genetics at the beginning of the 20th century, many researchers have expected that many complex biological phenomena can be indicated by single genes. And while some diseases, such as hemophilia, are caused by single gene mutations, the narrow approach to studying single genes fails to explain the myriad changes that occur in neurodegenerative diseases and aging.

“We’ve been focusing mainly on a few genes, thinking that a few genes explain the disease,” he said. “So, maybe we’re not focusing on the right things early on. Now that we have this new understanding, it’s like we have a new tool. Like Galileo looking through a telescope into space. Looking at gene activity through this new lens allows us to look at biological phenomena in a different way.

Long insights

After compiling the large data sets, many of them were used by other researchers in the researchers[{” 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 acid, which then forms a protein. A very long gene, therefore, yields a large protein. And a short gene yields a small protein. According to Stoeger and Amaral, a cell needs to have a balanced number of small and large proteins to achieve homeostasis. Problems occur when that balance gets out of whack.

Although the researchers did find that long genes are associated with increased lifespans, short genes also play important roles in the body. For example, short genes are called upon to help fight off pathogens.

“Some short genes could have a short-term advantage on survival at the expense of ultimate lifespan,” Stoeger said. “Thus, outside of a research laboratory, these short genes might help survival under harsh conditions at the expense of shortening the animal’s ultimate lifespan.”

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 COVID-19. Although a patient might recover from the initial virus, the body experiences damage elsewhere.

“We know cases where infections — predominantly viral infections — lead to other problems later in life,” Amaral said. “Some viral infections can lead to cancer. Damage moves away from the infected site and affects other areas of our body, which then is less able to fight environmental challenges.”

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.