Aging is driven by imbalanced genes

Aging is driven by imbalanced genes

Researchers at Northwestern University have discovered a previously unknown mechanism that drives aging.

In a new study, researchers used artificial intelligence to analyze data from a wide variety of tissues, collected from humans, mice, rats and killifish. They found that gene length can explain most of the molecular-level 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 longer lifespans and shorter genes are linked to shorter lifespans. They also found that aging genes change their activity depending on length. More specifically, aging is accompanied by a shift in activity towards short genes. This causes an imbalance of gene activity in the cells.

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

The new discovery could potentially lead to interventions designed to slow the rate of aging, or even reverse it.

The study was published today (December 9) in the journal Nature Aging.

“Changes in gene activity are very, very small, and those small changes involve thousands of genes,” said Thomas Stoeger of Northwestern, who led the study. “We found that this change was consistent in different tissues and in different animals. We found it almost everywhere. I find it very elegant that a single, relatively concise principle seems to account for almost all of the changes in gene activity that occur in animals as they age.

“Gene imbalance causes aging because cells and organisms work to stay balanced – what doctors call homeostasis,” said Luís AN Amaral of Northwestern, lead author of the study. “Imagine a waiter carrying a large tray. This board should have everything balanced. If the board is not balanced, the server must go the extra mile to combat the imbalance. If the balance in the activity of short and long genes shifts in an organism, the same thing happens. It’s as if aging is this subtle imbalance, far from balance. Small changes in genes don’t seem like a big deal, but those subtle changes weigh on you and require more effort.

An expert in complex systems, Amaral 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.

Look through 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 tissue bank that archives human donor samples 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 gene length shifted between the ages of 4 months and 9 months, a finding that hinted at a process with an early onset. Next, the team analyzed samples from rats, aged 6 to 24 months, and killifish, aged 5 to 39 weeks.

“It already seems like something is going on early in life, but it becomes more pronounced with age,” Stoeger said. “It seems that, from an early age, our cells are able to counter disturbances that would lead to an imbalance in gene activity. Then, all of a sudden, our cells are no longer able to counter it.

After completing this research, 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+. Measurable changes in gene activity as a function of gene length have already occurred by the time humans reach 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, of the same sex and raised in the same laboratory conditions, but humans are all different. They all died of different causes and at different ages. We analyzed male and female samples separately and found the same pattern.

Changes “at the system level”

In all the animals, the researchers noticed subtle changes in thousands of different genes across the samples. This means that it’s not just a small subset of genes that contribute to aging. Aging, on the contrary, is characterized by changes at the systems level.

“Now that we have this new understanding, it’s like having a new instrument. It’s like Galileo with a telescope, looking into space. Examining gene activity through this new lens will allow us to see biological phenomena differently. — Luis Amaral, Data Scientist

This view differs from mainstream biological approaches that study the effects of single genes. Since the advent of modern genetics in the early 20th century, many researchers expected to be able to attribute many complex biological phenomena to single genes. And although some diseases, such as hemophilia, result from mutations in a single gene, the narrow approach to studying single genes has yet to lead to explanations for the myriad changes that occur in neurodegenerative diseases and aging.

“We mainly focused on a small number of genes, thinking 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 having a new instrument. It’s like Galileo with a telescope, looking out into space. Examining gene activity through this new lens will allow us to see biological phenomena differently.

Long prospects

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

The length of a gene is based on the number of nucleotides it contains. Each chain of nucleotides translates into an amino acid, which then forms a protein. A very long gene therefore gives a large protein. And a short gene gives a small protein. According to Stoeger and Amaral, a cell must have a balanced number of small and large proteins to achieve homeostasis. Problems arise when this balance is out of whack.

Although researchers have found that long genes are associated with increased lifespan, short genes also play an important role in the body. For example, short genes are known to help fight pathogens.

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

Suspected links to the long COVID-19

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

“Instead of just dealing with the cut, the body also has to deal with this imbalance of activity,” Amaral hypothesized. “This 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, no matter where the disease begins. This could potentially explain illnesses like the long COVID-19. Although a patient may recover from the initial virus, the body suffers damage elsewhere.

“We know of cases where infections – mostly viral infections – lead to other problems later in life,” Amaral said. “Some viral infections can lead to cancer. The damage travels away from the infected site and affects other areas of our body, which is then less able to deal with environmental challenges.

Hope for medical interventions

The researchers believe their findings could open new avenues for the development of therapies designed to reverse or slow aging. Current therapies to treat the disease, researchers say, simply target the symptoms of aging rather than aging itself. Amaral and Stoeger compare it to using Tylenol to reduce fever instead of treating the disease 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 is the same. The problem is the imbalance of gene activity. If you can help correct the imbalance, then you can deal with the downstream consequences.

Other Northwestern co-lead authors include Richard Morimoto, professor of molecular biosciences at Weinberg College of Arts and Sciences; Dr. Alexander Misharin, associate professor of medicine at Feinberg; and Dr. GR Scott Budinger, Ernest S. Bazley Professor of Airway Diseases at Feinberg and Chief of Pulmonary and Critical Care at Northwestern Medicine.

The study, “Aging is associated with a length-associated systemic transcriptome imbalance,” was supported by the Office of the Assistant Secretary of Defense for Health Affairs, the U.S. Department of Defense, the National Institutes of health (grant numbers AG068544, AG049665, AG054407, AG026647, AG057296, AG059579), Veterans Administration, National Science Foundation, and a gift from John and Leslie McQuown.

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