Unbalanced Genes Cause Aging

Northwestern University researchers have uncovered a previously unknown aging mechanism. Researchers employed artificial intelligence to assess data from a wide range of tissues obtained from people, mice, rats, and killifish in a new study. They discovered that gene length can explain most molecular-level alterations that occur with aging.

All cells must maintain a balance of long and short genes. Longer genes are associated with longer lifespans, while shorter genes are associated with shorter lifespans, according to the study. They also discovered that aging genes modify their activity as they age. Aging, in particular, is associated with a shift in activity toward short genes. This disrupts the equilibrium of gene activity in cells.

Surprisingly, this discovery was almost ubiquitous. This pattern was discovered in various animals, including humans, and in many tissues (blood, muscle, bone, and organs such as the liver, heart, intestines, brain, and lungs) studied in the study.

The discovery could pave the way for therapies to halt – or perhaps reverse – the aging process.

The findings will be published in the journal Nature Aging.

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Aging is a Subtle Imbalance in the Genes

“The changes in the activity of genes 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 was consistent across 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 nearly all of the changes in the activity of genes that happen in animals as they age. The imbalance of genes causes aging because cells and organisms work to remain balanced- what physicians denote as homeostasis,” said Northwestern’s Luís A.N. Amaral, a senior author of the study. “Imagine a waiter carrying a big tray. That tray needs to have everything balanced. If the tray is not balanced, then the waiter needs to put in extra effort to fight 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 do not seem like a big deal, but these subtle changes are bearing down on you, requiring more effort.”

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

The Genotype-Tissue Expression Project, a National Institutes of Health-funded tissue bank that archives samples from human donors for research reasons, was used by the researchers to perform the study.

The researchers first examined tissue samples from mice aged four months, nine months, twelve months, eighteen months, and twenty-four months. They discovered that the median length of genes shifted between the ages of 4 and 9 months, indicating an early initiation of the process. The researchers then examined samples from rats aged 6 to 24 months and killifish aged 5 to 39 weeks.

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How is Your Age linked with Aging

“There already seems to be something happening early in life, but it becomes more pronounced with age,” Stoeger said. “It seems that, at a young age, our cells can counter perturbations that would lead to an imbalance in gene activity. Then, suddenly, our cells are no longer able to counter it.”

Following the completion of this study, the researchers shifted their attention to humans. They examined alterations in human genes from 30 to 49, 50 to 69, and 70 and older. By the time people reached middle age, measurable changes in gene activity based on gene length had already happened.

“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, the same gender and raised in the same laboratory conditions, but the humans are all different. They all died from different causes and at different ages. We analyzed samples from men and women separately and found the same pattern.”

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Aging is not just Related to Genes

The researchers observed modest alterations in thousands of distinct genes across all animals. This suggests that aging is caused by more than simply a limited selection of genes. Aging, on the other hand, is defined by system-level alterations.

This viewpoint varies from current biology approaches that focus on the impact of single genes. Many academics expected to be able to ascribe many complicated biological events to single genes from the beginning of modern genetics in the early twentieth century. While single-gene mutations cause some diseases, such as hemophilia, the narrow approach to examining single genes have failed to yield answers for the numerous changes that occur in neuro-degenerative diseases and aging.

“We have been primarily focusing on a small number of genes, thinking that a few genes would explain the disease,” Amaral said. “So, maybe we were not 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 at space. Looking at gene activity through this new lens will enable us to see biological phenomena differently.”

How Gene Length Affects Aging

Stoeger came up with the idea to study genes based on their length after accumulating the vast datasets, many of which were used in other studies by researchers at Northwestern University Feinberg School of Medicine and in studies outside of Northwestern.

The amount of nucleotides within a gene determines its length. Each nucleotide string is translated into an amino acid, which is subsequently combined to make a protein. As a result, a lengthy gene produces a huge protein. A short gene produces a tiny protein. To achieve homeostasis, a cell must contain a balanced quantity of tiny and large proteins, according to Stoeger and Amaral. When that balance is thrown off, problems arise.

Although the researchers discovered that long genes are related to longer lifespans, they also discovered that short genes play crucial roles in the body. Short genes, for example, are used to help fight diseases.

“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.”

What Leads to Long COVID-19

This discovery may also help to explain why our bodies take longer to recuperate from illnesses as we age. Even with a minor injury, such as a paper cut, an older person's skin takes longer to heal. Cells have fewer reserves to combat the harm as a result of the imbalance.

“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.”

Because millions of genes change at the system level, it makes little difference where the illness begins. This could explain disorders such as extended COVID-19. Although a patient may recover from the initial virus, the body is damaged in other ways.

“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.”

Medical Interventions to Reverse Aging

The researchers believe their discoveries could pave the way for the creation of therapies that can reverse or delay the aging process. Current treatments for illness, the researchers suggest, focus on the symptoms of aging rather than the disease itself. Amaral and Stoeger equate it to taking Tylenol to treat a fever rather than treating the underlying ailment that produced 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.”

Source-Medindia