A previously unknown mechanism that drives aging is universal to many animals, including humans.
- A new study shows that most molecular-level changes during aging are related to gene length.
- Organisms balance the activity of short and long genes.
- Aging is associated with a shift in gene activity toward short genes associated with accelerated aging.
- Researchers: “Aging is a subtle imbalance, away from equilibrium” that requires cells to exert more effort to function properly.
- Findings could lead to medical interventions that slow or even reverse biological features of aging.
A groundbreaking study by Northwestern College researchers has uncovered a previously unknown mechanism that controls aging.
The team analyzed data from various tissues from humans, mice, rats and killifish using artificial intelligence. They discovered that gene length plays an important role in molecular changes during aging.
All cells must balance the activity of long and short genes. The researchers found that longer genes are associated with a longer lifespan and shorter genes are associated with a shorter lifespan. They also found that aging genes change their activity depending on their length. More specifically, aging is associated with a shift in activity toward short genes. This causes gene activity in cells to become unbalanced.
Surprisingly, this finding was nearly universal. The researchers discovered this pattern in several animals, including humans, and in many tissues (blood, muscle, bone and organs, including liver, heart, intestine, brain and lung) analyzed in the study.
The new findings could lead to interventions to slow or reverse aging. The study was recently published in the journal Nature Aging.
“The changes in gene activity are very, very small, and these small changes affect thousands of genes,” said Thomas Stoeger of Northwestern, who led the study. “We found this change is the same in different tissues and animals. We found it almost everywhere. I think it’s very elegant that a single, relatively short principle seems to be responsible for almost all of the changes in the activity of genes that occur in animals as they age.”
“Gene imbalance causes aging because cells and organisms work to stay in balance – what medical scientists call homeostasis,” said Luís A.N. Amaral of Northwestern, one of the study’s lead authors. “Imagine a waiter carrying a large tray. Everything on that tray has to be in balance. If the tray is not in balance, the waiter has to make an extra effort to compensate for the imbalance. When the balance of activity of short and long genes in an organism shifts, the same thing happens. It is as if aging is a subtle imbalance, away from balance. Small gene changes do not seem like a big deal, but these subtle changes stress you and require more effort.”
Amaral is an expert in complex systems and the Erastus Otis Haven Professor of Chemical and Bioengineering at Northwestern College’s McCormick School of Engineering. Stoeger is a postdoctoral researcher in Amaral’s lab.
Cross-age study
To conduct the study, the researchers used several large data sets, including the Genotype-Tissue Expression Project, a tissue bank funded by the National Institutes of Health that archives samples from human donors for research purposes.
The research team first analyzed tissue samples from mice at 4 months, 9 months, 12 months, 18 months and 24 months of age. They found that the mean length of the genes shifted between 4 months and 9 months, indicating an early-onset process. The team then analyzed samples from rats aged 6 months to 24 months and from killifish aged 5 weeks to 39 weeks.
“There seems to be something happening early in life, but it becomes more pronounced as we get older,” Stoeger said. “It seems that at a young age, our cells can compensate for perturbations that would lead to an imbalance in gene activity. Then, suddenly, our cells can no longer compensate for this.
After completing this research, the researchers turned their attention to humans. They studied the changes in human genes at ages 30 to 49, 50 to 69, and then 70 and older. Measurable changes in gene activity as a function of gene length already occurred in middle age.
“The result for humans is very meaningful because we have more samples for humans than 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 laboratory conditions, but the humans are all different. They all died of different causes and at different ages. We analyzed the samples from males and females separately and found the same pattern.”
Changes at the system level
In all animals, the researchers detected subtle changes in thousands of different genes in the samples. This means it’s not just a small subset of genes contributing to aging. Rather, aging is characterized by system-level changes.
This view differs from prevailing biological approaches that study the effects of individual genes. Since the advent of modern genetics in the early 20th century, many researchers assumed that they could attribute many complex biological phenomena to single genes. And although some diseases, such as hemophilia, can indeed be traced to single gene mutations, the narrow approach to studying single genes hasn’t yet led to explanations for the myriad of changes occurring in neurodegenerative diseases and aging.
“We focused primarily on a small number of genes, thinking that a few genes would explain the disease,” Amaral said. “So maybe we weren’t focusing 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. When we look at gene activity through this new lens, we’ll be able to see biological phenomena differently.”
Lengthy findings
After compiling the large data sets, many of which have been used in other studies by researchers at Northwestern College Feinberg School of Medicine and in studies outside Northwestern, Stoeger came up with the idea of studying genes by their length.
The number of nucleotides in that gene determines the length of a gene. Each nucleotide chain is translated into an amino acid, forming a protein. So a very long gene results in a large protein. And a short gene results in a small protein. According to Stoeger and Amaral, cells must balance small and large proteins to achieve homeostasis. Problems occur when this balance gets out of whack.
Although researchers found that long genes are associated with longer life expectancy, short genes also play an important role in the body. Short genes are used, for example, to fight pathogens.
“Some short genes may have a short-term survival advantage at the expense of ultimate lifespan,” Stoeger said. “So outside of a research lab, these short genes could promote survival under harsh conditions at the expense of shortening the animal’s ultimate lifespan.”
Suspected links to long COVID-19
This finding could also explain why the body takes longer to heal from disease as we age, even with a simple injury like a paper cut, an older person’s skin takes longer to recover. Because of the imbalance, the cells have fewer reserves to counteract the injury.
“Instead of just taking care of the cut, the body also has to deal with this activity imbalance,” Amaral hypothesized. “This could explain why, as we age, we don’t cope as well with environmental challenges as we did when we were younger.”
And since thousands of genes change at the system level, it doesn’t matter where the disease starts. This could be a possible explanation for diseases like COVID-19. Even if a patient recovers from the original virus, the body suffers damage elsewhere.
“We know of cases where infections – especially viral infections – lead to other problems later in life,” Amaral said. “Some viral infections can lead to cancer. The damage moves away from the infected site and affects other parts of our body, which then becomes less able to fight environmental challenges.”
Hope for medical interventions
Researchers believe their findings could open new avenues for developing therapeutics to reverse or slow aging. The researchers argue that current therapeutics to treat disease target only the symptoms of aging and not aging itself. Amaral and Stoeger liken this to using Tylenol to lower a fever rather than treating the disease that caused the fever.
“Fever can occur for many, many reasons,” Amaral said. “It can be caused by an infection that needs to be treated with antibiotics or appendicitis that requires surgery. It’s the same thing here. The problem is the imbalance of gene activity. If you can correct this imbalance, then you can also address the downstream consequences.”