Northwestern University researchers 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 discovered that the length of genes can explain most 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 according to length. More specifically, aging is accompanied by a shift in activity toward short genes. This causes the gene activity in cells to become unbalanced.
Surprisingly, this finding was near universal. The researchers uncovered this pattern across several animals, including humans, and across many tissues (blood, muscle, bone and organs, including liver, heart, intestines, brain and lungs) analyzed in the study.
The new finding potentially could lead to interventions designed to slow the pace of — or even reverse — aging.
The study was published today (Dec. 9) in the journal Nature Aging.
“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 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.”
An expert in complex systems, Amaral is the Erastus Otis Haven Professor of Chemical and Biological Engineering in Northwestern’s McCormick School of Engineering. Stoeger is a postdoctoral scholar in Amaral’s laboratory.
Looking across ages
To conduct the study, the researchers used various 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 the median length of genes shifted between the ages of 4 months and 9 months, a finding that hinted at a process with an early onset. Then, the team analyzed samples from rats, aged 6 months to 24 months, and killifish, aged 5 weeks to 39 weeks.
“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 are able to counter perturbations that would lead to an imbalance in gene activity. Then, suddenly, 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 and older. Measurable changes in gene activity according to gene length already occurred by the time humans 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, 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.”
In all animals, the researchers noticed subtle changes to thousands of different genes across samples. This means that not just a small subset of genes that contributes to aging. Aging, instead, is characterized by systems-level changes.