A new discovery in genes could help researchers understand longevity

“The changes in the activity of genes are very, very small, and these small changes involve thousands of genes,” said Thomas Stoeger, lead author of the study and a postdoc at Northwestern University. “We found this change was consistent across different tissues and in different animals.

The research team used 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 researchers then analyzed tissue samples from humans, mice, rats and killfish to discover the new findings.

Assessing genes in rodents and fish

Researchers first examined tissue samples from mice at ages 4 months, 9 months, 12 months, 18 months, and 24 months. They noticed the median length of genes shifted between 4 months and 9 months old. They analyzed gene 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.”

Studying human genes

After studying the rodents and fish, the researchers began studying humans. They had more gene samples for humans than the other animals, leading to stronger results. They evaluated 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 occurred by the time the participants were middle-aged.

Luís A.N. Amaral, senior author of the study and professor at Northwestern University, also mentioned the variety that could be studied in assessing humans, yet all leading to the same outcome and pattern in the genes.

“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,” Amaral stated.

Analyzing multiple genes instead of only single genes

In the animals studied, the researchers observed small changes to thousands of different genes. This confirmed that there wasn’t only a small subset of genes that caused aging, but it was caused by systems-level changes.

The new perspective diverges from a previous biological approach that attributes biological phenomena to single genes. Although there are diseases that form from single gene mutations, the researchers believe that studying single genes haven’t led to explanations for changes in that occur in aging or neurodegenerative diseases such as Alzheimer's disease, multiple sclerosis, and Parkinson's disease.

“We have been primarily focusing on a small number of genes, thinking that a few genes would explain disease,” said Amaral. “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,” he continued.

Length of genes

Once Stoeger collected the large datasets using AI, he conceptualized the idea to examine genes based on the length. The length of a gene is based on the number of nucleotides —organic molecules forming the structure of DNA and RNA— inside of it.

A long gene produces a large protein, while a short gene produces a small one. Stoeger and Amaral said that a cell needs to have a balanced number of both small and large proteins, otherwise they become unbalanced and distorted. “The imbalance of genes causes aging because cells and organisms work to remain balanced—what physicians denote as homeostasis,” Amaral stated.

The study was published yesterday, Dec. 9, in the journal Nature Aging.

The results could potentially help researchers slow the aging process and find cures for diseases

Researchers hope the study will help them develop therapies to slow or reverse aging in the future. The breakthrough study could also potentially lead to cures for neurodegenerative diseases.

The current medications that are used target symptoms of aging rather than the causes of it. The lead researchers compared the current treatments to taking pain medicine to reduce fever, instead of treating the ailment 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."