People with shorter genes age faster, die sooner, more prone to disease

EVANSTON, Ill. — A new study finds that people with shorter genes age faster and die sooner than those with longer genes — opening the door to a potential “fountain of youth” pill.

“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,” says study lead author Dr. Thomas Stoeger from Northwestern University in a media release.

The research team used AI (artificial intelligence) to analyze data collected from the tissue of humans, mice, rats, and killifish. They discovered the phenomenon explains most molecular changes, with longer and shorter genes linked to longer and shorter lifespans, respectively.

Specifically, aging is accompanied by a shift toward short genes, causing activity in cells to become unbalanced. The finding was near universal with the pattern identified across several species, including humans. It affects blood, muscle, bone, and organs — including the liver, heart, intestines, brain, and lungs.

The researchers 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,” says senior author Professor Luis Amaral. “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.”

This could explain why older adults don’t heal as well

After compiling the large datasets, Dr. Stoeger brainstormed an idea to examine genes, based on their length. The length of a gene is based on the number of nucleotides within it. Each string of nucleotides translates to an amino acid, which then forms a protein.

A very long gene, therefore, yields a larger protein and a short gene yields a smaller protein. A cell needs to have a balanced number of small and large proteins to achieve good health. Problems occur when that balance gets out of whack.

“The changes in the activity of genes are very, very small, and these small changes involve thousands of genes,” Stoeger adds. “We found this change was consistent across different tissues and in different animals.”

The study provides new insight into why older individuals struggle to recover from minor illnesses or small injuries, like a paper cut. Out of sync cells have fewer reserves.

“Instead of just dealing with the cut, the body also has to deal with this activity imbalance,” Amaral explains. “It could explain why, over time with aging, we don’t handle environmental challenges as well as when we were younger.”

Thousands of genes change, so it doesn’t matter where the illness starts. It could help get to the bottom of long COVID. Although a patient might recover from the initial virus, the body experiences damage elsewhere.

“We know cases where infections — predominantly viral infections — lead to other problems later in life,” Amaral continues. “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.”

Could this lead to a new anti-aging drug?

Researchers hope the study in Nature Aging will lead to the development of therapies designed to reverse or slow the aging process.

“The imbalance of genes causes aging because cells and organisms work to remain balanced — what physicians denote as homeostasis,” the senior author notes. “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.”

Current medications merely target symptoms rather than the cause — similar to painkillers easing a fever.

“Fevers can occur for many, many reasons,” Amaral says. “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.”

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

Although the researchers did find that long genes have a connection to increased lifespans, short genes also play important roles in the body. For example, short genes are called upon to help fight off pathogens.

“Some short genes could have a short-term advantage on survival at the expense of ultimate lifespan,” Stoeger concludes. “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.”

South West News Service writer Mark Waghorn contributed to this report.

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