Ageing is an inevitable phenomenon. Researchers from Northwestern University recently discovered a previously unknown mechanism that drives ageing, using artificial intelligence. The researchers analysed data from a wide variety of tissues, collected from humans, rats, mice and killifish, and discovered that the length of genes can explain most changes occurring during ageing at the molecular level. The analysis has revealed that ‘unbalanced’ genes cause ageing.
The study describing the findings was recently published in the journal Nature Aging.
Role of longer genes and shorter genes in life expectancy
It is important for cells to balance the activity of long and short genes. Longer genes are linked to longer lifespans, and shorter genes are linked to shorter lifespans, the study found. Also, ageing genes change their activity according to length.
According to the study, ageing is accompanied by a shift in activity toward short genes, causing gene activity in cells to become unbalanced.
The researchers observed that the finding was universal. The pattern was uncovered across several animals, including humans, and across various tissues, such as blood, bone, muscle, and organs such as liver, kidney, heart, intestines and lungs.
Several studies are focused on slowing the pace of, or reversing ageing, and the new finding could pave the way toward achieving this.
Changes in gene activity are consistent across different animals
In a statement released by Northwestern University, Thomas Stoeger, who led the study, said the changes in the activity of genes are very, very small, and these small changes involve thousands of genes. He added that the researchers found this change was consistent across different tissues and different animals, and they found it almost everywhere.
Stoeger said he finds 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.
How gene imbalance causes ageing
Luís A.N. Amaral, a senior author on the paper, said the imbalance of genes causes ageing because cells and organisms work to remain balanced. Referred to as homeostasis, this is a self-regulating process by which an organism tends to maintain stability while adjusting to conditions best suited for its survival.
Comparing the process to a waiter carrying a big tray, Amaral said the tray needs to have everything balanced. He explained that if the tray is not balanced, the waiter needs to put in extra effort to fight the imbalance. The same thing happens if the balance in the activity of short and long genes shifts in an organism. Ageing is like a subtle imbalance, away from equilibrium. While small changes in genes do not seem like a big deal, these subtle changes bear down upon an organism, requiring more effort.
How the study was conducted
The researchers used various large datasets, including a National Institutes of Health-funded tissue bank that collects samples from human donors for research purposes.
First, the researchers analysed tissue samples from mice, followed by rats and killifish. The rats analysed were aged four months, nine months, 12 months, 18 months and 24 months. The team observed that the median length of genes shifted between the ages of four months and nine months, indicating an early onset of ageing. The rats analysed were aged six months to 24 months, and the killifish were aged five weeks to 39 weeks.
Cells can counter imbalance in gene activity at a young age
Stoeger said there already seems to be something happening early in life, but it becomes more pronounced with age. He explained that at a young age, cells are able to counter perturbations that lead to an imbalance in gene activity. Then, suddenly, the cells are no longer able to counter it, he said.
Findings about human genes
Then, the researchers analysed humans, looking at changes in human genes from ages 30 to 49 years, 50 to 69 years and then 70 years and older. By the time humans reached middle age, measurable changes in gene activity according to gene length already occurred.
Amaral said the result for humans is very strong because researchers have more samples for humans than for other animals. He added that the human samples analysed were all different. The samples from men and women were analysed separately, and the same pattern was observed.
Analysis of genes based on length
The researchers noticed subtle changes to thousands of different genes across samples in all animals, indicating that not just a small subset of genes contributes to ageing. Instead, ageing is characterised by system-level changes.
Researchers have always studied single genes and their contributions to different diseases, but the new finding will allow scientists to study genes with a new approach.
Next, the team examined genes based on their length. The number of nucleotides within a gene determines its length. Each string of nucleotides codes for an amino acid, and a group of amino acids form a protein.
Therefore, a very long gene codes for a large protein, and a short gene translates to a small protein.
In order to achieve homeostasis, a cell needs to have a balanced number of small and large proteins, according to Stoeger and Amaral. When the balance goes haywire, problems occur.
Short genes fight against pathogens
While long genes are associated with increased lifespans, short genes also play important roles in the body. For instance, short genes help fight against pathogens.
Stoeger said some short genes could have a short-term advantage on survival at the expense of ultimate lifespan. Therefore, outside of a research laboratory, short genes might help survival under harsh conditions at the expense of shortening the animal’s ultimate lifespan, he added.
How gene activity imbalance contributes to diseases and conditions like long Covid
The study results may help explain why bodies take longer to heal from illnesses as they age. An older person’s skin takes a longer time to recover from even simple injuries such as a paper cut, compared to younger individuals. Due to the imbalance in the body, cells have fewer reserves to counteract the injury.
Amaral said the body not only has to deal with the cut, but also with the activity imbalance. He added that this could explain why, with ageing, people cannot face environmental challenges in the same way they used to counter when they were younger.
Since thousands of genes change at the system-level, it doesn’t matter where the illness starts. According to the study, this could explain long Covid, because although a patient recovers from SARS-CoV-2, the body experiences damage elsewhere.
Amaral said infections can lead to other problems later in life because damage moves away from the infected site and affects other areas of the body, which are then less able to fight environmental challenges.
The findings could lead to medical interventions and the development of therapeutics to reverse or slow ageing, according to the researchers.
Amaral said one can address the downstream consequences of ageing by correcting the gene activity imbalance.