Ageing might not primarily hinge on specific “ageing genes” but rather on the length of a gene. That is the perspective researchers offer in an opinion piece published on March 21 in Trends in Genetics. Many ageing-related changes might stem from a reduced expression of long genes. This trend has been observed across various animals, from worms to humans, various human cells and tissue types, and even individuals with neurodegenerative diseases. Experiments with mice have demonstrated that known anti-ageing interventions, such as dietary restrictions, can alleviate this decline in the expression of long genes with age.
Jan Hoeijmakers, a molecular biologist at Erasmus University Medical Center, Rotterdam; the University of Cologne; and Oncode Institute/Princess Maxima Institute, Utrecht, and co-author of the study, believes this to be a key driver of systemic ageing throughout the body.
The study combines findings from four research groups based in Spain, the Netherlands, Germany, and the United States. All are converging on similar conclusions through diverse methodologies.
Ageing manifests in various molecular, cellular, and organ-level changes, ranging from altered protein production and suboptimal cell metabolism to compromised tissue integrity. These alterations are often attributed to DNA damage accrued from exposure to harmful agents like UV radiation or the reactive oxygen species produced by metabolism.
Historically, ageing research has focused on specific genes linked to the ageing process, seeking to identify those that might hasten or slow it down. However, investigations into which genes are most affected by ageing have not uncovered a consistent pattern regarding gene function. Instead, vulnerability appears to be related to gene lengths.
Ander Izeta, co-author of the paper and of the Biogipuzkoa Health Research Institute and Donostia University Hospital in Spain, points out that the focus on ageing-associated genes may be misplaced. Susceptibility to ageing seems more a matter of physical chance related to gene length than the specific functions or identities of the genes.
The researchers compared the problem to a road trip, where the longer the journey, the greater the chance of encountering problems. Some cell types are more prone to expressing long genes and are more susceptible to accumulating DNA damage over time. Non-dividing or rarely dividing cells are particularly vulnerable compared to those that divide rapidly, as the former have more time to accrue DNA damage and rely more heavily on DNA repair mechanisms, whereas the latter are generally short-lived.
Neural cells are mainly at risk. They are known for expressing longer genes and their slow or non-dividing nature, making them highly susceptible to ageing and neurodegeneration. Notably, many genes that prevent protein aggregation in Alzheimer’s disease are exceptionally long. Additionally, pediatric cancer survivors treated with DNA-damaging chemotherapy often experience premature ageing and neurodegeneration.
The researchers propose that damage to long genes could underlie many ageing characteristics. This damage correlates with known ageing accelerants and can be mitigated by established anti-ageing treatments like dietary restriction. This diet has been shown to limit DNA damage.
Another co-author, Thomas Stoeger of Northwestern University, notes that various ageing factors could lead to this length-dependent regulation, including different types of radiation, smoking, alcohol consumption, diet, and oxidative stress.
Yet, while the link between long-gene expression decline and ageing is vital, proving causation remains a challenge. “Of course, you never know which came first, the egg or the chicken, but we can see a strong relationship between this phenomenon and many of the well-known hallmarks of ageing,” says Izeta.
In future studies, the research team plans to delve deeper into the mechanisms behind this phenomenon, its evolutionary implications, and its connection to neurodegeneration.
More information: Sourena Soheili-Nezhad, Olga Ibáñez-Solé, Ander Izeta, Jan H.J. Hoeijmakers, Thomas Stoeger et al, Time is ticking faster for long genes in aging, Trends in Genetics. DOI: 10.1016/j.tig.2024.01.009
Journal information: Trends in Genetics Provided by Cell Press
