Aging may have less to do with specific “aging genes” and more to do with the length of a gene. Many of the changes associated with aging could occur due to lower expression of long genes, researchers say in an opinion article published March 21 in the journal Trends in genetics. A decrease in the expression of long genes with age has been observed in a wide range of animals, from worms to humans, in various types of human cells and tissues, and also in individuals with neurodegenerative diseases. Experiments with mice show that the phenomenon can be mitigated by known anti-aging factors, including dietary restriction.
“In my opinion, this is the main cause of systemic aging throughout the body,” says co-author and molecular biologist Jan Hoeijmakers from Erasmus University Medical Center Rotterdam; the University of Cologne; and the Oncode Institute/Princess Máxima Institute, Utrecht.
The authors span four research groups from Spain, the Netherlands, Germany and the United States, and each group reaches the same conclusions using different methods.
Aging is associated with changes at the molecular, cellular and organ levels, from altered protein production to suboptimal cellular metabolism and compromised tissue architecture. These changes are believed to originate from DNA damage resulting from cumulative exposure to harmful agents such as ultraviolet radiation or reactive oxygen species generated by our own metabolism.
While much aging research has focused on specific genes that might speed up or slow down aging, research into exactly which genes are most susceptible to aging has not revealed a clear pattern in terms of gene function. Rather, susceptibility appears to be related to gene length.
“For a long time, the field of aging has focused on genes associated with aging, but our explanation is that it is much more random: it is a physical phenomenon related to the length of genes and not to the specific genes involved or the function of those genes,” says co-author Ander Izeta, from the Biogipuzkoa Health Research Institute and the Donostia University Hospital, Spain.
Basically, it all comes down to chance; Long genes simply have more potential sites that could be damaged. Researchers compare it to a road trip: the longer the trip, the more likely something is to go wrong. And because some cell types tend to express long genes more than others, these cells are more likely to accumulate DNA damage as they age. Cells that do not (or very rarely) divide also appear to be more susceptible compared to cells that replicate rapidly because long-lived cells have more time to accumulate DNA damage and must rely on DNA repair mechanisms to repair them, while cells that divide rapidly tend to divide. be short-lived.
Because neuronal cells are known to express particularly long genes and also be slow or do not divide, they are especially susceptible to the phenomenon, and researchers highlight the link between aging and neurodegeneration. Many of the genes involved in preventing protein aggregation in Alzheimer’s disease are exceptionally long, and pediatric cancer patients, who are cured with DNA-damaging chemotherapy, subsequently suffer premature aging and neurodegeneration.
The authors speculate that damage to long genes could explain most features of aging because it is associated with known accelerators of aging and because it can be mitigated by known anti-aging therapies, such as dietary restriction (which has been shown to limit damage to the DNA). ).
“Many different things that are known to affect aging appear to lead to this length-dependent regulation, for example, different types of irradiation, smoking, alcohol, diet, and oxidative stress,” says co-author Thomas Stoeger of Northwestern University.
However, although the association between decreased expression of long genes and aging is strong, causal evidence remains to be demonstrated. “Of course, you never know which came first, the chicken or the egg, but we can see a strong relationship between this phenomenon and many of the well-known characteristics of aging,” says Izeta.
In future studies, the researchers plan to further investigate the mechanism of the phenomenon and its evolutionary implications and explore its relationship with neurodegeneration.