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In a recent opinion piece published in the journal Trends in Genetics, researchers propose a novel perspective on aging, suggesting that the process may be less about specific "aging genes" and more about the length of the genes themselves. This theory arises from observations of a decline in the expression of long genes across a broad spectrum of species, including worms and humans, and across various human cell and tissue types, as well as in individuals suffering from neurodegenerative diseases. Intriguingly, mouse experiments have indicated that this decline can be countered by known anti-aging interventions such as dietary restriction.
"If you ask me, this is the main cause of systemic aging in the whole body," explains Jan Hoeijmakers, a molecular biologist and co-author of the study. This view is supported by collaborative findings from four international research groups from Spain, the Netherlands, Germany, and the United States, despite employing varied methodologies in their research.
Traditionally, the search for insights into the aging process has focused on identifying specific genes that might influence the pace of aging. However, this new research suggests that the susceptibility to aging may not be determined by the functions of these genes but rather by their lengths. Ander Izeta of the Biogipuzkoa Health Research Institute and Donostia University Hospital, Spain, elaborates, "For a long time, the aging field has been focused on genes associated with aging, but our explanation is that it is much more random—it’s a physical phenomenon related to the length of the genes and not to the specific genes involved or the function of those genes."
The logic behind this hypothesis is straightforward: longer genes have more potential sites for damage simply due to their size. The analogy drawn by the researchers is to a road trip, where the likelihood of encountering problems increases with the journey's length. Certain cell types that tend to express longer genes are more prone to accumulating DNA damage over time. This is particularly true for cells that divide infrequently or not at all, as these cells have more time to accumulate damage and depend heavily on DNA repair mechanisms, in contrast to rapidly dividing cells which are naturally short-lived and less susceptible.
This phenomenon is notably relevant in the context of neurodegeneration, as neural cells typically express longer genes and divide slowly or not at all, making them particularly vulnerable. The link between long genes and the prevention of protein aggregation in Alzheimer’s disease, as well as the premature aging and neurodegeneration observed in pediatric cancer survivors treated with DNA-damaging chemotherapy, underscores the significance of gene length in aging and disease.
Thomas Stoeger of Northwestern University notes, "Many different things that are known to affect aging seem to lead to this length-dependent regulation, for example, different types of irradiation, smoking, alcohol, diet, and oxidative stress." This suggests that interventions known to mitigate aging could be acting, at least in part, by influencing the expression of long genes.
While the correlation between the decline in long-gene expression and aging is compelling, the researchers acknowledge that causative proof is yet to be established. "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 aging," says Izeta.
Future studies will aim to elucidate the mechanisms behind this phenomenon, its evolutionary basis, and its connection to neurodegenerative conditions, potentially paving the way for novel therapeutic strategies.
"If you ask me, this is the main cause of systemic aging in the whole body," explains Jan Hoeijmakers, a molecular biologist and co-author of the study. This view is supported by collaborative findings from four international research groups from Spain, the Netherlands, Germany, and the United States, despite employing varied methodologies in their research.
Traditionally, the search for insights into the aging process has focused on identifying specific genes that might influence the pace of aging. However, this new research suggests that the susceptibility to aging may not be determined by the functions of these genes but rather by their lengths. Ander Izeta of the Biogipuzkoa Health Research Institute and Donostia University Hospital, Spain, elaborates, "For a long time, the aging field has been focused on genes associated with aging, but our explanation is that it is much more random—it’s a physical phenomenon related to the length of the genes and not to the specific genes involved or the function of those genes."
The logic behind this hypothesis is straightforward: longer genes have more potential sites for damage simply due to their size. The analogy drawn by the researchers is to a road trip, where the likelihood of encountering problems increases with the journey's length. Certain cell types that tend to express longer genes are more prone to accumulating DNA damage over time. This is particularly true for cells that divide infrequently or not at all, as these cells have more time to accumulate damage and depend heavily on DNA repair mechanisms, in contrast to rapidly dividing cells which are naturally short-lived and less susceptible.
This phenomenon is notably relevant in the context of neurodegeneration, as neural cells typically express longer genes and divide slowly or not at all, making them particularly vulnerable. The link between long genes and the prevention of protein aggregation in Alzheimer’s disease, as well as the premature aging and neurodegeneration observed in pediatric cancer survivors treated with DNA-damaging chemotherapy, underscores the significance of gene length in aging and disease.
Thomas Stoeger of Northwestern University notes, "Many different things that are known to affect aging seem to lead to this length-dependent regulation, for example, different types of irradiation, smoking, alcohol, diet, and oxidative stress." This suggests that interventions known to mitigate aging could be acting, at least in part, by influencing the expression of long genes.
While the correlation between the decline in long-gene expression and aging is compelling, the researchers acknowledge that causative proof is yet to be established. "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 aging," says Izeta.
Future studies will aim to elucidate the mechanisms behind this phenomenon, its evolutionary basis, and its connection to neurodegenerative conditions, potentially paving the way for novel therapeutic strategies.