2023-08-11 11:48:59
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It escapes no one that the chronological age does not always coincide with the “biological” one. It is the reason why we feel in a bind when someone asks us “how old are you?” But beyond the calculation “by eye”, the discrepancy between what our DNI marks and what state our body is in can be measured with the help of markers, the epigenetic clocks of aging.
If chronological age is a direct measure of time, the biological one is more aligned with the health and risk of disease or mortality of an individual. Recent research indicates that biological age may be a more accurate predictor of morbidity and mortality than chronological age.
Over the past decade, tools have been developed that estimate age from chemical modifications to DNA, known as epigenetics or, more accurately, methylation. This mechanism controls the expression of genes in cells, turning them on or off like a switchr. Through mathematical formulas, scientists have been able to identify whether certain parts of the DNA that are related to aging are methylated or not.
He first epigenetic clock was developed by the geneticist and biostatistician Steve Horvath, who was actually looking for epigenetic changes that determined people’s sexual orientation. He did not find any, but unexpectedly he did see that there were changes that were associated with the age of the volunteers analyzed.
Based on this finding, in 2011, Horvath’s group formulated in his laboratory, then at the University of California at Los Angeles (UCLA), the first specific clocks for humans, initially in saliva, and which two years later they extended to cover all human tissues.
Ten years after that achievement, a universal clock, applicable to all species of mammals. This is presented in two studies that are published this Thursday en Science y and Nature Aging.
Both works are based on the analysis carried out by the about 200 researchers who make up the Methylacin Mamfera Consortium and who have analyzed data from more than 15,000 animal tissue samples from 348 mammalian speciesincluding the human being.
patterns preserved
The panmammalian clock “indicates that the elements of aging are dictated by an underlying program and not just as a result of random damage over time,” explains Steve Horvath, lead author of both papers, who is now working as a principal investigator in the labs, via email. Altosin San Diego.
“Historically, there has been a debate about whether aging is purely stochastic or governed by an inherent program. By examining whether epigenetic changes persisted across species, we hoped to provide clarity. Our findings confirmed that aging processes they are conserved in all mammals and in most tissues. In addition, we suggest that aging can be seen as an extension of developmental processes. The watches we have developed can track changes from the moment of conception to old age.”
Specifically, the study reveals that “essentially, long-lived mammals have more pronounced DNA methylation patternswhile those of shorter-lived species have fainter, more linear methylation patterns“says the scientist.
The end of the legend of Methuselah
Research thus underlines the deterministic aspect of aging. “The findings of our Science article on maximum lifespan studies in mammals suggest that there are fixed limits of longevity intrinsic to each species. Unless we undertake innovative interventions that greatly alter the methylome, seems unlikely to extend human life beyond 122 years. Interventions such as lifestyle changes or caloric restriction have only a marginal impact on maximum lifespan, as do harmful behaviors such as smoking. Our research on methylation strongly suggests that the longevity of a species is essentially predetermined.”
Therefore, against the belief that aging is due solely to random cellular damage that accumulates over time, something similar to what happens to objects, which deteriorate due to the erosion of the years, which raises this group of scientists is that aging is programmed through a series of molecular changes.
Farewell to the legend of the millenary Methuselah. The good news is that work can be done to develop “interventions that modulate conserved aging processes.” In short, finding the formula for a youth that is not eternal, but rather long-lived.
treat aging
The discovery of an epigenetic clock pan mamfero it has a key implication in translational research: allowing the discoveries obtained in experimental models to be applied to humans. In fact, as indicated in the Science study, the methylation state of certain elements “responds to disturbances such as the restriccin calricathe deactivation growth hormone receptorshe consumption of high-fat diets and the expression of Yamanaka factors“. According to what was exposed in the works, if interventions of this type manage to influence the biological age in a mouse, they could also do so in humans.
Among all the interventions, Horvath highlights that “the growth hormone receptor inactivationwhich results in the creation of dwarf mice, has shown losmost significant rejuvenating impacts. Other interventions exhibited more modest effects. In collaboration with Vadim Gladyshevfrom Harvard, we found that administer young blood via heterochronous parabiosis profoundly rejuvenates multiple organs in mice, as demonstrated by our panmammalian clocks.”
the scientist Juan Carlos Izpisascientific founder and director of the Altos laboratories, who has also participated in this research with the contributions of his group on cell reprogramming, points out to this medium that “the uniform increase in methylation within certain regions of DNA among all species of mammals suggests that these alterations have substantial biological significance in aging. our animal studies reveal that reprogramming these chemical alterations to DNA results in cell rejuvenation that achieves an increase in health and resilience to disease”.
And he underlines the translational implications of the finding: “These studies help us to better understand the process of aging and the cellular deterioration that occurs during the disease and to transfer to the human clinic the knowledge that we are acquiring in the laboratory”.
a bold idea
The development of the universal clock has been an odyssey through fauna. As he recounted in a comment in Nature Aging, members of the Paul Allen philanthropic organization “contacted us and invited us to make an ambitious proposal, out of reach of traditional funding sources. Thus was born a bold idea: to build an epigenetic clock not only for mice, but for all vertebrates”, which has finally materialized in mammals.
For this, a vast collaboration has been necessary, which the scientist highlights, in the collection of samples from zoos, aquariums and laboratories. They have had the DNA of all kinds of animals, from the Tasmanian devil to the shrew, without forgetting the longest-lived in the study, a 139-year-old Greenland whale (Balaena mysticetus).
“Future efforts could aim to encompass all vertebrates, since they all exhibit cytosine methylation. However, certain invertebrates, such as flies or worms, lack this feature,” he says.
In clinical studies
Horvath’s clock, the standard for determining human biological age, has been improved over time and has given rise to similar watches, some even commercially available, claiming to tell us the eventual gap (advance or delay) between our chronological and biological age.
And the use of epigenetic clocks has also been spread in laboratories and has even reached clinical research. In it triim rehearsal, where a combination of treatments to regenerate the thymus is evaluated, with the aim of preventing immunosenescence and potentially reversing certain aspects of aging. The biological clock is used here to measure biomarkers of regeneration.
“The application of epigenetic clocks in human clinical trials is already underway, exploring various interventions,” says Steve Horvath. “In a personal capacity, my twin brother and I were active participants in one of those trials. We are optimistic that these methylation-based predictors of mortality may offer insight into intrinsic aging processes.”
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