It escapes no one that the chronological age does not always coincide with the “biological”. It is the reason why we feel in a bind when someone asks us “how old do you make me?” 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, biological age is more closely aligned with an individual's health and risk of disease or mortality.. Recent research indicates that biological age may be a more accurate predictor of morbidity and mortality than chronological age.

Over the last decade, tools have been developed that estimate age based on chemical modifications to DNA, known as epigenetics or, more precisely, methylation.. With this mechanism, the expression of genes in cells is controlled, turning them on or off like a switch.. Through mathematical formulas, scientists have been able to identify whether certain parts of the DNA that are related to aging are methylated or not.

The first epigenetic clock was developed by geneticist and biostatistician Steve Horvath, who was actually looking for epigenetic changes that determine 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 in Los Angeles (UCLA), the first specific clocks for humans, initially in saliva, and that two years later they expanded to cover all human tissues.

Ten years after that achievement, a universal clock has been obtained, applicable to all species of mammals.. This is presented in two studies that are published this Thursday in Science and in Nature Aging.

Both works are based on the analysis carried out by the nearly 200 researchers that make up the Mammalian Methylation Consortium, who have analyzed data from more than 15,000 animal tissue samples from 348 mammalian species, including humans.

patterns preserved

The pan-mammalian clock “indicates that the elements of aging are dictated by an underlying program and not just the result of random damage over time,” Steve Horvath, lead author of both papers, who is now working as a researcher, explains by email. principal at Altos Laboratories, in 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 are conserved in all mammals and in most tissues.. Furthermore, 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 patterns, while those of shorter-lived species have more tenuous and linear methylation patterns,” says the scientist.

The end of the legend of Methuselah

The research thus underlines the deterministic aspect of aging. “Findings from 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, extending human life beyond 122 years seems unlikely.. 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.”

For this reason, compared to 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 millennial 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 a pan-mammalian epigenetic clock has a key implication in translational research: it will allow discoveries obtained in experimental models to be applied to humans. In fact, as indicated in the Science study, the methylation status of certain elements “responds to perturbations such as caloric restriction, deactivation of growth hormone receptors, consumption of high-fat diets, and 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 “inactivation of the growth hormone receptor, resulting in the creation of dwarf mice, has shown the most significant rejuvenating impacts.”. Other interventions exhibited more modest effects. In collaboration with Harvard's Vadim Gladyshev, we found that delivering young blood via heterochronous parabiosis profoundly rejuvenates multiple organs in mice, as demonstrated by our pan-mammalian clocks.”

The scientist Juan Carlos Izpisúa, scientific 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 the DNA among all mammalian species suggests that these alterations have substantial biological significance in aging.. In fact, our animal studies reveal that reprogramming these chemical alterations to DNA results in cellular rejuvenation leading to increased health and resilience to disease.”

And he underlines the translational implications of the finding: “These studies help us to better understand the aging process 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 the 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 refined over time and has given rise to similar clocks, 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 spread in laboratories and has even reached clinical research.. In the Triim trial, where a combination of treatments to regenerate the thymus is being evaluated to prevent immunosenescence and potentially reverse 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,” said Steve Horvath.. “In a personal capacity, my twin brother and I were actively involved in one of those trials.. We are optimistic that these methylation-based predictors of mortality may offer insight into intrinsic aging processes.”

The astronomer Rafael Bachiller reveals to us in this series the most spectacular phenomena of the Cosmos. Pulsating research topics, astronomical adventures and scientific news about the Universe analyzed in depth.

Observations with the giant radio telescope ALMA show that a triple system of forming stars is accompanied by large spiral arms that act like conveyor belts, funneling material from interstellar space toward the stars that are being born.

infrared

In the constellation of Taurus, about 460 light-years away, are the closest interstellar clouds in which we can observe the birth of low-mass stars like our Sun.. The vast majority of these stars are not born one by one, but as members of small swarms (so-called open clusters) or in the form of multiple systems.

IRAS04239 is one of these multiple systems: it is made up of three protostars that, together, emit intense infrared radiation. In fact, when it was captured by the small IRAS space telescope in 1983, this emission is what allowed the discovery of the stellar system.. Being located at a short distance from Earth, the IRAS04239 system can be observed with a high level of detail, which makes it possible to study star formation phenomena in all their details.

streamers

Astronomer Jeong-Eun Lee, from the University of Seoul, has coordinated an international team that has used the giant radio telescope ALMA to observe the emission of the molecular gas in which the IRA043239 system is embedded.. However, the emission of different molecules of that gas can be used to delineate some areas or others.

IRAS04239: observations and simulation ESO/NRAO/NAOJ/ALMA/Lee

Lee's team used the emission of sulfur monoxide (SO) to study regions that were particularly dense and, quite possibly, subjected to the passage of shock waves.. Such waves would be responsible for ejecting sulfur into the gas phase, which is preferably usually found in solid grains of interstellar dust.

Well, by following the trace of these emissions, the astronomers observed that the emission is concentrated in three large filaments that, like spiral arms, connect the surrounding interstellar medium with the protostars.. These filaments look like streamers made of gas that stretch up to 400 times the Earth-Sun distance.

The protostars in IRAS04239 are still in formation, they continue to accumulate material from the natal cloud, which allows them to continue to fatten.. Observations indicate that the way they accumulate this material is through such filaments or streamers that act as great conveyor belts that channel the material from the cloud to the surfaces of the stars.

supercomputers

To test these ideas, the team of astronomers performed numerical calculations that simulate the formation of multiple stars taking into account that they are within their natal cloud and that the stars can interact with the gas in the cloud.. These are very complex calculations as they must take into account a wide variety of physical phenomena (gravitation, turbulence, magnetic fields, etc.). Therefore, for this type of work, you have to resort to large supercomputers.

Lee and colleagues used the largest machines at the National Astronomical Observatory of Japan (NAOJ) Center for Computational Astrophysics.. In simulations, they observed how naturally disturbed gas in the region surrounding a forming triple system ends up exciting shock waves that trigger the formation of spiral arms.. And they confirmed that such filaments act as channels that supply gas to the forming stars from the parent cloud.. The gas velocities that emerge from the simulations agree well with those measured in the observations, which confirms that these calculations are a good representation of the real situation.

This work illustrates very well how the synergies of ALMA observations and numerical simulations can shed a lot of light on the formation of very complex systems such as IRAS04239, which should allow discerning between different star formation theories.. Observation and theoretical interpretation are the two essential facets of astrophysical research: one would be of little use without the other.

The article by Lee et al. entitled Triple spiral arms of a triple protostar system imaged in molecular lines has just been published in the prestigious American magazine The Astrophysical Journal and can be consulted at this link.

Rafael Bachiller is director of the National Astronomical Observatory (National Geographic Institute) and academic of the Royal Academy of Doctors of Spain.