Although we humans believe that we control our lives and that we have a certain capacity to prolong the time we inhabit the Earth, genetic programming sets limits that are difficult to exceed. Reaching 100 years is unusual and surpassing them almost impossible. Still, it’s much longer than the equivalent five years for a mouse or 20 for a dog. Why do some animals live much longer than others? What happens when we get old? Is it possible to avoid it? These questions are behind the work of a large international consortium that today publishes its results in the journals Science and Nature Aging and which, in part, is intended to help overcome some seemingly immutable limits.
The project, which includes nearly 200 researchers from around the world, is led by Steve Horvath, known for his discovery of epigenetic clocks. The researcher from the University of California in Los Angeles (USA) proposed a decade ago a method of measuring biological age by observing the addition of chemical marks in DNA that act as switches and change the expression of genes. Analyzing this process, known as DNA methylation, which accumulates changes in bodies with aging, makes it possible to calculate the age of an individual with a margin of error of just over three years.
To gain perspective and find out how much of aging is unique to each species and how much is shared by many, the researchers applied these DNA methylation clocks to 15,000 tissue samples from 348 mammalian species and compared epigenetic changes across regions of the genome. , conserved over millions of years of evolution, which we share with mice or dogs. The results, published in Science, show differences between the longest-lived animals, which tend to be the largest, and those that live the shortest and fastest. The long periods of gestation and development of humans or elephants give rise to a landscape “with prominent peaks and valleys”, in the words of Horvath, compared to other flatter and less defined ones in animals such as mice.
The possibility of making analogies is very important to predict the effects in humans of results obtained in animals. A study in mice published this year, for example, observed how stressful situations accelerate actual aging, but that the process is reversible with rest or drugs such as tocilizumab, an anti-inflammatory that accelerates the recovery of normal biological age. The authors, led by Vadim Gladyshev, a professor at Harvard Medical School, and in which Horvath also participated, believe that this type of technique could be used to better assess the effectiveness of some drugs, particularly those aimed at alleviating the damage of the passage of time.
published results in Nature Aging reinforce the value of methylation clocks for estimating the aging of species with very different lifespans, from short-lived rats to long-lived whales. The same happens with the calculation of the risk of mortality, something that can be useful to know the state of health of a person, but also, as Horvath explains, “for the conservation of endangered species”, as a system to monitor the state of wild animal health.
slow down aging
Although the fact that certain environmental factors accelerate aging is not denied, the results of this second study refute, according to the authors, the belief that aging only occurs as a result of random cell damage that accumulates over time. The epigenetic factors of aging, which are popularly attributed to circumstantial aspects of life, such as what one eats, if one smokes or stress levels, also follow a predetermined program. Asked about the possibility that the genome’s instruction book, which establishes our eye color, height or how hungry we feel, also defines the methylation processes of each species, Horvath acknowledges by email that “it is not yet known for sure the answer” to whether the epigenome evolves via a separate pathway and selective pressures.
Those responsible for these works have also observed how certain epigenetic marks can influence from very early stages of development, modifying the activity of genes that regulate the production of stem cells and that set the maximum life expectancy of an individual. In previous works, as one published in PNAS in 2022, several of the signatories of the articles published today observed some paradoxical effects in the relationship between life expectancy and size of dogs. Unlike most animals, small dogs live longer than large ones. This may be because in this species the chemical marks related to life expectancy also influence the higher levels of fat in the blood of large dogs, for which it is detrimental.
The results published today represent, for the moment, a tool to better understand what happens when mammals get old and will be an important source of information for scientists who see possible the extension of life beyond what is “programmed” by the evolution. More than 80 years ago, the American Clive McCay and his collaborators managed to prolong the life of mice by a third by reducing the calories in their diet, and other pharmacological treatments have had similar successes since, but they have never been able to transfer to humans to the same extent. . The possibility of studying the reasons for the differences can help to understand why. Horvath and others of the signatories of these latest analyzes now work for Altos Labs, a company financed by moguls like Jeff Bezos and Yuri Milner, which offers juicy salaries to the best aging researchers with the aim of combating it. Tearing down, if necessary, the walls built over millions of years of evolutionary history.
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