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 the age of 100 is unusual — surpassing it, 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 aging? These are the questions behind the work of a large international consortium that, today, has published its results in the academic journals Science and Nature Aging. The project — which includes nearly 200 researchers from around the world — aims to help overcome some seemingly immutable limits.
The study was led by Steve Horvath, known for his discovery of epigenetic clocks. A decade ago, the UCLA researcher proposed a method to measure biological age by observing the chemical marks in DNA, which act as switches and change the expression of genes. This form of analysis, known as DNA methylation, makes it possible to calculate the biological age of an individual with a margin of error of just over three years.
To gain perspective and find out to what extent aging is unique to each species and which factors of aging are shared by many, the researchers applied these DNA methylation clocks to 15,000 tissue samples from 348 mammalian species. They compared epigenetic changes across regions of the genome, which humans, mice and dogs have in common.
The results, published in Science, show differences between the animals who have long lifespans and those who have the shortest ones. The long periods of gestation and development in 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.
It’s more feasible to predict the effects of aging in humans once results are obtained from animal studies. A study of mice published this year, for example, observed how stressful situations accelerate biological aging, but that the process is reversible with rest, or even with drugs, such as tocilizumab — an anti-inflammatory that hastens the recovery of normal biological age. The study — which was led by Vadim Gladyshev, a professor at Harvard Medical School — shows 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.
The results published in Nature Aging reinforce the value of methylation clocks for estimating the aging of species with very different lifespans, from mayflies to longevous whales. The same happens with the calculation of the risk of mortality — something that can be useful to knowing a person’s state of health, but also, as Horvath explains, “for the conservation of an endangered species.” These clocks can help monitor the health of wild animals.
Slowing down aging
While the idea that certain environmental factors accelerate aging hasn’t been denied, the results of this second study — according to the authors — refute 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 has high stress levels, also follow a predetermined program.
When 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 replies via email that “the answer still isn’t known for sure.” It’s unclear whether the epigenome evolves via a separate pathway or through certain pressures on the body.
Those responsible for these works have also observed how certain epigenetic marks can have an influence from very early stages of development. They can modify the activity of genes, which regulates the production of stem cells and sets the maximum life expectancy of an individual. In previous works — such as a study published in PNAS last year — several researchers observed some paradoxical effects in the relationship between life expectancy and size of dogs. Unlike with 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, which is detrimental to longevity.
The latest results offer, for the moment, a tool to help better understand what happens when mammals get old. This will provide important information to scientists who see possible extensions of life beyond what is “programmed” by evolution.
More than 80 years ago, the American biochemist Clive McCay and his fellow researchers managed to prolong the life of mice by a third, by reducing the calories in their diet. Other pharmacological treatments have had similar successes since, but they have never been able to transfer the extended lifespan to humans to the same extent. The possibility of studying the reasons for the differences can help scientists understand why this is the case.
Horvath and some of the other authors of the study now work for Altos Labs – a company financed by moguls such as Jeff Bezos. The firm offers juicy salaries to the best researchers in the field of aging, with the aim of combating it. If necessary, they’re willing to tear down the walls built over millions of years of evolutionary history.
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