Death is the price we pay for who we are: the science of the quest for immortality

The limit of human life was set by Jeanne Louise Calment: at 122 years old, this French woman became the longest-standing woman in known history.His case has opened the door to endless questions: is there a maximum in human life? Which? As technology and medicine advance, there are those who become more ambitious. What if we could break that limit? Is it possible to achieve immortality? Is it really what we want?

Gompertz, Makeham and the limit of longevity

Last summer a rather curious study was published on the limit of our mortality. In it, the authors explained that upon reaching 105 years, the probability of dying reaches its limit of 50%. Before that, it follows a function determined by Benjamin Gompertz and corrected by William Makeham in the 19th century.

This function indicates that the probability of mortality doubles every eight years (between 30 and 80). In the elderly, this ratio falls in what is known as "slowdown in long life." Moving away from the numbers and their cumbersomeness, these data awaken an interesting idea: have we reached our top?

Calment reached 122 years, but we do not know if it is the maximum that can be achieved. Many experts, however, believe that this figure is well below the limit that we can reach. On the other hand, estimates say that we will live longer and longer, but that does not necessarily mean that this limit shifts.

Studies like the one we mentioned put the limit of our longevity at 125 years, maximum. If this does not change, we will live more and more, but it will be extremely unlikely that we will surpass the French super centenary. What drives our longevity? The secret is in our body, of course.

Why do we age?

Statistical studies are very useful, but it is impossible to talk about aging without delving into the complicated world of biology. In order to better understand the ins and outs of our body, we have spoken with two experts in physiology and genetics. Darío Acuña Castroviejo, doctor and Professor of Physiology at the University of Granada, and Arcadi Navarro Cuartiellas, professor and associate researcher at the Catalan Institution for Research and Advanced Studies (ICREA) and specialist in evolutionary genomics.

"We age because the body's ability to regenerate cells is less than their destruction," Darío tells us when asked about our body. "As we age [from the age of 35 or 40, the doctor indicates], the organism loses cognitive, neural, physical abilities, etc." This is because the organs and tissues are reducing their metabolic capacity, and in this way fewer hormones are produced, cellular energy processes slow down, cells reduce their energy production capacity, since mitochondria, their power plants, they are declining ".

According to Darío, from the cellular point of view a vicious circle occurs: "The less cellular energy, the less capacity cells have to carry out their functions, including cellular regeneration and repair. It is an old vehicle, worn out everywhere, which reduces its efficiency. " Arcadi gives us another, complementary point of view about our genes:

"We know relatively little when we talk about aging, but much more than we thought. For example, in the genetics of aging, what has been found in human populations are some changes in the genome methylation patterns as we get older; changes in patterns splicing, in the protein forms present in our cells; some small genetic variants have been found, presumably associated with longevity ... ", comments the expert.

"Actually what happens is that there are a huge number of human diseases that affect longevity"

Methylation is a process by which a molecule is added in a way that "blocks" that gene, regulating its expression, as if it were a switch. On the other hand, the splicing Protein is a process by which protein chains are cut and spliced, removing or adding amino acids so that the protein becomes active or inactive. It is another control mechanism in the form of a switch.

"Of course, at the molecular and physiological level there is a lot of information," agrees Arcadi. "There are proteins [like sirtuins] that have to do with aging ... But having said all that, in reality what happens is that there are a huge number of human diseases that affect longevity." As the researcher explains, we must take into account not only "healthy" aging, but the relevance of these diseases and risk factors when considering the limits of human life.

What happens to the body when it gets old

"All living species, animals and plants, we have a life cycle that, from the phylogenetic point of view, Darwinian, perfectly fulfills its mission," says Darío, expanding his explanation. "We have to maintain the species, for which we are born, we grow, we mature sexually, we reproduce, and we die. The fact of dying soon is important because the older we are, the more mutations we accumulate, increasing the probability of transmitting genetic defects to our offspring "

"Medicine has interfered in this evolution, so that we cure diseases, we live many more years than we are entitled to. This is not bad! But it allows gestation at older ages, which are often accompanied by gestational risks." The doctor delves a little deeper into the changes that occur when our cells begin to age:

"[The most important physiological factors in aging are manifested in] the inability of the stem cells of each tissue and organ to regenerate each one of them to keep it young, as well as the epigenetic factors that affect the DNA of these and other cells, that can negatively affect you, "he continues.

Mesenchymal stem cells

For Dr. Acuña, oxidative stress is possibly the main mechanism of cell wear and death underlying aging. "Oxygen is vital to us, but it kills us slowly. Not everything is perfect and the mitochondria, where 95% of the oxygen we breathe is consumed, also generate free radicals that cause oxidative damage in the mitochondria itself and in the cell."

"It has powerful antioxidant systems," he continues. "But, with age, their activity decreases because they are damaged by free radicals themselves, entering that vicious circle of aging and cellular damage. We know that by stopping oxidative stress we improve mitochondrial and cellular function, and we delay aging. more important is not so much lengthening life as reducing diseases associated with the passage of time. In other words, living with a better quality of life, "he points out.

And what about our genes?

There is a gene known as a cyclin-dependent kinase 2A inhibitor, more also called a p16 or CDKN gene that can serve as a great example. "It is a very relevant gene," explains Arcadi. "It has long been known to have a number of important effects on senescence in mice. It is also known that with age this gene becomes dysregulated and expressed at higher levels. This affects the ability of muscle regeneration in mice".

One of the basic mechanisms of "death" is that the genetic variants that cause problems in old age appear to have had a positive effect on youth.

"If you manage to downregulate the expression of this gene, and you go overboard, the mice die of cancer. However, if you manage to control it by regulating it more precisely, what you do get is that the mice build muscle even though they are older." Arcadi's team worked with this gene in humans, identifying its role in various diseases.

"The interesting part of this gene [in humans] is that the genetic variants that protect you from suffering a glioma in childhood, for example, are the same ones that cause a higher incidence in old age. It seems that one of the basic mechanisms "Death" is that the genetic variants that cause problems in old age seem to have had a positive effect on youth, "says Arcadi. "When you look at the genome from this perspective, you find a whole host of gene variants that seem to meet this pattern."

"For example, the genetic variants that cause physical degeneration naturally," explains the genetic expert, "wrinkles, diseases, etc., have had a positive effect during our development: they have protected us from certain problems, they have made stronger, more capable of processing certain foods ... When you analyze the genome from this perspective, you find all kinds of genes that behave this way, regulating themselves according to age. "

The team at Arcadi's Evolutionnary Genomics Lab has worked hard in this field. "One of the most interesting patterns we found," says the researcher, "is that these genes have a greater tendency than the rest of the genome to change, for example, their methylation patterns with age."

The bulk of our genes, he says, has a tendency to change these patterns, but these, in particular, change significantly. "This makes sense, because if a gene has different functions, one way to control it is to change its methylation pattern with place and also with time. Obviously the regulation of all this is extremely complicated."

In search of immortality

What if we could stop aging suddenly? There is no omnipotent "switch" capable of paralyzing all the processes that make us age, that is clear. But maybe there are many switches. Could we find the right combination to avoid death?

"The probability of finding a solution seems very low," Arcadi replies to this example. "In the end, what we observe is that the causes of mortality are extremely diverse. One can die of many things and suffer from many kinds of 'unhealth' with age. One can hardly find a solution to all this. That does not mean that ways and methods cannot be found to extend life. "

For his part, Darío agrees with Arcadi when he explains something more about these possible switches: "Let's say that the epigenetic marks of our DNA correspond to our life history, which is thus marked. If we were able to eliminate all those marks, we would have a young cell, intact, we would almost say virgin to start again its stage or life cycle. "

"Very interesting studies are being done removing these marks from some cells, rejuvenating the corresponding tissue or organ. Perhaps the works in this sense by the scientist Juan Carlos Izpisua, who currently directs the Salk Institute in Los Angeles, United States, are marking a before and after aging. " But if the issue already seemed complex, the debate has only just begun.

Do we really want to live forever?

"I do not think that extending life is prudent," Dr. Acuña does not hesitate to answer. "Living 140 years would lead us to overpopulation, lack of global economic resources and, ultimately, to wars because space is limited. I think that those who say that we are going to live forever do not have a minimally serious approach."

The ecological environment of an organism regulates the optimum of the optimal age of this

From a practical point of view, Arcadi points to another idea: "There is an explanation, on which much work has yet to be done, but which seems quite plausible. This says that it is the ecological environment of an organism, which determines its extrinsic mortality it is not tied to its own nature], it is what regulates the optimum age of an organism ".

The question here would be, once this age optimum varies, what evolutionary mechanisms come into play for the organism to be well? The same is what we can see in human beings: with the increase in life expectancy, new unexpected physiological problems appear.

"There are literally hundreds of laboratories around the world trying to figure out the solution to these problems. There are those who work on sirtuins, there are those who focus on cancer variants, there are those who focus on cognitive, molecular issues ..." confirms the researcher.

"Yes, we can fight pathological aging," continues Darío. "In this sense, great progress is being made, although unfortunately we have not yet managed to eradicate the diseases of aging. Many things probably have to be changed," he explains.

"A huge amount of money is being spent studying Alzheimer's and Parkinson's genetic alterations, to give two epidemiologically significant examples, when only 7% of those diseases are of genetic origin." For the doctor it is also important to diversify efforts and make other experimental approaches.

Because if we do not end these diseases, in the end, we could be immortal, but the disease would make us suffer for a very long period. That's not to mention the resources. As we talk about it, we live in a world that will hardly be able to bear the pressure we are putting it under. Ultimately, the question may not be whether we want to be immortal, but the quality of life that we want during our period of existence. When we have settled that question, who knows, we may be much closer to living forever if we so choose.

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