The great challenge of extending human life: a story of advances and disappointments

The great challenge of extending human life: a story of advances and disappointments

The day Jeanne Calment's heart stopped beating, this French woman marked an extremely difficult milestone to overcome. Jeanne, the oldest (documented) person in human history, passed away at the age of 122 years and 164 days in 1997. This was not just an isolated, individual achievement, but the pinnacle of a collective trend. For more than half a century, the number of supercentenarians, those who have overcome the biological barrier of 110 years, has multiplied in the world. This phenomenon does not respond only to the increase in the global human population, but is closely related to the progressive increase in life expectancy of the human being throughout the planet. Thus, it is estimated that at this time there are hundreds of supercentenarians hot on Calment's heels.

Today it might be a difficult idea to conceive but, just a few centuries ago, the normal thing for anyone was not to reach the age of 40. Today, however, global life expectancy stands at around 73, with large differences between nations (from 86 in Singapore to 51 in Lesotho). This happy and drastic change in human demography would not have been possible without the help of numerous advances that began to appear in the 19th century.

Thus, mortality due to a multitude of infectious diseases plummeted thanks to the hygiene achieved by the sewage system or the purification of the water. Later, the appearance of vaccines marked the beginning of the end of epidemics that had plagued humans for millennia (such as smallpox) and antibiotics prevented many bacterial infections from becoming death sentences. Improvements in various facets of daily life, such as nutrition, public health strategies for the prevention of various diseases or health care have further contributed to extending life expectancy around the world.

For now, there is no indication that the steady increase in global life expectancy has a limit (although the COVID-19 pandemic has been a bump in the road), but could it in the near future? Is there an insurmountable biological barrier that prevents us from reaching a certain age? This question has been repeated countless times among scientists and even today it continues to give rise to an intense debate: there is still no clear and convincing answer, due to the limited data we have. On one side, there are the researchers who defend that there is a limit to the age that a person can reach (which would be around 120 years). On the other side are those who claim that there is no specific biological barrier.

All we know for sure on this matter is that the oldest documented person lived 122 years and 164 days and that since 1997 no one has managed to break this biological record, for now. Beyond this key fact, research on centenarians and supercentenarians has given us interesting clues about what factors are important in the aging process.

For example, women have an indisputable advantage in the field of extreme longevity. 80% of centenarians and 90% of supercentenarians are women. This phenomenon is not only due to differences in lifestyles (for example: men tend to consume more alcohol and tobacco), but also to genetic (presence of double X chromosome) and hormonal (estrogen) factors. Beyond biological sex, the supercentenarians seem to have few traits in common except for two important details: none of them had been obese and the vast majority were non-smokers or smokers very little.

On the other hand, the most recent research indicates that there are two essential factors that have a great weight when it comes to determining our potential longevity: genes and lifestyles. Thus, reaching 70-75 years of age depends 70% on our health-related habits: physical exercise, diet, stress, sleep quality, consumption of toxic substances... However, as more years , the weight of lifestyles is becoming less and less. In this way, exceeding 100 years of age is a feat that happens to depend mainly on genes (by 70%). In other words, in the "lottery" of human longevity there are certain people who have many more ballots, from birth, to become centenarians or supercentenarians.

In any case, much remains to be discovered in the field of the genetics of older people, but little by little we are learning more details. For example, it seems that individuals who have certain variants of genes responsible for DNA damage repair are more protected against diseases associated with aging. This is probably because mutations in your cells repair themselves more effectively, slowing down the effects of aging.

In recent years, several Silicon Valley billionaires, including Larry Page (Google co-founder), Jeff Bezos (Amazon founder) or Peter Thiel (Paypal co-founder), have decided to invest part of their fortune in the human life extension research. These actions represent a major financial boost to a field of science that until recently had little relevance, despite the fact that progressively aging Western societies are looking at it with increasing interest.

Obtaining treatments that manage not only to add years to life but also to add healthy life to years would be a great relief for the populations that in the coming decades will suffer the great impact of age-related diseases such as Alzheimer's, cancer, osteoarthritis, strokes and heart attacks, osteoporosis...

What have we learned in recent decades about longevity? The moral of the body of scientific research could be summed up as follows: We now know so much more about the complex molecular processes behind ageing, to the point that we can considerably extend the lives of many laboratory animals, including worms. , flies, mice, rats... However, this success is, for now, elusive in humans. Why? A key factor in this story is the different biology between these animals and us. Some scientists propose that perhaps humans already have a fairly long life expectancy, compared to many other species, and therefore the room for maneuver we have to expand human life is small. However, this possible explanation is only a small part of the many obstacles in the way of increasing our longevity.

The absolute majority of the different treatments that have been applied to animal models to extraordinarily lengthen their lives are totally experimental and their application in humans would not, today, be justified for this uncertain purpose. Many are very risky therapies, with potential serious adverse effects. Precisely for this reason, and because these treatments would not be used to treat people suffering from diseases, but rather healthy individuals, ethical committees would not yet approve the use of almost any of them in clinical trials. Thus, genetic modifications to expand telomeres (chromosome ends) or to activate or silence specific genes, which have been very successful in extending the life of various animals, are not an option, for now, in humans. Other strategies, such as administering certain drugs that destroy aging cells (called senolytic drugs) or that activate/inhibit certain molecular pathways, also have very good results in laboratory animals, but it is still early to transfer many of their applications to humans because of the unknowns that surround them. However, there are several exceptions, among which rapamycin stands out.

Rapamycin is a very peculiar drug discovered on Easter Island. This molecule inhibits a protein with many functions called mTOR and has been widely used in medicine as an immunosuppressive drug to prevent rejection of transplanted organs. In addition, multiple laboratory investigations have shown that chronic administration of rapamycin slows aging and reduces the risk of cancer in animals. The long experience of clinical use of this drug and the encouraging results achieved in various animal species have allowed it to be approved for use in clinical trials at low doses in order to slow down aging.

It is still early to know if rapamycin is beneficial (the trials carried out have few participants, are of short duration and are in phases 1 and 2), but it is currently one of the most promising molecules to slow down aging. Many other compounds, such as vitamins and different antioxidants, have been failing in recent times when it comes to offering short-term health benefits, so there is nothing to indicate that they will help against aging. Other drugs that are also being investigated to find out their clinical effectiveness are metformin (used in medicine to treat diabetes), senolytic drugs such as dasatinib (used against cancer) and antioxidants such as quercetin.

Another practical detail that makes it very difficult to know if a therapy is effective in delaying aging in humans is precisely our long life expectancy. In the laboratory, animals are used that usually have life expectancies of weeks, months or a few years, so it is easy and quick to check if a certain strategy is successful in expanding their life. In humans, who can live beyond 70-80 years, everything becomes hopelessly slow and it is much more complicated to find out if something is effective or not to delay aging. In fact, it is possible that today we have measures that could be useful to extend life in humans, but we cannot know for sure because not enough time has passed to confirm it.

One strategy that could perhaps be effective in delaying aging to some extent is caloric restriction (reducing calories consumed compared to a normal diet). Thanks to a limited caloric intake, multiple animal species have significantly extended their lives. However, the long-term benefits of restricting dietary calories in humans are a mystery, for the simple reason that there hasn't been enough time in ongoing clinical trials to find out.

While we don't yet know if calorie restriction or other restrictive diets, such as intermittent fasting, have any use in slowing aging, clinical trials are seeing some evidence of health benefits. For example: after reducing caloric intake in individuals by 15% for two years, oxidative stress was observed to decrease. This data could be important, since oxidative stress is involved in many diseases associated with aging. On the other hand, it has also been seen that this type of diet was effective in reducing the risk of lipid deposits in the blood vessels (a process called atherosclerosis).

So while animal research and human trials continue, the options available to us to curb aging, or at least age healthier, aren't exactly cutting-edge, but they are widely recommended: physical exercise frequent, healthy diet, limitation of daily stress, good quality sleep and no consumption of alcohol, tobacco and other drugs. These actions may not guarantee us to live beyond 110 years (for this, the genes have to be on our side), but they will increase the chances of living longer and better.

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