Questions for the future of humanity: Will we defeat aging?

"Mr. Kristall's achievement is remarkable," Guinness president Marco Frigetti officially stated. The average life expectancy of men in the developed world is approximately 80 years. Only about two out of every 100,000 people live to be 100, and the vast majority are women. At over 112 years old, Krystal is close to the maximum lifespan observed in humans. No human being ever lived longer than Jean Clement of France who died at the age of 122.

What if instead of dying at age 80 or 85, the average person lived to age 100 or even 112 like Crystal? False promises of long life and even eternal life flourished back in the days of the alchemists. But until now no facts have been found to support this optimism. And yet some scientists believe that those who live over 100, like Crystal, do age more slowly than the average person. Reliable findings of contemporary biological studies suggest that periods of famine, or Extreme restriction of calorie intake, - possibly like those that the candy maker went through - affect the lifespan of cells. The research points to more precise ways to stretch the limits, not through diets but through drugs.

It turns out that half a dozen drugs or supplements, all of which are already approved for use in humans for other purposes, affect mechanisms that improve the control of internal damage within cells and thus help prolong life. Some of these substances, which also include an anti-cancer drug, have already been found to increase the average and maximum lifespan in mice and other laboratory animals. Metformin, a popular diabetes drug, this year will enter the first clinical trial ever designed to find out if a drug can slow aging in humans.

Because of this activity, a small and established group of aging researchers believe that actual life extension could become a reality within the lifetime of you, the readers of this article. "There has been so much talk about eternal life and the 'hacking' of aging that it dwarfs what we know is possible now," says Matt Kaberlein, a leading aging researcher at the University of Washington. "At the rate research is progressing, there could be a 20% to 50% increase in healthy life expectancy over the next 40 to 50 years."

"This arouses huge reactions and huge interest and a feeling that something big is going to happen," he says Nir Barzilai, the leader of the metformin trial and director of aging research at the Albert Einstein College of Medicine. "I think we will achieve significant results, and the next drugs will be better."

Moving on to nutrition

The roots of aging lie, at least in part, in our appetite. Already in the 30s, scientists knew that starving laboratory animals such as mice and rats allowed them to live up to 20% longer. Even Kristal, who is not a scientist, believes that the periods of his life when he suffered from hunger during and after World War II contributed to his longevity. in an interview He told Haaretz newspaper, "I eat to live and I don't live to eat." Don't need too much. Anything that is too much is not good."

Unfortunately – or fortunately, depending on the point of view – in experiments where they radically limited the amount of calories in the diet of monkeys, animals that are more similar to humans, mixed results were obtained. Low calorie intake worked well in one trial, but another well-designed trial showed that eating natural, organic food with no added preservatives, colors or anything else, with low sugar content helped just as much, regardless of the amount of calories. And in any case, only a few people can stick to a diet that requires a 25% reduction in calories.

Conversely, experiments in less developed organisms have revealed unique and beneficial molecular cellular pathways that are activated under conditions of food deprivation. These pathways evolved to allow creatures to survive long periods without food. Theoretically, activating such pathways with drugs could produce the same benefit without the agony of self-starvation. In one example the enzyme is involved AMPK Acting like a cellular fuel gauge. When there is a lack of nutrients, as happens during intense sports activity or in times of hunger, AMPKK immediately comes into action, leads glucose into the cells to create energy and increases the sensitivity of the cells to hormones that help with transport, such as insulin. It also helps break down fats to generate more energy. During sports practice, AMPK stimulates creation Mitochondrions New, the energy producers in the cells. All these actions improve health.

There is fascinating evidence that there is a direct connection between the aging process and the rate of metabolism, the process by which the body turns food into energy. In 1993 she found Cynthia Kenyon from the University of California, San Francisco, that mutations in a single specific gene, DAF-22, can double the lifespan of the roundworm Caenorhabditiss elegans, and that this gene is related to metabolic rate. But scientists still know relatively little about the genetics of aging, so currently their preferred targets are higher-order cellular mechanisms.

One of the most promising anti-aging mechanisms was discovered by chance. In 2001, the biologist came out Walter Longo from the University of Southern California for a weekend vacation and forgot to feed the yeast cells he used in the experiment. He was surprised to find that their absolute starvation during the vacation period extended their lives. He learned that the reason lies in a chain of molecular actions often named after the central enzyme in the chain, mTOR.

This pathway was first discovered many years earlier thanks to the drug Rapamycin found in soil bacteria. Scientists have learned that the drug affects a central cellular pathway that regulates cell growth and division, acting just like a central switch in a tiny factory. Researchers named the pathway mTOR because it serves asThe mechanistic target of rapamycin. When the mTOR pathway is activated, the "factory" (the cell) begins to work and produce new proteins, grow and eventually divide. When mTOR is blocked, such as under the influence of rapamycin, or as a result of a short period of starvation, the growth and reproduction processes of the cells slow down or stop. This is why rapamycin is effective in suppressing the immune system and is therefore used in the protection against rejection of transplanted organs, and recently also in the treatment of cancer: conditions involving uncontrolled cell division.

Longo's work led to the discovery of mTOR's crucial role in aging. When there is a lack of food, the mTOR pathway is inhibited, and the plant enters a more efficient mode where it recycles old proteins to make new ones, increases the cell's cleaning and repair mechanisms, and waits for the end of starvation. Cell division is slowed down, so the animal can survive better until the next meal.

"Actually, the mTOR pathway senses the environment, and if there's a lot of food around, it kicks in and causes simple organisms to develop and multiply quickly," explains Kaberlein. "It makes a lot of sense because when food is plentiful it's a really good time to have babies." It is therefore no wonder that the mTOR mechanism was such a hit during evolution and is used up and down the tree of life, from single-celled yeast to humans and whales.

The change in the activity of this molecular pathway affects survival. in 2009 Reporting A team of scientists in the scientific journal Nature reported that laboratory mice given rapamycin lived longer. It was a remarkable finding: no drug had ever extended the lifespan of mammals in this way in a controlled trial. And it is not just one group of mice, but three groups of genetically different mice. All the groups lived longer and not just on average: the maximum lifespan of the mice was extended, and some see this as evidence that the drug slows down the aging process itself.

Mice given rapamycin seem to stay healthy and young longer than rodents who did not receive the drug. Their tendons, for example, remained more flexible and springy as well as their hearts and blood vessels. Even their livers were in better condition than those of the control mice. They remained more active even as we aged. What's more, rapamycin extended both their average lifespan and their maximum lifespan even when they started receiving the drug as early as 20 months of age. It's like giving a 70-year-old woman a pill that will allow her to live beyond the age of 95. Or to put it another way: imagine a drug that will allow Crystal to reach the decade after 130.

Other laboratories were able to repeat the results and extend them. The life span of mice given rapamycin as adults was extended by 25%, the same result obtained with caloric restriction. Obviously, mice are not people, but the rapamycin experiment at least raised the possibility that something could slow down the rate of aging and delay the onset of senile diseases. "Rapamycin was the pioneer, the first drug that everyone said could be the real thing," he says Brian Kennedy, executive director of the Beck Institute for the Study of Aging in Novoto, California.

But the use of rapamycin is not without problems. There may be very unpleasant side effects, such as mouth sores and more frequent infections (due to suppression of the immune system response). In studies conducted on mice, the males suffered from shrinking of the testicles. These effects are plausible in cancer patients and transplant recipients who are already quite ill, but they could pose an obstacle to using the drug to slow aging processes in healthy people. In this case the cure can be worse than the disease. But what will happen when this medicine is given to healthy people in a different way or at a lower dose? Will the medicine be able to extend life in humans even then?

To try to answer these questions, Kaberlein and his colleague Daniel Promislo They are starting an unusual clinical trial in which they will give low-dose rapamycin to adult dogs. Our canine friends can serve as a logical substitute for us: "They share the environment with us and when they get old they get the same diseases of old age that attack us," says Kaberlein. According to their preliminary data, dogs treated with rapamycin for several weeks showed younger heart activity as measured by echocardiogram. "We can clearly see that the heart contracts better in the dogs that received rapamycin than in the dogs that did not," Kaberlein says. "In aging animals, poor blood flow is probably the cause of deterioration in the rest of the body's tissues."

According to Kaberlein, one encouraging sign of the drug's potential to slow aging is that at low doses, rapamycin can work as an immune system regulator rather than a suppressant. In fact, at these low levels it appears to enhance certain functions of the immune system. Novatris, which markets a version of rapamycin called Afinitor for cancer treatment, showed in a small human trial that older adults who took the drug responded better to the flu shot, showing that there are cases where it can boost the immune response. Another interesting piece of evidence was obtained from a Dutch study that showed that in healthy people over 90 years of age, a slowdown in low activity mTOR pathway is evident.

The next step, depending on funding, is to conduct an ongoing, long-term trial in older dogs and follow them as they age. If the results mirror what was obtained in mice, that is, if the dogs live longer healthy lives, they will justify a clinical trial in humans. "We will be able to know in five years to what extent rapamycin actually works," says Kaberlein.

a stretch of life

The key is the connection of "healthier" to "longer". Our life span is indeed stretched, but the last part of our life is destined for diseases and disabilities. As demonstrated by the demographers James V. Waffle and Jim Oppen In an article in the journal Science in 2002, the life expectancy of the world's oldest populations has increased more or less linearly since the 40s (now Japanese women are at the top of the list). People are living longer today than they have ever lived in all of human history.

At the same time, health expectancy, defined as the duration of a healthy life, did not increase at the same rate. From this it follows that, in fact, the period of illness and disability at the end of life, that dreaded deterioration of old age, is lengthening. The only thing that changes when we live longer is that we fall victim to various ailments. As death rates from heart disease and cancer decline, we become more vulnerable to Alzheimer's disease. One in nine Americans over the age of 65 has Alzheimer's or other forms of cognitive decline, and the risk increases dramatically over the age of 80.

"The increase in Alzheimer's disease is amazing, but this is exactly what you should expect if you push people into the age range where it is common, the 70s and 80s," says SJ Olshansky, a demographer at the University of Illinois at Chicago. "If we continue on this path, I think it will be worse, the alternative is to slow down aging as much as possible and compress morbidity and mortality for a shorter period of time."

Olshansky hasn't met Krystal, but the Guinness World Record holder is the kind of old man he thought of. At 112 years old, Krystal is still sharp and sharp and a witty conversationalist. He managed to ward off the deadly diseases of aging: not only cancer and heart disease, but also Alzheimer's and diabetes, which together account for half of the deaths in the developed world. For people over 100 like him, the sick period at the end of their lives is often much shorter than for those who die in their 70s. According to Olshansky, a successful drug to slow down the aging process should have the same beneficial effect: not just prolonging life at the expense of physical and mental health and well-being.

But until recently, researchers were face to face with a formidable obstacle in the development of this type of drug: the American Food and Drug Administration (FDA) did not consider aging a disease and therefore did not approve any drug intended only for the aging process. From the agency's point of view, the policy made sense: there is no objective way to "measure" aging, for example, there is no blood test that can determine whether a person is going to age faster or slower than normal. Thus, how do we know if an antiaging drug is working? This official position thwarted any incentive for pharmaceutical companies to invest in research into the aging process and drugs that could slow it down. There was no simple way to approval and marketing.

The horizon began to brighten in 2015 when the agency gave approval to a clinical trial designed to gauge metformin's anti-aging properties. The drug was approved in the UK in the 50s for the treatment of type 2 diabetes (the most common) and approved by the US Food and Drug Administration in 1994. Since then, millions of diabetics receive metformin as a first-line treatment. Today, when the drug is available as a cheap generic drug, its prescription is one of the most common in the world, so much so that the World Health Organization has declared it an "essential" drug. Metformin increases the cells' sensitivity to insulin, the hormone that signals them to consume sugar (glucose) from the blood.

Because so many people are taking the drug, researchers can discover intriguing patterns among them. Epidemiological studies have found that among those who take the drug there is a lower incidence of cancer. Other studies suggest that metformin has beneficial effects in cardiovascular disease. What's more, while diabetics lose several years of life expectancy to diabetes, a 2014 analysis of British patient data found that older diabetics taking metformin actually lived 18% longer than matched non-diabetic controls. They also live longer than diabetics using another common group of drugs, sulfonylureas, which suggests that the effect of metformin itself, and not just the control of sugar levels, confers a longevity advantage.

It is still not entirely clear how exactly metformin works. The mechanism of action of metformin, which is produced by extracting a traditional medicinal herb called French lilac or galega, was in the course of several decades a source of debate among researchers. One thing is known: Metformin activates the AMPK enzyme pathway and the positive metabolic changes it triggers. It appears to affect insulin through other pathways and even inhibits mTOR to some extent.

The possibility that metformin could extend life expectancy caught the attention of Nir Barzilai of Albert Einstein College and others. As the head of the main study on Ashkenazi Jews over 100 years old, Barzilai knew that long-lived people usually do not suffer from problems with blood pressure and diabetes; Radically efficient processing of blood glucose is actually a marker for longevity. He thinks that metmorphine can change the metabolism to more like that of 100+ year olds. "Its vigorous activity against diabetes also prolongs life and thus improves cellular function and insulin sensitivity," says Barzilai. In fact, he takes the medicine himself as a preventive measure because his parents were diabetic. He was not far from saying that everyone over the age of 50 should think of a way to get a prescription (Barzilai is 60). "It seems like a panacea for many things related to aging."

"Data accumulated over 60 years of administering the drug to humans show that it targets a large number of conditions, all of which lead us to believe that it targets the underlying aging processes," agrees James L. Kirkland Director of the Robert and Arlene Kogod Center for the Study of Aging at the Mayo Clinic and a partner in studies on metformin.

And yet, another obstacle faces the researchers who intend to test in humans drugs that are supposed to act as anti-aging agents: time. It takes decades to complete research on a normal life span: a lifetime, literally. In 2015, a clinical trial called the machine was approved TAME For the study of the treatment of aging with metformin, in which a different approach was taken. Instead of comparing the lifespan of healthy people who receive the drug with the lifespan of healthy people who do not receive it, the scientists will examine the progression of age-related diseases in each participant.

One of the signs of aging is the way older people often develop several chronic diseases, such as high blood pressure and diabetes or heart disease and brain damage. This co-morbidity of disease upon disease is the reason for suffering in old age (as well as the reason for the increase in financial expenses for health care). In the TAME trial, scientists plan to give metformin to elderly people who already have one of the conditions associated with old age, such as high blood pressure or diabetes. The researchers will monitor the participants for five to seven years and compare them to a control group that agreed not to receive the drug to examine the rate at which they will develop another age-related disease, if at all. If metformin does slow down the aging process, it should prevent the development of associated morbidity.

In such a case, the TAME trial will truly measure the effect of metformin on the length of the health period and evaluate its effect as an essentially preventive medicine. "The same process happened, for example, with the administration of antihypertensive drugs to prevent a heart attack," says Kirkland.

Barzilai thinks that if the TAME trial ends successfully and the FDA shows openness to testing new drugs aimed at preventing aging, the pharmaceutical companies will start "flying into space" - and not only the traditional pharmaceutical companies, but also entrepreneurs like ProjectCalico (to prevent aging) that Google funds. Google appointed Cynthia Kenyon, who discovered the DAF-22 aging gene two decades ago, as vice president of aging research. According to some reports, Project Calico is investing more than a billion dollars in the search for drugs that will prolong the period of health in old age, an amount close to the total budget of the American Institute for Research on Aging.

"And if longevity is a side effect" of extending the duration of health, jokes Barzilai, "we apologize."

Pills for future generations

The pipeline of potential anti-aging drugs is already starting to fill up. For example, another antidiabetic drug, Acarbose, extended the lives of male mice. Acarbose, like metformin, is already approved for use in humans, so it too could be a candidate for an anti-aging clinical trial. Also another medicine, the hormone alpha-estradiol, obtained good results in the same type of experiments in which they discovered the effect of rapamycin in slowing down aging.

A new, and possibly more promising, class of anti-aging drugs does not act on metabolic pathways but instead removes aging cells that have stopped dividing, even though they are not yet dead cells. Like cellular zombies, these cells stay put and secrete small proteins known as Cytokines which may harm the cells around them. Kirkland believes their real function is to serve as a defense mechanism against cancer, a way for the body to kill neighboring cells that may be malignant. Senescent cells also participate in wound healing because the cytokines they secrete regulate the activity of the immune system. Unfortunately, their toxic effects reach far beyond their immediate environment and they contribute to the low level of general inflammation that characterizes aging bodies, paradoxically increasing the risk of cancer in nearby tissues. Kirkland and others believe that these cells drive the aging process.

And even worse than that, as we age, we carry more aging cells in our bodies. What if we could drive them out? Kirkland and his colleagues, including Jean Van Dersen, who works in molecular biology at the Mayo Clinic, showed that removing senescent cells from genetically modified mice extended their period of health. The problem is that it is very difficult to isolate the aging cells, scattered among the healthy cells, and it is even more difficult to kill them. "They are very resistant to death," says Kirkland. "They are extremely tough."

A team of researchers at Mayo, the Scripps Research Institute, and other institutes searched for drugs that could kill aging cells by inducing Apoptosis, or cell suicide. In 2015, they reported in a paper that they had found three drugs: two of them, DestinibוNavitoclax, are used to treat cancer and one, Quercetin, She flavonoid Natural, an antioxidant compound that also acts as a pigment found, among other things, in apple peel and caper (and in many other foods).

In one experiment, radiation was used to damage one of the legs of an animal and cause the muscles in the leg to atrophy, similar to muscle loss that occurs with aging. The radiation also caused the formation of many senescent cells in the muscle, a condition also observed in cancer patients who underwent radiation or chemotherapy. After a short treatment with these drugs, the function of the leg returned to normal almost completely. Kirkland believes the dramatic effect was because the drugs killed more senescent cells than other types of cells. "We gave just one dose, and the fitness improved considerably - and stayed that way for seven months," says Kirkland. This confirms and ensures that the drugs actually eliminate aging cells. And when they die - they die."

They may have to die for us to live.

For more articles in the series:

• Questions for the future of humanity: How will climate change change us?
• Questions for the future of humanity: What geological imprint will we leave behind?
• Questions for the future of humanity: Will we survive the economic disparities?
• Questions for the future of humanity: who will prosper and who will be left behind in a world of 10 billion people?