A New Path to Longevity / David Stipe

Researchers have discovered an ancient mechanism that delays aging. Drugs that regulate it are able to delay cancer, diabetes and other diseases related to old age

On a bright morning in November 1964, the Royal Canadian Navy ship Cape Scott set out from Halifax, Nova Scotia for a four-month voyage. On board was a group of 38 scientists, headed by the late Stanley Skorina, an energetic professor at McGill University, on its way to Easter Island, a volcanic mound rising from the Pacific Ocean 3,500 kilometers west of Chile. Following plans to build an airport on the remote island, known for its huge and mysterious head sculptures, the group sought to investigate the inhabitants, the fauna and flora, just before the modern world penetrates them.

The islanders warmly welcomed the group of scientists, who collected hundreds of plant and animal samples, in addition to blood and saliva samples from all 949 local residents. But a test tube containing soil turned out to be the greatest treasure of all: it contained a bacterium that produced a protective substance with an amazing property: the ability to extend the lives of many biological species.

Several research groups have shown that the substance, called rapamycin, extends the maximum lifespan of laboratory mice beyond that of untreated animals. Sometimes dubious claims are made regarding success in slowing down the aging process. But in most cases they are based on data showing an increase in average life expectancy. This is achieved through the use of antibiotics or other drugs that indeed reduce premature deaths but have nothing to do with aging. Conversely, an increase in maximum life expectancy (which is often measured as the average life expectancy of the oldest ten percent of the population) is evidence of slowed aging. Extending the maximum lifespan of any biological species in the mammalian kingdom, the gerontologists' long-awaited equivalent of breaking the sound barrier, has not been convincingly achieved by any other drug. Because of this, the success of rapamycin in mice changed the rules of the game among scientists who study aging and try to reduce its effects. Gerontologists long to find a simple solution to slow aging, not only to extend life span, but to delay or slow down the progress of so many processes that go wrong as we age, from cataracts to cancer.

For years, gerontologists' hopes of discovering compounds associated with slowing the aging process have had ups and downs. Optimism increased with the discovery of genetic mutations that extend the maximum lifespan in animals, and with new insights into how calorie restriction causes this in many biological species. But the promising progress has not led to the discovery of drugs capable of stretching the limits of mammalian longevity. Limiting the consumption of calories in mice, which includes a diet on the verge of starvation but nutritionally sufficient, can extend life expectancy, as well as inhibit the development of cancer, neurodegeneration, diabetes and other age-related diseases. But such a rigid diet is not a reasonable option for slowing down the aging process in most people.

Credit: Emily Cooper

In 2006, the substance resveratrol, the famous ingredient in red wine, which mimics some of the effects of calorie restriction in mice, seemed to break the barrier when it was shown to stop the life-shortening consequences of a high-fat diet in rodents. But this substance, which is believed to act on enzymes called sirtuins, failed to extend the maximum lifespan in mice fed a normal diet. But this gloomy picture suddenly became clearer when the results of the research on rapamycin were published in mid-2009. Three laboratories jointly reported that rapamycin, already known as a substance that inhibits cell growth, extended the maximum lifespan in mice by about 12% in three parallel experiments funded by the American National Institute on Aging. Moreover, to the astonishment of gerontologists, rapamycin extended by a third the average survival time of old mice that the researchers previously thought that aging had already damaged them so much that they were no longer able to respond to the drug.

Breaking the lifespan barrier in mammals by rapamycin has drawn attention to a billion-year-old mechanism that likely controls aging in mice and other animals, and may even in humans. The heart of the mechanism is the protein called TOR (target protein of rapamycin) and the gene that codes for it. The TOR protein (called mTOR in mammals) is currently the subject of vigorous research, both in gerontology and in applied medicine, since more and more animal and human studies indicate that suppressing the activity of the protein in mammalian cells can reduce the risk of many age-related diseases, including cancer, Alzheimer's, Parkinson's, muscle degeneration The heart, type 2 diabetes, bone loss and macular degeneration. The astonishing range of potential benefits suggests that if drugs can be discovered that can safely and reliably attack mTOR, it may be possible to use them to slow the aging process in humans, as rapamycin has done in mice and other biological species, a possibility with far-reaching implications for preventive medicine. (Unfortunately, rapamycin itself has side effects that make it impossible to test whether it is able to slow aging in humans.)

Similar hopes were placed on drugs that act on other molecules, especially sirtuins. So what's different about mTOR? The finding that a drug acting on this molecule significantly extended the maximum lifespan in a mammal indicates that mTOR is a key component in the aging process in mammals and that researchers are now close to discovering ways to interrupt the aging process. "Without a doubt, it [TOR] seems to be the main attraction today and will probably remain so for the next decade," says Kevin Florecki, a gerontologist at the Jackson Laboratory in Bar Harbor, Maine, and one of the authors of the paper on rapamycin in mice.

The story of TOR

The research that led to the discovery of the TOR protein's effect on aging took shape when Skorina's expedition moved its soil samples to what were then the Ayerst laboratories in Montreal. Pharmaceutical researchers have found antibiotics in soil samples since the 40s, so Ayerst's researchers scanned the samples for antimicrobial substances. In 20, they isolated a fungus-inhibiting substance from the samples and named it rapamycin because Easter Island is also known by the locals as Rapa Nui. At Irst Labs, they first hoped to use rapamycin to treat Candida infections. However, scientists who studied the properties of the substance in cell cultures and in the immune systems of animals, found that it is capable of inhibiting the proliferation of immune system cells. For this reason, the drug was developed to prevent immune rejection of transplanted organs. In 1972, rapamycin was approved by the US Food and Drug Administration (FDA) for kidney transplant patients. In the 1999s, researchers also discovered that the drug inhibits the development of tumors, and since 80 two of its derivatives, temsirolimus from the Pfizer company and everolimus from the Novartis company, have been approved for the treatment of various types of cancer.

Biologists focused much interest in rapamycin's ability to suppress the rapid growth of both yeast and human cells, because this ability implied that the compound inhibited the actions of a growth-controlling gene that had been conserved during the billion years of evolution between yeast and humans. (Cells grow and expand as they prepare to divide and reproduce.)

In 1991, Michael N. Hall and his colleagues at the University of Basel in Switzerland identified the early target of rapamycin by discovering that rapamycin inhibited the effects of two growth-controlling yeast genes, which they called TOR1 and TOR2. Three years later, several researchers, including Stewart Schreiber of Harvard University and David Sabatini who now works at the Whitehead Institute for Biomedical Research in Cambridge, Massachusetts, independently isolated the TOR gene in mammals. Many other biological species, including worms, insects and plants, are now known to have these genes that control cell growth processes.

During the 90s, researchers deepened their understanding of the functions of genes in cells and the entire body, many of which turned out to be related to aging. They discovered that the gene encodes an enzyme, or protein catalyst, that binds in the cytoplasm (the intracellular fluid) to other additional proteins to form a conjugate called 1TORC, which oversees many activities in the cell related to growth. Rapamycin mainly affects 1TORC. A second conjugate, much less known, is called 2TORC and it also includes the TOR enzyme.

Moreover, the researchers showed that TOR is a sensor of nutrients. When food is abundant, its activity increases, which encourages cells to increase overall production of proteins and divide. When the amount of food is limited, the activity of TOR decreases, and as a result there is a decrease in the production of proteins in the cells and their distribution and preservation of resources. At the same time, the process called autophagy (self-swallowing) increases: cells break down damaged components such as proteins with a distorted shape and dysfunctional mitochondria (the power plants responsible for producing energy in the cell), and as a result, by-products are created that can be used as fuel or building materials; Mouse pups rely on autophagy to provide energy before they start nursing. When there is food again, the inverse relationship between TOR and autophagy is restored: TOR activity increases and autophagy decreases.

Researchers have also discovered in animals that the signal transduction pathways activated by TOR and insulin are interconnected; Signal transduction pathways are series of molecular interactions that control cellular activities. Insulin is a hormone that the pancreas releases after eating food to send signals to muscles and other cells to absorb glucose from the blood for energy production purposes. But that's not the only thing insulin does: it also acts as a growth factor. Insulin and other proteins help increase the activity of the TOR pathway, which helps cells in the body grow and multiply quickly in response to food intake. The relationship between TOR pathways and insulin pathways includes a negative feedback that is also important for health: activating the TOR pathway makes cells less sensitive to insulin signals. If so, constant overeating will cause excessive activation of TOR and lead to cells becoming less and less sensitive to insulin. This "resistance" to insulin can lead to high blood sugar levels and diabetes, and can also cause other age-related disorders, such as heart problems.

Apart from nutritional deficiencies, TOR also responds to other stress conditions in the cell, including low oxygen levels and DNA damage. In general, TOR activity slows down when cells feel their existence is threatened. Slowing down the rate of protein production and cell culture allows the cells to channel resources for DNA repair and other protective measures. Studies in fruit flies show that while protein production generally decreases in these emergency situations, there is selective production of key mitochondrial components, which likely help the cell renew its energy systems. Undoubtedly, this "stress response", in its many aspects, evolved to help cells cope with harsh conditions, but as a side effect, it can also fortify them against the ravages of time.

Finding the connection to old age

Proposition that TOR affects aging stems from findings from the mid-90s, according to which in cells without nutrients, growth is slowed by a decrease in TOR activity. Gerontologists have already encountered such a phenomenon in the past: in 1935, nutritionist Clive McKay of Cornell University showed that young rats fed a diet close to starvation grew slowly and lived unusually long. Since then it has been shown that restricting calorie intake extends the maximum lifespan in various biological species, from yeast to spiders and dogs, and there is preliminary evidence of this in monkeys as well. Cutting normal caloric intake by about one-third early in life often increases maximum lifespan by 30% to 40%, probably by delaying age-related decline. In long-term calorie restriction studies, rhesus monkeys whose diet was cut down were found to be unusually healthy and young-looking for their age.

But this approach is not always helpful. In some strains of laboratory mice it actually shortens life. Yet the accumulating evidence suggests that calorie restriction can lead to healthy aging in humans just as it does in monkeys. Because of this, scientists who study aging are trying to find compounds that have effects such as limiting calorie intake without causing hunger.

At the beginning of the previous decade, researchers already knew enough about the activity of TOR to suspect that blocking its effect in cells might mimic the restriction of calorie consumption. In 2003, Tibor Wolay, a Hungarian researcher visiting the University of Friborg in Switzerland, conducted a study in worms that produced the first evidence that inhibiting TOR might delay aging. By genetically inhibiting TOR synthesis in worms, Walley and his collaborators extended the average life span of the worms by more than twofold. A year later, a study at the California Institute of Technology led by Pankaj Kaphi, who now works at the Buck Institute for the Study of Aging in Novoto, California, showed that suppressing TOR activity in fruit flies also extended their average lifespan and protected them from the effects of a rich diet, just as caloric restriction did. Doing. And in 2005, Brian Kennedy, then working at the University of Washington, and his colleagues demonstrated the link between TOR and aging by showing that disabling various genes in the TOR signaling pathway in Schmer cells extended lifespan.

These studies, and others on TOR, were particularly interesting because they suggested that TOR inhibition mimics not only caloric restriction but also mutant genes known to extend lifespan. These first "gerontogens" were discovered about ten years earlier in worms whose average and maximum lifespan was doubled by mutations affecting the insulin signaling pathway. The discovery that aging, previously thought to be complex and difficult to solve, can be slowed considerably by changing a single gene has made gerontology a hot topic. Among other things, she raised the possibility that it is possible to delay aging in humans by means of drugs. The idea gained momentum after several gerontogens were discovered in mice in the late 90s and early 1s, which block signals related to growth, including signals transmitted into the cells by insulin and a hormone called insulin-like growth factor 2003. In 30, a mouse with such a mutation set the record for longevity of its biological species: almost five years. Lab mice typically live less than XNUMX months.

One would think that the connections discovered between TOR, caloric restriction, and gerontogens would encourage a hot race to test the life-extending effect of rapamycin in mammals. But experts in mammalian aging "didn't really take TOR seriously" before the end of the last decade, says Steven Ustad, a gerontologist at the Burshop Institute for the Study of Longevity and Aging at the University of Texas Health Science Center in San Antonio. This is because rapamycin was known to suppress the immune system; Therefore, long-term use is assumed to be toxic to mammals. But Zelton Dave Sharp, Osted's colleague at the Barshop Institute, formed a different mindset after studying the literature on TOR. In 2004, he initiated a large study on lifespan in mice that received rapamycin continuously.

The study was funded by the US National Institute on Aging, and at first it seemed that it would not succeed. Problems with combining the drug in the food for the mice delayed the start of the drug administration until the study rodents were 20 months old, an age equivalent to 60 years in humans. At that point, Ousted says, "nobody, and I mean nobody, really thought it would work." Indeed, even restricting caloric intake does not reliably extend lifespan in such old animals. But in 2009, three gerontology labs that conducted the study together, Randy Strong's lab at the Burshop Institute, David A. Harrison's lab at Jackson Laboratories, and Richard A. Miller's lab at the University of Michigan in Ann Arbor, made history when they reported that the drug dramatically increased the lifespan by 28% in the old male rodents and by 38% in the females, compared to the control animals. Maximum life expectancy increased by 14% in females and 9% in males.

Additional studies highlighting the importance of TOR in aging were published shortly after the exciting results in mice. Researchers at University College London reported that disabling a gene called S6K1, which is responsible for the formation of an enzyme and mediates mTOR's control of protein production, gives mice resistance to age-related diseases and extends their maximum lifespan. (Mysteriously, the males showed minimal benefit.) And the three American laboratories that first tested rapamycin in mice reported that the effect of the drug on extending life span was similar whether it was given at 9 months or at 20 months, suggesting that rapamycin is most beneficial after midlife, probably Because this is the stage where most of the deterioration occurs, it slows it down.

The fact that TOR inhibition prolongs life in various biological species stands out today as a spotlight in the molecular darkness of aging. However, this does not mean that other aging-related pathways are not important for longevity. Indeed, more and more gerontologists describe the pathways affected by caloric restriction as belonging to a complex and branched network that can be controlled in different ways to promote healthy aging. The components of the network include insulin-related enzymes and proteins called FoxOs that are responsible for stress responses in cells. There is also substantial evidence that citroens help promote the benefits of caloric restriction in mammals and may in some cases participate in the inhibition of TOR. But at this point, TOR appears to be the closest thing to the network's master control unit, which integrates input from various sources to control the rate of aging, at least in some biological species and possibly in humans.

The mystery becomes clear

During the attempt to better understand how inhibiting TOR and restricting calorie intake prolongs life span in so many biological species, researchers faced an ancient mystery: why would any mechanism develop to delay aging?

The issue is puzzling to evolutionary biologists because natural selection works to encourage successful breeding, and not to allow creatures to get an extension in the game of life by continuing to be vital at ages when members of their species naturally disappear due to predators, infections, accidents, and the like. Because of the "external" risks to survival, evolution allows creatures to live long enough to reproduce before the environment wipes them out. Then, as their chances of continued survival diminish, they deteriorate like abandoned houses. Nevertheless, caloric restriction delays end-of-life decline in widely divergent biological species, suggesting that it depends on an ancient mechanism that has been preserved and shaped by natural selection to slow aging processes in some cases.

A common solution to the mystery holds that calorie restriction uses the starvation response that evolved to delay the aging of creatures in hard times so that they can survive long enough to allow them to reproduce when conditions improve. On the other hand, skeptics, such as Osted from the Barshop Institute, claim that there is no evidence that a low-calorie diet makes animals in the wild live longer. Extending lifespan by restricting caloric intake has only been observed in pampered laboratory animals. Living in the wild, emaciated and weak due to starvation, there is a low chance of surviving long enough to benefit and pass on genes, which slow down aging processes and therefore cause the development of a starvation response.

Some gerontologists believe that another solution to the puzzle is more plausible: restricting calorie intake extends life span as a side effect of responses that have evolved for purposes unrelated to aging. Ustad, for example, developed a theory that in difficult times animals adapt and eat things that are unfamiliar to them, and are thus exposed to toxic substances that are not found in their normal food. This behavior may have resulted in the survival of individuals with a tendency to increase the internal defense mechanisms against toxins when starvation begins, the same mechanisms that activate the cell's response to stress and the repair processes accompanying it and because of this, as a side effect, slow down the aging process.

A few years ago, Michael V. Blagoskloni, a cancer researcher at Roswell Park Cancer Research Institute in Buffalo, New York, relied on discoveries about TOR to propose another theory, explaining the wonders of caloric restriction as a kind of accident. A native of Russia who researched a wide range of topics in the field of cancer and cellular biology, Blagoskloni was inspired by a novel idea: the ability to grow, considered the essence of youth, leads us to the grave later in life. He hypothesizes that caloric restriction extends lifespan by interfering with the negative effects of growth pathways at advanced stages in life, the most important of which are the effects of TOR.

Blagoskloni's theory holds that TOR, necessary for development and reproduction, becomes an engine of aging once puberty is reached. Because TOR supports growth, it encourages the proliferation of smooth muscle cells in the arteries (a key step in the formation of atherosclerosis), the accumulation of fat (which helps stimulate inflammatory processes throughout the body), the development of insulin resistance, the growth of cells, called osteoclasts, that break down bone tissue , and the development of cancerous tumors. What's more: by reducing the autophagy process, TOR encourages the accumulation of proteins that tend to become aggregates and of dysfunctional mitochondria, which emit free radicals that damage DNA and cell metabolism. In neurons, TOR also contributes to the accumulation of proteins that are resistant to degradation, a process that plays a role in Alzheimer's disease and other forms of neurodegeneration. Blagoskloni showed that late in life the TOR signals can also stop cell division and cause them to age, a condition that harms nearby cells and impairs tissue regeneration.

Blagoskloni claims that all of this proves that evolution did not create a mechanism designed to delay aging. The life-prolonging effects of rapamycin, of restricting calorie intake, and of genetic mutations that block growth-promoting hormones are nothing more than accidents of nature, ones that happen to interfere with what he calls "distorted growth" during aging, and therefore slow down the process. In fact, the behavior of the TOR signaling pathway is very similar to the aging program, although it was created to aid early development.

Although Blagoskloni's theory is novel, one of its main sources of inspiration was a well-regarded hypothesis proposed in 1957 by the evolutionary biologist George Williams. He developed a theory that aging is caused by two-faced genes that are beneficial early in life but harmful later. These "pleiotropic antagonist genes" are favored by evolution because, as Williams puts it, natural selection "favors youth over old age whenever a conflict of interest arises." Blagoskloni sees TOR as a perfect example of this type of genes.

Like many innovative theories, Blagoskloni's theory is controversial. Some scientists believe that it places too strong an emphasis on TOR. On the other hand, others believe that the key lies in other characteristics of TOR and not in its ability to encourage growth. For example, some believe that inhibition of autophagy by TOR, which allows regeneration of cellular components, is the source of the protein's main effect on aging. Nevertheless, some TOR experts think the theory is plausible, and Basel's Michael Hall praises Blagoscloni for "connecting dots that others don't even see" and says: "And I tend to think he's right."

TOR and the future of medicine

If TOR is the main cause of aging, what are the options to take its sting out of it? Rapamycin's side effects may disqualify it as an antiaging drug in humans, because it may raise blood cholesterol levels, cause anemia, interfere with the wound healing process, and more.

Another drug, metformin, may serve as a substitute, although many tests are needed to test the idea. Metformin is the most common treatment for diabetes and millions have used it for long periods to lower blood glucose. Its mechanism of action is not well understood, but it is known to inhibit the TOR pathway and activate another aging-related enzyme called AMPK, which is activated by limiting calorie intake and encourages the stress response in cells. Metformin is also known to mimic the effect of caloric restriction on gene activity levels in mice, and there is some evidence that it may extend maximum lifespan in rodents. It will be years before we know if metformin can mimic caloric restriction in humans, although rigorous studies are already underway testing its ability to extend lifespan in mice.

Extending life span in humans relative to the extension that rapamycin extends life span in mice, may add an average of 5 to 10 years to human life. This can be an amazing achievement. Indeed, life expectancy in the developed world has increased so much over the past century that when it comes to aging, we are like Olympic athletes trying to squeeze in small increments. The average life expectancy in the US increased by more than 50% during the 20th century but during the last decade it increased by less than 2%.

Because we have greatly reduced mortality in the early stages of life, a significant extension of life expectancy today depends on delaying diseases associated with aging. This is an especially important task due to the enormous costs of geriatric medicine. But drugs that slow down aging processes are certainly economically feasible. In fact, they can be used as preventive drugs that can postpone or delay the diseases in the later stages of our lives such as dementia, bone depletion, cataracts, cancer, a decrease in muscle mass and strength, deafness, and even wrinkles, just as drugs that lower blood pressure and cholesterol today help to reduce the frequency of attacks The middle-aged heart. And these drugs will also provide us with quality time, by extending the duration of our vitality before we wear out and die.

The development of drugs to prevent diseases will not be easy. One obstacle is the lack of a reliable way to measure the rate of aging in humans. A good benchmark will allow researchers to test effectiveness without needing too long trials. However, finding safe anti-aging drugs will pay off, if only to promote healthy aging regardless of extending life expectancy. Who would have thought that a vial of soil scooped up almost fifty years ago on a remote island would become fertile ground for research that could lead to more years of quality of life?

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About the author

David Stipp is a Boston-based science reporter who has focused on gerontology since the early 90s. His book "The Pill of Youth: Scientists on the Brink of an Anti-Aging Revolution" was published in 2010. His blogs on the science of aging are published at www.davidstipp.com.

in brief

In 2009, scientists discovered that the drug rapamycin is able to significantly extend the lifespan of mice by interfering with the activity of a protein called mTOR.

This finding is the most convincing evidence to date that it is possible to slow down aging in mammals by using drugs, and it has sparked interest in the role of mTOR in the aging process.

The finding also focused interest in a mystery: Why does suppressing cell growth and division, one result of interfering with mTOR, extend life span?

Research into this question may lead to the development of drugs that delay or reduce diseases associated with aging, from Alzheimer's disease to cancer and heart failure, and may even extend the lifespan of humans.

And more on the subject

TOR Signaling in Growth and Metabolism. Stephan Wullschleger et al. in Cell, Vol. 124, no. 3, pages 471-484; February 10, 2006. www.ncbi.nlm.nih.gov/pubmed/16469695

Growth and Aging: A Common Molecular Mechanism. Mikhail V. Blagosklonny and Michael N. Hall in Aging, Vol. 1, no. 4, pages 357-362; April 20, 2009. www.ncbi.nlm.nih.gov/pubmed/20157523

Rapamycin Fed Late in Life Extends Lifespan in Genetically Heterogeneous Mice. David E. Harrison et al. in Nature, Vol. 460, pages 392-395; July 16, 2009.

Aging and TOR: Interwoven in the Fabric of Life. Zelton Dave Sharp in Cellular and Molecular Life Sciences, Vol. 68, no. 4, pages 587-597; February 2011. www.ncbi.nlm.nih.gov/pubmed/20960025