Geroprotectors: will be done and is already being done

The idea is to die young,
however, at the same time as late as possible.
Ashley Montague,
English anthropologist (1905-1999)

The elixir of immortality (or, at worst, ways to prolong life and youth) has been sought for many thousands of years by shamans, priests and alchemists. They say some of them have succeeded, but they took the secret of eternal life with them to the grave. Like, for example, A. A. Bogomolets, Vice-President of the USSR Academy of Sciences, academician and president of many other Soviet academies, Honored Scientist of the RSFSR, Hero of Socialist Labor, laureate of the USSR State Prize and so on and so forth and, without any doubt, an outstanding scientist. According to rumors, his career was also pushed by Comrade Stalin – in the hope of the academician's success in creating the "elixir of longevity": like many gerontologists before and after him, Bogomolets was sure that a person can and should live up to 150 years. According to legend, Stalin, having learned in 1946 about the death of a 65-year-old Worshipper, exclaimed: "Deceived, bastard"!

Gerontology – the science of youthGerontology (from Greek.

gerontos – the old man) studies all aspects of aging at all levels, from molecules and cells to the body and society, the causes of aging and ways to prolong life and biological rejuvenation (not to be confused with plastic surgery and cosmetology!). This science was born at the beginning of the XX century, with the publication of Ilya Mechnikov's book "Studies of Optimism". True, the theory of the founder of modern immunology, gerontology, evolutionary embryology, a Nobel laureate and an undoubted genius has not stood the test of time. Mechnikov considered the intestinal microflora to be the cause of aging (as it turned out later, absolutely necessary for the "host" organism) and suggested drinking more kefir to prolong life, or better yet, removing the large intestine along with the "putrid" microbes inhabiting it. He himself, however, did not dare to do this – maybe that's why he lived only 71 years?

In less than a hundred years, enough knowledge has accumulated in genetics, molecular and cellular biology, immunology, biotechnology and other life sciences to begin developing methods that allow a person to fully realize the life span of 120-125 years allowed by nature. And maybe – and push back this border.

However, so far none of the dozens of geroprotectors (anti-aging drugs) tested on animals has turned out to be sufficiently effective and safe to allow its use for humans.

Do not drink, do not smoke, do not eat, do not breathe…The only scientifically proven and more or less suitable way for a person to prolong life is a low-calorie diet.

Since the mid-1930s, it has been known about an increase of 30-50% in both maximum and average life expectancy in rats and mice, who since childhood received twice as much food as their relatives in the neighboring cage, who were fed according to scientifically based standards. Since then, this fact has been confirmed on a variety of animal species and even on yeast. And in the summer of 2009, Ricky Coleman and his colleagues from the Wisconsin Primate Research Center published in the journal Science the results of a twenty-year observation of two groups of rhesus monkeys.

All this time, the monkeys from the control group ate as much as they wanted. The scientists measured the rations for the experimental subjects by a third less and estimated the biological age of those and others by three hundred indicators. For 20 years, out of 38 macaques who were on a diet, only 5 died, and in the control group – 14 out of 38. In most cases, the cause of death was typically senile diseases – cancer, diabetes, strokes, heart attacks and neurodegenerative diseases like human Parkinson's and Alzheimer's diseases. The monkeys of the control group looked much older than the little ones, they had more fat, less muscle, and their hair was grayer and rarer… Of those who were still alive at the time of writing, five were diabetic, and another 11 were in a prediabetic state. In macaques on a diet, sugar remained normal, and cardiovascular diseases were twice as rare. It is not known, however, how much the long-lived monkeys were dissatisfied with the main undesirable effect of a starvation diet – a violation of reproductive function…

The experience that enthusiasts from the Society of Low-calorie Nutrition put on themselves is not over yet. And does it make sense? The effect of prolonging life in all experiments was observed only in animals that had been starving since childhood, and not put on a diet in adulthood or old age. Dr. Luigi Fontana from the University of Washington Medical School, who has been regularly examining members of this society for the second decade, claims that their hearts are 15 years younger than those of people of the same age, the pressure is like that of teenagers, and so on. But the same effect can be achieved due to the usual rational nutrition and other well-known rules of a healthy lifestyle.

However, according to a study published in the summer of 2009 in the American Journal of Medicine, out of almost 16,000 surveyed Americans in the prime of life (from 45 to 64 years), only 8% adhere to the four golden commandments of a healthy lifestyle – do not smoke, eat vegetables and fruits every day, maintain their weight and at least 20 minutes a day are allocated for small physical activities. So you can not wait for the invention of the old age pill…

The study of the effect of starvation at the molecular and gene level in experiments on yeast, nematode worms, fruit flies and mice, from which a person is already at hand, allowed us to find out which biochemical pathways are turned on with a low-calorie diet, and which genes are responsible for this. And even find substances that include the same mechanisms, but without starvation. Several variants of "old age pills" acting on these anti–aging mechanisms are already being tested on humans - although so far as drugs for the treatment of certain senile diseases. At the same time, their effect on life expectancy is being tested on animals, and the results – ugh, ugh, would not jinx it…

Target Search

In the summer of 2009, three groups of American researchers working in parallel showed that mice who were given the long–known drug rapamycin in old age (600 days, 60 years for humans) lived longer than control animals: males – by 9%, females – by 13%. In fact, scientists planned to feed mice with rapamycin since childhood, but it turned out that it was impossible to simply add it to mouse food – at the same time, the drug is destroyed very quickly. While the experimenters were developing the technology of packaging rapamycin in microcapsules, the mice prepared for the experiments had time to grow old. But the results from this have become even more interesting: it is more difficult to slow down the aging that has already begun than to achieve life extension by influencing animals from a young age. And if we recalculate the results obtained, it turns out that taking rapamycin during the entire mouse life would prolong it for females by one and a half times, and for males by a third.

The main disadvantage here is that the "long–known drug" is known as an immunosuppressor and is used only in transplantology to prevent the immune system from rejecting the transplanted organ. At the same time, a weakened immune system may not be able to cope with a trifling cold. So rapamycin is completely unsuitable as a geroprotector.

A big plus is that it has now been proven that not only worms and insects, but also mammals have a mechanism for prolonging life by suppressing the activity of the TOR protein (target of rapamycin, target of rapamycin). TOR regulates a number of vital processes, including the rate of cell division and the rate of protein synthesis, and in animals placed on a low-calorie diet, its synthesis slows down. It can be said that rapamycin mimics the effects of malnutrition, but at the same time, apparently, does not affect height, weight, sensitivity to cold and the reproductive system.

The task is clear, the goal is defined: to find a substance that can suppress TOR and not damage the immune system. Get to work, comrades!

Red, 120-degree

In 1992, Serge Renaud and Michel de Lorgeril published an article in the famous medical journal "Lancet", explaining the French love of red wine for a long-known "French paradox": the low incidence of atherosclerosis compared to the rest of Europe (with all the resulting coronary heart disease, heart attacks and strokes) with the same or greater consumption fats, tobacco and other risk factors.

It turned out that the main secret of the "Mediterranean diet" is resveratrol contained in the peel and bones of grapes, a substance belonging to the class of flavonoids. Unlike his classmates, resveratrol is not only an antioxidant that can protect cellular structures from free radicals – one of the causes of age-related diseases and aging in general. It activates the synthesis of sirtuins, a group of regulatory proteins that control a complex system of genes and proteins involved, among other things, in the mechanisms of resistance to various stresses, as well as in the processes of aging and cell death. The enhanced work of the molecular mechanisms controlled by sirtuins also mimics the effect of a starvation diet, but, unlike rapamycin, without undesirable side effects.

Everyone be silent!
A low-calorie diet mobilizes all the cells of the body to fight for survival. One of the mechanisms of such a struggle begins with an increase in the activity of sirtuins (sirtuins, silent information regulator proteins – regulators of information silencing). The DNA molecule in the chromosomes is tightly wound on "coils" of histone proteins.

In order to read information from a gene and begin synthesis of the protein encoded in it, a section of the chromosome is unwound under the action of the histone acetyltransferase (histone acetyltransferases – HAT) enzyme. Sirtuins can detach acetyl groups from histones – labels to which HAT is attached. As a result, the DNA remains tightly packed, and the genes in this area are "silent".
To activate sirtuins, an auxiliary substance (coenzyme) nicotinamide-adenine dinucleotide (nicotinamide adenine dinucleotide, NAD+) is needed, which is involved in most metabolic and energy processes. With a lack of calories in the cells, the concentration of NAD+ increases and the level of its antagonist, a reduced form of the same substance, NADH, decreases. This leads to increased activity of sirtuins.
Another important function of sirtuins is participation in DNA repair (repair of damage).
In young animals, DNA breakdowns do not occur often, so the sirtuins in their cells have time to repair the damage and return to histones in time. With age, due to the malfunction of worn-out mitochondria, more free radicals are formed in cells – one of the main causes of DNA damage. Sirtuins have to repair these damages more often and for longer, meanwhile histones unwind the unattended areas, and proteins completely unnecessary to it are synthesized in the cell.
Resveratrol and its synthetic analogues enhance the activity of sirtuins and trigger mechanisms that protect cells from the generally recognized causes of aging: reduced efficiency of energy production and DNA repair systems, imbalance of gene activity and accelerated apoptosis (programmed cell death).

The developers of geroprotectors drew attention to sirtuins in 1999, when Leonard Guarente, a biologist from the Massachusetts Institute of Technology, showed that yeast with extra copies of the gene encoding one of the sirtuins, the enzyme Sir2, live much longer than usual. After 4 years, David Sinclair, one of the employees of the Guarente laboratory, found out that resveratrol is able to activate sirtuins in the cells of ordinary yeast and increase their lifespan. A year later, he also published the results of a study on more complex organisms: C. elegans nematodes (and adults whose cells have already stopped dividing!), transplanted into a substrate with the addition of resveratrol, lived one and a half times longer than usual.

Unfortunately, to achieve the same concentration of resveratrol in the body, a person would have to drink a couple of buckets of wine a day. Manufacturers of dietary supplements, without even waiting for testing on mice, have established the production of concentrates from waste from the production of wine and grape juice, although it is not yet known how much resveratrol in them corresponds to what is stated, what side effects can occur from an overdose and whether resveratrol acts on humans as well as on worms. While it is undergoing clinical trials as a potential cure for diabetes.

Meanwhile, Sinclair, in 2007, with the help of venture capitalist Christoph Westphal, founded Sirtris Pharmaceuticals Inc. (just a year later, sensing the smell of billions, it was bought by one of the leaders of Big pharma, GlaxoSmithKline).

Synthetic sirtuin activators under the codes SRT1720, SRT2183 and SRT1460 found after sorting through thousands of low-molecular compounds turned out to be a thousand times more effective than resveratrol (not by action, but by the dose necessary to obtain the same effect). Two drugs, whose safety for humans has been confirmed in phase I clinical trials, are already undergoing phase II, which will allow preliminary evaluation of the effectiveness of one of them as a means to treat cancer, and both as drugs for type II diabetes.

The third, SRT1720, has so far been tested only on animals – with encouraging results. Now it is also positioned as a future cure for diabetes, but its potential effect seems to be wider. The mice from the control group, who were on an enhanced diet (40% more calories than usual), not only got fat and weakened physically – they began to develop atherosclerosis and diabetes during the experiment. Mice that were fed the same way, but with the addition of SRT1720, not only had normal cholesterol and sugar. They, despite gluttony, did not gain excess weight and did not lose physical shape.

Up to a hundred – without old age?The theory of academician V.P. Skulachev unites several generally recognized causes of aging.

Firstly, the aging and death of an individual organism is a genetically programmed process necessary for biological species to accelerate evolution. Secondly, the trigger of this program is damage to proteins, DNA and other biopolymers. Thirdly, the main cause of these damages are free radicals, or rather, reactive oxygen species, which are formed in cellular power plants – mitochondria – during the oxidation of nutrients and the synthesis of ATP – a universal "fuel". Fourth, damage to cellular structures (and, first of all, mitochondria) leads to voluntary suicide of cells that are not capable of full–fledged work for the benefit of the whole organism.

Isn't the aging program a relic of the dark animal past? And shouldn't a reasonable person try, if not to cancel the execution of this program, then at least delay its inclusion?

According to Skulachev, antioxidants can block the aging program. The main thing is to find the right one and be able to deliver it to the mitochondrial membranes. And this has already been done.

The most effective of the "Skulachev ions", SkQ1 (from Skulachev and quinone – quinone), consists of two parts. In fact, the antioxidant plastoquinone (this substance serves as a carrier of electrons and protons in the membranes of chloroplasts in plants) is attached to an "electric locomotive" – a lipophilic positively charged part capable of penetrating into the only negatively charged compartment of a living cell – the inner layer of the mitochondrial membrane, consisting, like other cell membranes and their organelles, of fats (lipids).

SkQ-based preparations protect mitochondria from oxidative stress and increase the lifespan of a wide variety of organisms, from ascomycete fungi (microscopic relatives of stitches, morels and truffles) to mice. However, not twice or even one and a half, but by 10 percent, and above all – by reducing mortality in middle age. But, although the maximum life expectancy in mice has not increased much, another aspect of the fight against old age is equally important: not only to prolong life, but also to improve its quality and achieve active longevity. In fact, Skulachev set this task for himself and his colleagues by organizing the Mitotech company.

Mice receiving the optimal dose of the drug showed no signs of aging almost until death. They developed senile diseases much later than the control group – the same as in humans: cataracts, retinopathy, glaucoma, baldness and graying, depression, osteoporosis, sexual dysfunction, etc. Infectious diseases rarely turned out to be the cause of death – the immune system of the subjects worked until old age, as in the young.

Unfortunately, the end of work on preclinical studies of "human" drugs coincided with the beginning of the global financial crisis, and Oleg Deripaska, who sponsored Mitotech since 2003, stopped financing the project. The developers only managed to establish the production of the drug "Vetomitin" for the treatment of eye diseases in animals.

Fortunately, the Rusnano Corporation joined the fight against old age. The goal of the project supported by her is to bring to the Russian and world markets first a drug for the treatment of eye diseases, and then a drug of systemic action – for the prevention and treatment of all age–related diseases. Clinical trials on the first volunteers began in 2010, and if everything goes smoothly, ophthalmic drugs will enter the market in 2013, and the pill "from everything" – in 2016.

And other comrades

The search for methods of rejuvenation and prolongation of life goes in dozens of directions. This is also the activation of telomerase– an enzyme that provides eternal youth to embryonic, sexual, stem (and, alas, cancer) cells. And cell therapy: the rejuvenating effect of stem cells has not been proven, but the first protocols for treating various diseases with their help should appear in the coming years. Clinical studies on the cultivation of artificial organs have already begun, while mammary glands are on the way, hair and teeth are on the way, and then something more vital will be put on stream. And the development of analogues of current antidepressants that can improve the state of the brain without undesirable side effects. And the regulation of genes is already a reality. True, intervention in the "aging genes" and "longevity genes" in humans is not a quick thing, but the introduction of gene therapy methods for a variety of diseases, including typically senile ones, into the clinic is a prospect for the coming years.

Alexander Chubenko
Portal "Eternal youth" http://www.vechnayamolodost.ru20.10.2010

The journal version of the article was published in Popular Mechanics No. 10-2010