18 May 2017

The fight against aging: is there hope?

What anti-aging funds do investors invest in

and what are the prospects for the latest discoveries

Vladislav Rakhmanov, vc.ru

Vice-President of the Science for Life Extension Foundation Yuri Deigin spoke about how real the invention of a cure for old age seems today and whether investors will be able to find their "unicorn" in this market.


At the forefront of the fight against aging, a high-profile event has recently occurred: a group of scientists led by Harvard geneticist David Sinclair published the results of their latest study, which has already been called "a huge leap in the fight against aging."

They even say that an open "drug that really reverses aging" may appear in pharmacies as early as 2020. Moreover, NASA became interested in the development: according to experts, Sinclair's discovery can help maintain the health of astronauts during long flights to Mars.

The "old age pill" is called NMN. It is based on nicotinamide, a precursor of the enzyme NAD+ (nicotinamide adenine dinucleotide), synthesized in all cells. It has not demonstrated any miraculous properties until recently: except that nicotinic acid (vitamin B3), which, by the way, has been known for more than a hundred years, has been successfully used against pellagra (a type of vitamin deficiency), but its benefits with a balanced diet are minimal.

Nevertheless, Sinclair's group managed to achieve impressive, at first glance, results: NMN increased the ability of cells to repair DNA after damage. The studies were conducted on mice and, according to Sinclair himself, within a week after treatment, the cells of old individuals were indistinguishable from the cells of young ones. Clinical trials in humans will begin this year at Brigham Women's Hospital, Boston, USA.

Does this mean that the fight against aging will finally cease to be the lot of mostly philanthropists and will be a much more attractive direction for investment, and investors will finally find their "unicorn" in this market?

A little history

Dreams about the source of eternal youth appeared to mankind quite a long time ago – after all, Herodotus wrote about it, and before him, according to rumors, the Sumerian ruler Gilgamesh was looking for such a source.

The rapid development of science may well make dreams come true: more and more scientists are saying that aging is a disease that must and, most importantly, can be fought if we want to increase the duration of a healthy human life and rid the world of age–dependent diseases, including cancer and Alzheimer's disease.

This optimism is not groundless: there are many successful experiments on extending the life of a variety of model animals (from worms and flies to primates), and nature shows that aging is not at all a prerequisite for the existence of living organisms.

What are, for example, eternally young and immortal hydra or naked diggers – real superheroes of the animal world – who do not feel pain, can do without oxygen, and live 10-15 times longer than their mouse cousins.

It is difficult to say when a person will have the ability not to age. There is still no unified theory of aging that would explain all the factors of this process and help in the search for a "cure". Against the background of this uncertainty, the "symptomatic struggle" for life extension looks much clearer. And billions of dollars are allocated for the treatment of cancer, cardiovascular diseases and other pathologies, the risk of which, however, despite all efforts, continues to grow with age, and exponentially.

Compared to spending on cancer or Alzheimer's, the amount of spending on fighting aging itself is not nearly as impressive. Two leading research organizations that are purposefully engaged in fundamental research of aging mechanisms – the American Buck Institute for Aging Research and the American Salk Institute – have annual budgets of $40 million and $110 million, respectively.

The US Scientific Grant Agency and the National Institute of Aging in 2015 allocated $1.4 billion for various studies, but the lion's share of these grants was issued for the development of therapy for Alzheimer's disease, which also falls under the mandate of the NIA.

Private investors are also wary of the confrontation between science and old age: there have been many more failures in this field so far than successes, and initially very promising technologies consistently did not justify the hopes placed on them.

In search of the "unicorn"

In the last 20 years alone, dozens of anti-aging strategies have been tested: researchers have proposed both "miracle pills" and gene therapy, but a means of radically prolonging life, which is the goal of this struggle, has not been found.

The best geroprotectors helped to increase its duration by only 20-30% for some model organisms, but in light of the fact that fasting prolongs the life of the same organisms by 40-50%, these achievements look very pale.

Among the most well-known approaches that disappointed with their results, we can single out rapamycin, metformin, modulation of the Wnt signaling pathway, thymus gland transplantation, and even half a century later, the newly fashionable blood transfusion of young donors. But none of them has yet shown any outstanding results - that is, extending the life of model animals by at least 50%.

In recent years, great hopes have been pinned on the rejuvenating potential of telomerase, a special enzyme that is produced in stem, germ and some other types of cells.

Scientists, including William Andrews, founder of Sierra Sciences, and Michael Fossell, professor of clinical medicine at the University of Michigan, hoped to use its properties to influence one of the cellular mechanisms of aging – shortening of telomeres, that is, areas at the ends of chromosomes, which are one of the oldest mechanisms for limiting the number of cell divisions.

With each subsequent division, these areas become smaller and smaller, and eventually, at a certain stage, the cell population stops dividing altogether.

The most notable achievement in the telomerase field was the results obtained by the team of the Spanish National Cancer Research Center under the leadership of Maria Blasco: telomerase gene therapy extended both the average and maximum life expectancy of experimental mice, however, by no more than 24%.

It is not surprising that the investment attractiveness of the "telomerase" approach to the fight against aging remains in question. Even the risky step of the American Elizabeth Parrish, CEO of BioViva, who decided to test the gene therapy developed by Blasco on herself, without waiting for the completion of all necessary clinical trials, did not help to increase it.

Investors are in no hurry to invest money in continuing research. This, by the way, is also mentioned by the already mentioned Michael Fossel, who also bet on telomerase and is not too successfully trying to attract investment for his company Telocyte to test it against Alzheimer's disease in clinical trials.

Investors reacted much more favorably to the development of "senolytics" – drugs designed to cope with senescent cells, that is, cells that stopped performing their functions with age, but for some reason did not go into apoptosis, that is, refused to obey the order to commit suicide.

This is evidenced by the success of the Unity Biotechnology startup, which attracted $116 million for its development and convinced even such sophisticated investors as PayPal creator Peter Thiel and Amazon CEO Jeff Bezos of the viability of the approach.

The fact is that senescent cells not only do not perform their functions, but also harm the body, because they produce a cocktail of signaling factors that leads to chronic inflammation. The developers of senolytics hope that if they can selectively remove senescent cells, this will rejuvenate the body.

While we are talking about the use of senolytics in the fight against atherosclerosis, however, in theory, they can already be tested in clinical studies and against other diseases that are somehow associated with the aging process.

The Future of Sinclair's Discovery

Sinclair's discovery, judging by the enthusiastic reviews in the press, should leave senolytics, telomerase, and other "pills for old age" far behind. Indeed, at first glance his work looks quite convincing, but the sophisticated reader will remember that a few years ago the name of the scientist was mentioned in connection with another development, which was also called a breakthrough.

We are talking about resveratrol, a special molecule that is synthesized in some plants as a response to infection and is a component of red wine. In animal experiments, resveratrol has demonstrated impressive capabilities for suppressing inflammation, oncological processes, as well as increasing life expectancy.

Sinclair sold this discovery in 2008 to the pharmaceutical giant GlaxoSmithKline (GSK), which invested $ 720 million in research, but could not confirm its effectiveness in humans (and twice), and in 2013 closed the project altogether.

Now Sinclair's team has turned to studying the properties of nicotinamide. Scientists are not among the discoverers: interest in this remedy (in the form of a riboside) arose about five or six years ago. First, it was handled by ChromaDex, which released nicotinamide riboside to the market as a dietary supplement under the NIAGEN brand, and then the Boston startup Elysium Health got involved in the race.

Its founder, Leonard Guarente, recruited six Nobel laureates, but even they could not make mice or worms live longer from taking NR (nicotinamide riboside) by more than a few percent.

It is worth noting that Guarente is a colleague and former research supervisor of Sinclair, and in addition to the nicotinamide riboside, the pterostilbene analogue of resveratrol is included in the dietary supplement "Basis" sold by him. So the "breakthrough" of NMN is still very similar to the story of resveratrol and other dietary supplements based on nicotinamide, which feel great on the market and bring their companies a good income, but do not bring victory over old age any closer.

Is there any hope

In fact, all the most popular approaches to combating aging today are reduced to eliminating any "symptom" of this process - be it "defective" cells or short telomeres. This looks quite logical, considering that most experts consider aging as an accident: due to some imperfection, the body accumulates various "breakdowns" and "mistakes" with age, which lead to old age and death.

However, for some reason this accident is strictly determined, and the stages of aging are clearly painted: starting from the appearance of wrinkles and ending with menopause. Hardly anyone has met a 20-year-old with wrinkles or a 60-year-old without them. And besides, the elimination of single "breakdowns" has not yet yielded any significant results, even in the course of experiments on mice, let alone humans.

All this makes us think about the falsity of the assumption that aging is accidental, and accept an alternative hypothesis, supported by a mass of evidence, which claims that aging is a program embedded in our genes.

This program begins to operate from the moment of puberty and slowly but inexorably leads to death. It is not surprising that such a ruthless evolutionary process is almost impossible to contain by influencing any one of its indicators. The main question is whether this program can be disabled or at least slowed down.

Fortunately, scientists are getting more and more evidence that the answer to this question is positive. Moreover, science has already learned to reverse aging, although so far only at the cellular level.

In 2006, scientists learned to do what nature does with each embryo, namely, to "reset" the age of cells – after all, the embryo begins its life path from the mother's egg, which is the same age as its mother. So, now we are able to "rejuvenate" any adult cell of the body, turning it back into a stem cell.

For the first time, Japanese scientist Shinya Yamanaka was able to achieve this with the help of four gene transcription factors (Oct4, Sox2, Klf4 and c-Myc, and all together – OSKM, or "Yamanaka factors"), closely related to the main stages of the cell life cycle, for which he received the Nobel Prize in 2012.

The risk of developing malignant tumors from reprogrammed cells kept scientists from actively using this technology inside the body. There is no guarantee that the skin cell, which Yamanaki factors have returned back to a pluripotent state, will not suddenly want to become a liver cell, and even multiply many times.

But last year, researchers led by Juan Carlos Ispisua Belmonte from the Salk Institute of California published a paper confirming a 2011 observation that the process of converting an ordinary cell into a stem cell occurs gradually. And if you find the optimal scheme of "inclusion" of Yamanaki factors, then the cell does not immediately turn into a stem cell, but only rejuvenates without changing its phenotype (which, in particular, avoids the occurrence of malignant tumors).

As a result, the life expectancy of experimental mice increased by 33-50%. However, these were rapidly aging mice, and the results of the effectiveness (and safety) of such an epigenetic rollback by Yamanaka factors on ordinary animals have not yet been published.

Despite this, the work of scientists is very remarkable for the fact that in mice receiving therapy, there was a decrease in almost all critical markers of aging, including markers of senescent cells. Even telomeres lengthened, which was confirmed in an independent study by Maria Blasco, who also recently began studying Yamanaki factors.

Perhaps, the discovery of the Belmonte group can be considered a breakthrough in the fight against aging – scientists managed to apply the main mechanism of cell rejuvenation to rejuvenate the entire body. Of course, it has to be improved, but this task is much simpler than the search for such a technology. A few years ago it seemed fantastic, but now the way is open for us to create a truly effective gene therapy for aging.

By the way, other "fighters" with aging have noticed all the prospects of this approach. In addition to Maria Blasco, who also focused on Yamanaki factors, Ned David, the head of Unity Biotechnology, already mentioned above, so beloved by investors of the caliber of Thiel and Bezos, became interested in the discovery.

Within a month after the publication of the Belmonte group, Ned David met with the scientist twice, and in March 2017 even discussed some potential further steps. Perhaps the company will soon switch from senolytics to Yamanaki factors?

Apparently, it is Belmonte's breakthrough that can become the "unicorn" that every investor dreams of getting into his portfolio. His group demonstrated an integrated approach to the aging program embedded in the body and showed the possibility of its "hacking". If investors believe in senolitics, then what will prevent a startup that has decided to commercialize a much more promising approach from achieving success?

Portal "Eternal youth" http://vechnayamolodost.ru  18.05.2017

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