Behind the failure is a failure
A brief history of the fight against aging
Yuri Deigin, Geektimes
For links, see the original article.
Despite the fact that there is still no consensus on what aging is – a program or an accident – almost all gerontologists agree on one thing: according to all clinical signs, aging is a disease from which the vast majority of the world's population dies. We must, and, most importantly, we can fight it if we want to prolong the period of healthy human life, defeat age-dependent diseases and in the future get rid of the need to die altogether. So, for me, it does not matter at all from which side scientists approach the solution of this issue – "programmatic" or "random". If only they decided.
I have no doubt that aging will eventually be defeated. At least because scientific and technological progress is only gaining momentum from year to year: for example, a few years ago epigenetic manipulations or technologies like CRISPR seemed fantastic. By the way, CRISPR inspired the famous Harvard geneticist George Church so much that he predicted the defeat of aging within 10 years. And although it is difficult even for me to share such optimism of a great scientist, the probability that at least in 50 years a therapy to stop aging will be developed is very high. Moreover, I think it is possible to implement this within 15-20 years, if, of course, the number of studies in this area is significantly expanded.
Well, anyway, let's go down from heaven to earth and take a look at the path traversed by science (and investors). This path is very sad – the dead with scythes stand on both sides of it.
Where does the money go
If we talk about public financing, the situation, to put it mildly, is not very encouraging. Aging is not even officially recognized as a disease yet, at the WHO level, so much less funds are allocated for the study of its fundamental mechanisms than for the study of its "derivatives" – age-dependent diseases, such as cancer and Alzheimer's.
This is how things are in the three leading international organizations that deal with the problems of aging. The Buck Institute for Research on Aging, for example, lives on a budget of $ 40 million a year, the Salk Institute spends a little more – $ 110 million. The division of the American National Institutes of Health, which is designed to study the problems of aging, the National Institute on Aging, at first glance, spends a much more impressive amount per year – $ 1.4 billion, but at a second glance it turns out that its main part is aimed at studying Alzheimer's disease and developing effective therapy against it, and not to fight with the root cause – aging itself.
Private investors are also in no hurry to help in the battle with the "tyrant dragon": a series of failures in the anti-aging market has led to the fact that investments in this area resemble, rather, charity, and few expect to meet their "unicorn" here. At best, the research ended with replenishment in the ranks of dietary supplements, at worst – the closure of the most promising projects.
The best geroprotectors developed over the past 40-50 years have been able to increase the life expectancy of some model organisms (worms, mice) by only 20%-30%. The results are hardly outstanding, especially when you consider that calorie restriction for the same mice or rats prolonged life by 40%-50%, but it turned out to be practically ineffective on primates. That is, for people there is nothing at all that is guaranteed to prolong life not by 40%, but at least by 15%.
At the same time, even in mice, no geroprotectors have so far been able to show better effectiveness than calorie restriction: neither metformin, nor rapamycin, nor thymus (thymus gland) transplantation, which is responsible for the immune system. No significant synergy was found from the simultaneous use of several geroprotectors at once – for example, the combination of meformin and rapamycin could not even reach 25% prolongation of average life expectancy. Other approaches, such as modulation of the Wnt signaling pathway or blood transfusion of young donors, have also demonstrated questionable effectiveness.
And this is not to mention other equally impressive disappointments.
Telomerase
In 2015, almost the whole world was discussing a bold experiment that Elizabeth Parrish, CEO of BioViva, put on herself: an American woman decided to test gene therapy that prevents telomere shortening, one of the cellular mechanisms of aging.
She was probably inspired to take such a risky step by the results obtained by Maria Blasco's group from the Spanish National Cancer Research Center (Centro Nacional de Investigaciones Oncologicas, CNIO): telomerase gene therapy was able to increase both the average and maximum life expectancy of mice, however, by only 24%.
Other gerontologists also pinned hopes on the rejuvenating potential of telomerase, for example, Bill Andrews, founder of Sierra Sciences (whose team isolated, by the way, the human telomerase gene), and Michael B. Fossel, professor of clinical medicine at the University of Michigan (Michigan State University).
Unfortunately, it was not possible to achieve more impressive results from telomerase, and its popularity soon faded. Parrish's experiment was received rather skeptically and did not help the "telomerase approach" to establish itself on the market. Perhaps in a few years its results will be more obvious and "resurrect" telomerase, but, apparently, investors are not counting on this. This, by the way, is evidenced by the words of Michael Fossel himself, who unsuccessfully tries to raise funds to study the potential of telomerase in the fight against Alzheimer's disease.
The path of nicotinamide and the "breakthrough" of the Sinclair group
David Sinclair, a professor at Harvard Medical School and one of the veterans of the fight against aging, is trying to replace telomerase on the market. He made a bet on the good old nicotinamide precursor of the NAD+ enzyme (Nicotinamide adenine dinucleotide, nicotinamide adenine dinucleotide) and recently published the results of his latest work.
It is difficult to call Sinclair a pioneer in this field: nicotinic acid has been known to gerontologists for centuries, and nicotinamide (still in the form of riboside) interested the scientific community about 5 or 6 years ago. The miraculous properties in it were first discovered by ChromaDex, which eventually brought NIAGEN dietary supplements (in the form of nicotinamide riboside) to the market, and then Elysium Health, a startup from Boston, notable for the fact that its founder, Leonard Guarente, attracted six Nobel laureates to work. However, this did not make any impression on either mice or worms – NR (nicotinamide riboside) extended their life by only a few percent and a drug based on it called "Basis" added to the list of dietary supplements.
Sinclair's latest work, related to the same nicotinamide (already in the form of a mononucleotide, NMN), unexpectedly caused a violent reaction: the media wrote about "a huge leap in the fight against aging" and even suggested that the new drug would help astronauts maintain health during future flights to Mars. The scientist himself noted that only a week of therapy was enough for the cells of old mice to be indistinguishable from the cells of young individuals – NMN restored DNA so well after damage. By the end of this year, the "old age pill" will have to confirm its effectiveness and safety in humans – the tests will be held at the Birgam Women's Hospital in the USA (Brigham and Women's Hospital, Boston, USA).
Of course, I really want to believe a respected specialist, but it is quite difficult to drive away doubts about the miracle of nicotinamide. This is hindered not only by the "market history" of this NAD+ precursor, but also by the history of Sinclair himself, who a few years ago already reported an equally impressive breakthrough.
Sinclair's previous brainchild, resveratrol, showed excellent results in animal experiments: it not only suppressed inflammation and helped to cope with oncological processes, but also increased the life expectancy of model organisms. Big Pharma believed in the discovery: GlaxoSmithKline (GSK) bought the rights from Sinclair and co for 720 million dollars, and spent several more years and a lot of money to study the molecule. Alas, Glaxo did not find evidence of the effectiveness of resveratrol in humans, although she tried twice (1, 2). As a result, the project was closed in 2013.
Will Sinclair be able to convince investors of the viability of the developed technology again? Unlikely. So far, the story with NMN makes you experience deja vu and reminds, on the one hand, of the failure of resveratrol, and on the other, of many other dietary supplements that feel great on the market, but cannot provide radical life extension.
Senescent cells
Senolytics – that is, drugs that fight with senescent cells - claim to be the most commercially attractive means of prolonging life today, which has shifted telomerase from the "throne" and is unlikely to let Sinclair with nicotinamide approach it. This is evidenced, for example, by the success of the Unity Biotechnology startup, in which such large investors as PayPal creator Peter Thiel and Amazon CEO Jeff Bezos believed, and invested $ 116 million.
The peculiarity of senescent cells is that, without performing their direct functions, they do not commit hara-kiri apoptosis, but begin to produce many signaling factors that provoke inflammatory processes in the body. Therapy for their removal was able to prolong the life of mice by 25%. So far, the Unity Biotechnology team is primarily focused on combating atherosclerosis, but in theory, the potential of senolytics can also be used to combat other diseases that are somehow related to the aging process.
Will senolytics repeat the fate of telomerase/nicotinamide and other means for radical prolongation of life? It is still difficult to say unequivocally, however, according to indirect signs, the answer to this question will most likely be positive.
Firstly, one of the most successful Russian biologists abroad, Andrey Gudkov, who is also engaged in the study of senescent cells, recently introduced new (and very revolutionary!) the data on this issue, which can be read here, and, apparently, believes that it is necessary to look for tools to influence other mechanisms of aging if we want to achieve a significant increase in life expectancy.
Secondly, the fact that senolytics are not a panacea for old age also makes us think about the steps taken by the head of Unity Biotechnology, Ned David. He has repeatedly met with my beloved Belmonte (Juan Carlos Izpisua Belmonte), who offers a completely different way to combat age-related degradation of the body. Perhaps Ned already wants to turn off the unpromising "senescent path"? But about everything in order.
The secret of eternal youth
If we consider the aging process as an accident and a consequence of the imperfection of our body, which accumulates breakdowns with age, then the fight against senescent cells, short telomeres and other symptoms of it looks quite logical. However, the failures that have befallen researchers over and over again and, most likely, will not bypass the most investment–attractive approach for today – senolitics - lead us to think that perhaps it's time to pay close attention to an alternative hypothesis, which, perhaps, will allow us to break the desired "jackpot" and find effective aging therapy.
We are talking, of course, about the assumption that aging is a program that is embedded in our genes and with the onset of puberty slowly but inevitably leads us to death. This, in my opinion, partly explains the failures in the market: how to slow down the evolutionarily embedded suicide program in us, affecting some one part of it? If we agree that aging is programmed, then another question naturally arises: is there a vulnerability in this program that will allow us to slow it down or disable it altogether?
The hope that such an opportunity exists was given to us in 2006 by Shinya Yamanaka, professor at the Institute of Advanced Medical Sciences at Kyoto University. The Japanese scientist managed to come close to solving the secret of eternal youth, which nature possesses: we are talking about its ability to reset the age of cells, which it uses for each embryo – after all, it begins its journey from an egg, which is the same age as its mother. Yamanaka learned how to transform any adult cell in the body into a stem cell, or pluripotent, using the joint expression of four transcription factors of the Oct4, Sox2, Klf4 and c-Myc genes (OSKM – "Yamanaka factors"). This breakthrough, by the way, in 2012 brought the Japanese the Nobel Prize and marked the beginning of a new round of research on aging processes.
Another way
For a long time there was no clear understanding whether the process of "dedifferentiation" – that is, the reverse transformation of a cell into a pluripotent one with the help of "Yamanka factors" – was abrupt or gradual. However, in December last year, a team from the Salk Institute led by the already mentioned Juan Carlos Ispisua Belmonte showed that, to our great happiness, this process of epigenetic rollback is quite gradual: by choosing a certain dosage of the "genetic cocktail", it is possible to preserve the phenotype of the cell, only slightly "rolling back" its age.
As a result of their manipulations, the life expectancy of experimental mice increased by 33%-50%, depending on the control group, and most importantly, they had a decrease in many key markers of aging, including senescent cells, DNA breaks, markers of inflammation, free radicals, etc. Moreover, telomeres were lengthened in mice receiving therapy. That is, the Belmonte group observed exactly the effects that I would expect to see with programmed aging. You can read more about this work here. In addition, Belmonte's results were confirmed in an independent study conducted by Maria Blasco, who switched from telomerase to "Yamanaki factors".
Despite the fact that the experiments were conducted on specially bred rapidly aging mice and confirmation of the results on ordinary animals has yet to be confirmed, this discovery has already inspired optimism in the fighters against aging. The success of the group from the Salk Institute was recognized even by their "competitor" David Sinclair, but I have already mentioned about the head of Unity Biotechnology and his meetings with the great Spaniard. And I'm talking about the "great one" without any irony: if Belmonte's results are confirmed on ordinary mice, he is guaranteed the Nobel Prize.
Of course, the technology has not yet been perfected: specialists will have to find the most suitable proportions of the Yamanaki cocktail, timing, the optimal way to deliver these genes to an adult organism, protect themselves from the occurrence of teratomas (cancerous tumors) and much, much more. However, in my opinion, the most important step has already been taken – one of the potential mechanisms of radical rejuvenation has been found, and all other difficulties no longer seem insurmountable.
It remains to be hoped that investors will not pass by the breakthrough of the Belmonte group – perhaps it is the technology of epigenetic rollback that will ensure the appearance on the market of a truly effective means to defeat aging. After all, if investors believe in senolitics, then why should they remain indifferent to a much more promising approach?
Portal "Eternal youth" http://vechnayamolodost.ru
14.07.2017