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谁来引领抗衰老?千岁教授又出招!

已有 3924 次阅读 2017-12-26 10:02 |个人分类:生命科学|系统分类:科研笔记| 衰老, 抗衰老, 千岁教授, Aubrey

“衰老研究”进入2.0阶段,换言之,全面进入“抗衰老研究”阶段以来,大名鼎鼎的千岁教授Aubrey de Grey又有一阵没有与观众和粉丝见面了。这个满脸络腮胡子的大牛人,《返老还童杂志,Rejuvenation Research》主编最近到底在忙啥呢?下面这篇跨年长篇采访告诉你“实情”,同时也告知各位“抗衰老研究”的国际前沿和最高境界……

Wake up people, it’s time to aim high!

brian wang | December 23, 2017

This is a long (14 page) interview with Dr. Aubrey de Grey by Ariel Feinerman.

Ariel is a polymath. He started his carrier as an entomologist and studied systematics, morphology and ecology of Stoneflies (Plecoptera). He went on several field expeditions, including one in the Caucasus Mountains. Then Ariel switched fields and became a software engineer. He designed several projects, including a framework for interactive multimedia books.

Shell - On Top of the world

In 2014 Ariel enrolled in the Physics Department of Saint Petersburg State University where he studiedphysics and pursued a research interest in medical nanomachines as potentialdrug delivery vehicles. His engineering expertise is a definite asset in thisresearch area.

Ariel believes that only an interdisciplinary approach can help us win the war against aging. So in 2015-2016 Ariel also worked at the Laboratory of Plant Genetic Engineering andLaboratory of Physiological Genetics at Saint Petersburg State University.There he studied PCR, Real-time PCR, DNA Extraction, DNA Gel Electrophoresis,and genetic engineering techniques.

Now he works as a consultantin bioengineering company Youthereum Genetics.

Preface

What is aging ? We can define aging as a process of accumulation of the damage which is just a side- effect of normal metabolism. While researchers still poorly understand how metabolic processes causedamage accumulation, and how accumulated damage cause pathology, the damage itself – the structural difference between old tissue and young tissue – is categorized and understood pretty well. By repairing damage and restoringprevious undamaged young–state of an organism we can really rejuvenate it! Sounds very promising, and so it is. And for some types of damage (for example, for senescent cells) it is already proved to work!

Today in our virtual studio somewhere between cold rainy Saint-Petersburg and warm sunny Mountain View we meet a famous person. I hope everyone knows Aubrey de Grey – the man who fell to Earth in order to change our vision of aging, to fight with and to finally save us fromit! For those of you who are not familiar with him here is a brief introduction.

Dr. de Grey is the biomedical gerontologist who researched the idea for and founded SENS Research Foundation. He received his BA in Computer Science and Ph.D. in Biology from the University of Cambridge in 1985 and 2000, respectively. Dr. de Grey is Editor-in-Chief of Rejuvenation Research, is a Fellow of both the Gerontological Society of America and the American Aging Association, and sits on the editorial and scientific advisory boards of numerous journals and organizations. In 2011, deGrey inherited roughly $16.5 million on the death of his mother. Of this heassigned $13 million to fund SENS research.

I will not ask Dr Aubrey deGrey any of those stupid questions that journalists usually annoy him with, abouthis appearance, overpopulation and so on. Instead, we will talk aboutscience and engineering that will rejuvenate our bodies, allow us to be healthy and live longer (I mean reallymuch longer). Because of the recent breakthroughs in many fields, from bionics(仿生学)and applied physics to molecular biology and regenerative medicine, it can (and, I am sure, will) be sooner than you think.

Interview

Feinerman: Hello, Dr de Grey!

de Grey: Hi – thanks for interviewing me.

Feinerman: In 2012, I read anarticle by David Sinclair, where he described reversing the loss ofmitochondrial function in old mice cells by using NAD+. I felt this was a major change. The past five years havebeen remarkable! Now every day I read new articles and news about agereversal. In three years, there has been the creation of a few dozen new bioengineering companieswhose main goal is to reverse aging. Billions of dollars are now investedin this area. I believe we will remember 2016– 2017 as the most important years in antiaging. Do you share this feeling?

Note: First phase 1 human aging reversal trials (GDF, Myostatin) will be in a year or two and GeorgeChurch discusses how to affordablyrejuvenate the whole body! The firstversion of human CRISPR/Cas9 was created in 2013 and now it is ready for use.

In 2015 eGenesis began to workon pigs for xenotransplantation and now they claim they have created retroviruses free pigs!

In 2016 Juan Carlos IzpisuaBelmonte has reprogrammed cells by using special factors and reverted back biological clock in live mice.And it’s only a tiny fraction of news.

de Grey: Yes and no. Yes, inthe sense that there are indeed more and more exciting breakthroughs being madein the lab – and of course I am very proud that SENS Research Foundation isresponsible for some of them. But no, in the sense that there is still aterribly long way to go; we need to fix a lot of different things inorder to get rid of aging, and for some of them we are still at a veryearly stage in the research.

Feinerman: George Church saidthat his lab is already reversing aging in mice and that human applications mayonly be a few years away. He said: “We have 65 gene therapies that are beingtested in mice and larger animals. If they go well we will go straight intohuman trials.” Church predicts that agereversal will become a reality within 10 years as a result of the newdevelopments in genetic engineering. However, he warns that age reversal at a molecular level doesn’t necessarilymean that everything else rejuvenates. No one knows what age reversal willmean for humans. Anyway, all that sounds very promising.

What do you think?

de Grey: George is exactlyright, both in his urgency and optimism,and also in his caution about how muchwe don’t yet know.

Feinerman: You have really changedthe world’s opinion, but now you arebehind the scene. I regularly read about new breakthroughs in the newswhile I don’t see much about your work, even though research in SENS is morefundamental in general! When I went to the SENS web page, I was wondered howmuch you do. This seems like an injustice and can it be fixed?

de Grey: Oh, I’m still quiteprominent – I’m still doing just as many talks and interviews as ever.If to some extent, my contributions are now being overshadowed by otherpeople’s breakthroughs, that’s a good thing! I have always said that my goal isto advance the crusade (圣战)far enough that I can retreatinto glorious obscurity(朦胧不明处) because others are doing myjob better than me.

Feinerman: For many people,their appearance is as important as their health. When you say that SENS 1.0panel of therapies can rejuvenate people from 60 to 30, do they look like 30?Or can they look like 30?

de Grey: Definitely yes. Whenwe thoroughly rejuvenate the inside of the body, the outside is the easy part!

Feinerman: Can we now say thatbiomedical engineering and biotechnology have entered an exponential phase?

de Grey: I think we can justabout say that, yes. It’s very exciting. “Ending Aging” revisited

Feinerman: Your famous book“Ending Aging” was published 10 years ago. Would you like to make a newversion?

de Grey: I probably should, atsome point, but it’s not a priority, because the overall approach that wedescribed in that book has stood the test of time: we have made plenty ofprogress, and we have not come across any unforeseen obstacles that made uschange course with regard to any of the types of damage.

Note: If you have not read“Ending Aging” yet I suggest you to do it as soon as possible, and to be morecomfortable with the ideas we are discussing below I highly recommend you toread a short introduction to SENS research on their web page. Also if you areinterested in recent news and up to date reviews about [anti]aging and rejuvenation research the best place to look for isFightAging! blog. Finally, if youare an investor or just curious, I highly encourage you to take a look at JimMellon’s book “Juvenescence”.

Feinerman: You look for bacteria who feed on dead animals tofind enzymes capable of breaking glucosepane. Do you consider insects? They caneat nearly everything – and much faster!

de Grey: Nice idea, but we’relooking for a different sort of eating. Insectseat stuff and excrete what they can’t digest, just like us. Bacteria aremuch more versatile.

Feinerman: Many insects have no special enzymes, insteadthey rely on bacteria who do all the work. In any case they are nice placeto look for!

de Grey: Yeah, well, notreally. Insects have commensal(共生的)bacteria, yes, but so do we. In general, though, bacteriathat are living freely in the environment are more diverse than those in theguts of animals.

Feinerman: How do you finduseful bacteria?

de Grey: We are using a“metagenomic” strategy for identifying enzymesthat can break glucosepane: we take standard E. colibacteria, we break one or two of their genes so that they become unable tosynthesise one or another chemical (in this case typically arginine or lysine) so that they need to take it up from theirsurroundings, and then we add random DNA from the environment (which could comefrom any bacteria, even unculturable ones) and add bits of it to the E. coli.Very occasionally the new DNA may encodean enzyme that breaks glucosepane, and if so, the bacteria will grow evenwithout any arginine or lysine in the environment, if (but only if) we give them glucosepane instead and theybreak it to create arginine and lysine.

Feinerman: In your book youproposed WILT – the removal oftelomerase in all cells in order of preventing cancer and reseeding stemcell population regularly. Is any success in that? And wouldn’t it be simplerto use non integrating telomerasetherapy to safely lengthen telomeres? Like approaches developed in Sierraand BioViva?

de Grey: We are makingprogress there, yes; in particular we have shown that telomerase-negative stemcell reseeding works for the blood. However, no, the problem withnon-integrating telomerase is that it will extend cancer telomeres just as muchas normal cells’ telomeres. I support that research, though, not leastbecause there may be breakthroughs in combating cancer in other ways(especially with the immune system), in which case it would be much safer to stimulate telomerase systemically.

Feinerman: Now we have very precise CRISPR, and removinggenes is easier than inserting ones because you can target the same cellmore than once. When we solve delivery problem can we be able to apply WILT?

de Grey: Yes, certainly.

Feinerman: Why don’t we knowif medicine can remove telomerase locally in compromised 调和tissue?

de Grey: It’s being tried, butit is very difficult to make the removal selective.

Feinerman: There is growingevidence that epigenetic changes arehighly organized and may be one of the causes of aging. This allows someresearchers to claim that aging is a programme. It does not matter,however, how researchers see such changes – as a programme or as a damage. But restoring previousepigenetic profile by special reprogramming factors we can turn old cell inthe young cell, and resetting profile we can turn adult cell to pluripotentstem cell. Experiments show that restoring epigenetic profiles of manycells in vivo rejuvenates an entire organism. What do you think? Maybe shouldwe consider epigenetic changes as another type of damage in SENS model, callingEpiSENS?

de Grey: We need to be muchmore precise with definitions in order to answer your question. Epigeneticchanges can be classified into two main classes: shift and noise. Shift means changes that occur in a coordinatedmanner among all cells of a given type and tissue, whereas noise means changes that occur in some such cells but not others,increasing the variability of that type of cell. Shifts are caused by some sortof program (genetic changes to the cell’s environment), so yes, they canpotentially be reversed by restoring the environment and putting the programinto reverse. Noise, on the other hand,is not reversible. And we have for several years worked on determiningwhether it happens enough to matter in a currently normal lifetime. We have notgot to a definitive answer, but it’s looking though no, epigenetic noise accumulates too slowly to matter, other than maybefor cancer (which, of course, we are addressing in other ways).

Feinerman: Should we usetranscription factors to reverse the epigenetic programme?

de Grey: Probably not. Theremay be some benefits in doing so, as a way to restore the numbers of certaintypes of stem cells, but we can always do that by other methods (especially bydirect stem cell transplantation), so I don’t think we will ever actually NEEDto dedifferentiate cells in vivo.

Feinerman: One thing keeps me out of bed at night:the fear that stochastic nuclear DNAdamage and mutations may play a big role in aging. Ten years ago youproposed that most of the cells which have critical DNA mutations either (不) make apoptosis, become senescent or cancerous. But if mutations are not critical, cells will live, accumulate them –one broken protein here, another one there – and it will finally lead tomalfunction of the organ.

RBP

de Grey: Don’t worry. These mutations don’t accumulate nearly fastenough to harm us, because they are prevented by the same machinery thatprevents cancer for a currently normal lifetime, and cancer can kill us as aresult of only one cell doing the wrong thing, whereas non-criticalmutations would need to affect a huge number of cells in order to affect thefunction of a tissue.

Feinerman: If it is provedthat nuclear DNA damage and mutations play a role in aging do you havesomething in your pocket? I believe you already thought on that. How willwe fix the problem? Maybe, extensive stem cell therapy (like proposedWhole-body Induced Cell Turnover)?

de Grey: Right. But they don’tplay a role. Note: Whole-body InducedCell Turnover (WICT) consists of the qualitative and quantitativecoordination of targeted cell ablation with exogenous cell administration so asto effect the replacement of a patient’s entire set of endogenous cells withexogenous cells (of the same quantity and cell type as the ablated endogenouscells they are replacing) derived from human pluripotent stem cells anddirectionally differentiated in vitro prior to their administration. Theidea of WICT was firstly proposed in 2016 and improved in 2017 year. Theaim of WICT is the removal from the organismal environment of accumulatedcellular and intracellular damage present in the patient’s endogenous cells, including telomere depletion, nuclear DNAdamage and mutations, mitochondrial DNA damage and mutations, replicativesenescence, functionally-deleterious age-related changes in geneexpression and accumulated cellular and intracellular aggregates.

Feinerman: What do you thinkon the WICT? Combined with WILT it lookslike all-in-one solution when implemented(履行契约).

de Grey: The general idea of accelerating cell turnover is definitely agood one. It is a bit like the ideaof replacing whole organs: if you replace the entire structure, youdon’t need to repair the damage that the structure contains. However, alsolike replacement of organs, it haspotential downsides, because evolution has give us a particular rate ofturnover of particular cells, and the function of each of our cell types isoptimised for that. So it may end up being complicated, with many pros and cons.

Feinerman: While otherrejuvenating therapies (excepting, maybe, OncoSENS) are achievable in the nearfuture and don’t involve special genetic surgery, full allotopic expression isa really long way to go. What do you think on the mimic approaches, forexample, NMN which raises NAD+ level andrestores mitochondrial function in a cell?

de Grey: It may help topreserve health a little, but I think it is very unlikely to extend life bymore than a year or two on average (and it could be even less than that). Butwe are working hard to develop better methods of gene therapy that may makeallotopic expression practical sooner than people think.

Feinerman: Oh, can you unveilthe mystery?

de Grey: Well, basically weare combining two technologiesthat are both very very safe (in the sense that they have very low incidence ofrandom DNA damage) but they have complementary limitations. One is CRISPR,which can make small changes very safely to a chosen location in the genomebut cannot insert more than very small amounts of new DNA. The other is a veryneglected system called BXB1 which caninsert large amounts but only into a location that does not exist in themammalian genome. Our idea is to use CRISPR to insert the BXB1 “landingpad” at a good location and then to use BXB1 to insert our chosen engineeredgenes at that location. We are developing this at the Buck Institute in BrianKennedy’s lab.

Feinerman: Thank you for yourexplanation! However, there is a big problem with all genetic therapies. We need to target every cell in the body,and now it is nearly impossible. Our best delivery systems involvingadeno-associated viruses (AAV) available today have only 10 – 50% efficiency.We should honestly admit that we stillhave no universal instrument for introducing new genes in an adult human.How will you solve this problem?

de Grey: We believe that theapproach I described in my earlier answer will achieve a much higherefficiency, because its lack of off-target effects means it can be used atmuch higher titer.

Feinerman: The main SENSapproach is to rejuvenate our own bodies, but also there is a regenerativemedicine which involves tissue and organ engineering. Won’t it be easier toprint or grow new organs instead of rejuvenating the old ones? Of course,we cannot replace everything, but we can replacesome critical parts: we can grow new heart, liver, muscles, and, indeed,skin.

Note: Tissue and organengineering is among the most fast-growing areas of regenerative medicine. Engineershave already bio-printed or grown in bioreactors almost all human organs. Nowthey are used mostly for testing new therapies or drugs. The main problem whythey cannot be used for transplantation now is the vascularisation challenge.While engineers can bio-print or grow arteries and big vessels, they arestill unable to create the vasculature – the web of tiny vessels andcapillaries within the organ. Companies like Organovo pursue this goal andpromise to solve it within next decade.

de Grey: That’s absolutelycorrect. I expect that in the early days of implementing SENS, some organs will be easier to replace thanto repair. However, of course replacing an organ requires invasive surgery,so we will want to develop repair eventually.

Feinerman: You emphasize thatstem cell research is already a well advanced field and SENS has not needed toget involved in this area. As far as I know many of them are for very specificdiseases and not for rejuvenation. Or will we get it as a side-effect?

de Grey: As you know, I don’tthink that “diseases of old age”should be called diseases at all – they are parts of aging, so their treatmentis definitely part of rejuvenation. A great example right now isParkinson’s disease – there are several stem cell clinical trials in progressor in preparation for it.

Feinerman: Do you mean theyare parts of aging like runny noses andcough are parts of flu? So treating them separately is as foolish as treatingcough without addressing the flu virus.

de Grey: It’s even worse thanthat. Treating runny nose and cough makes some sense, because the body will geton with attacking the flu virus anyway, and it makes sense to be less miserableduring that time. But with aging, we’re just talking about different partsof a phenomenon that the body does not know how to attack.

Feinerman: What in youropinion will be the order of arrival of rejuvenating therapies?

de Grey: Well, a lot of thestem cell side of things is in clinical trials already, and removal ofamyloid is there too in the case of Alzheimer’s. Next on the list will probablybe senescent cell ablation, which Unity Therapeutics is saying will be in theclinic next year, and removal of intracellular garbage for macular degenerationwill also be, courtesy of our spinout Ichor. The other three are harder butthey are all chugging along.

Feinerman: There are about twenty various types ofamyloids, we can see some success in removing transthyretin andbeta-amyloid. What is about others? Can we scale success in removing the abovetwo on the others?

de Grey: I’m very confidentthat the removal of other amyloids can be achieved using more or less the samemethods that have worked against those two. The next one on my list would be islet amyloid, which contributes todiabetes.

Feinerman: As far as I know intracellular junk in theeyes is not lipofuscin per se but A2E, oxidized form of vitamin A. Is anyprogress in removing true lipofuscin – more widespread form of intracellular junk.

de Grey: We have funded somepreliminary work on that, but it’s still early. The difficulty is thatlipofuscin is very heterogeneous, made up of many different components. Ourstrategy is to target it more like the way we target the extracellular matrix:rather than breaking it down, we want to identify some key crosslinks thatare protecting it from being degraded by our existing lysosomal machinery.

Feinerman: Now everyone isobsessed(着迷) with “aging biomarkers” and “biological clock”. Arethey valid conceptions? Is it possible to have a single “clock” for the wholebody? Maybe can we just use every typeof damage as a biomarker and keep it below certain threshold?

de Grey: I agree with you –ultimately, we still need to fix the damage, so there is not much more thatindirect proxy measures can tell us. These indirect measures are usefultoday, though, when we don’t have those repair therapies, because they help usto see what interventions may (slightly) slow down the accumulation of damage.WHO, FDA and new medicine.

Feinerman: FDA has a very longapproval for new therapies or drugs. What do you think on medical tourism andbiohacking as an alternative way?

de Grey: There have alwaysbeen places with less restrictive regulatory systems for new drugs – medicaltourism is nothing new. I think the key thing we should be doing more of ismaking better use of those who choose to go abroad to get treated: we shouldmake it as easy as possible for them to report on what treatment they receivedand how well it worked, any side-effects, etc, for a long time after thetreatment, so that such information can be analysed and used to guide futureresearch. The people who provide experimental therapies don’t have anyincentive (鼓励、刺激)to gather such data themselves, so it usually nevergets gathered.

Feinerman: Does SENS ResearchFoundation or associated companies hold regular meetings with FDA to informthem and clear the way for the new rejuvenation medicine? Some components ofthe SENS 1.0 panel are already in development or clinical trials, and otherswill arrive during next 20 years. These new coming medicine uses completelydifferent repair-based rather thancompensatory approach and needs different clinical trials protocols andthe whole new health paradigm. Transition period has already begun and weshould use it wisely, otherwise US may become an outsider in the medical world.

de Grey: I look forward to theday when we have such meetings, but that’s a little way off. That’s OK, though,because companies that are pursuing various components of SENS are indeedhaving such discussions. The FDA and its counterparts worldwide are being keptup to speed.

Feinerman: We already havemany amazing results in the lab which can save human lives just now, but lackof funding and up-regulated medical system don’t give them any chance to be inclinics in coming years. With current pace of progress they will already beoutdated before clinical trials. Do you think that translational researchbecomes the bottleneck?

Note: Even though 90% of US deaths and at least 80% of US medical costs arecaused by aging: National Institutes of Health budget ($M): ~30,000National Institute of Aging budget: ~1,000 Division of Aging Biology budget:~150 Spent on translational research (max): ~10 SENS Research Foundationbudget: ~5 These numbers speak for themselves, they are all you need to answerwhen all discussed amazing therapies will be available in the clinics.

de Grey: I think things areimproving. The idea of real rejuvenationis becoming more and more accepted. At this point, therefore, I would saythat the main bottleneck is still at the earliest stage: the funding forwork that is not yet investable.

Feinerman: The current WHO’sagenda is a kind of shame! They know that fireis coming but they prepare gasoline to put it out with. Do you agree thatthe conception of “healthy aging” is anonsense? Aging cannot be healthy because if you are healthy you do not age. WHO forces people to bemore comfortable with aging instead of fighting agaist it. They recommend tospend billions to build more nursing houses and buy more wheelchairs instead ofinvesting these money into rejuvenation biotechnology! It’s ridiculous!

de Grey: Well, I think we needto do both things: we need to maintainolder people’s quality of life as best we can with the limited tools wehave today, and we also need to developbetter tools. Terms like “healthy aging” are indeed double edged: on theone hand there is, indeed, obviously no such thing, but on the other hand theterminology helps to emphasise that thepurpose of all our work is to extend healthspan, with the extension of lifespan being simply a side-effect. Rejuvenationresearch won’t fund itself “可借力健康老龄化”。

Feinerman: When I ask peopleto donate to SENS Research Foundation they often say that their a few bucksdon’t matter. Of course, they are wrong! Every dollar, even every cent matters!For example, how many people may read this? We assume 10 000. Well, if every ofyou will donate $50, only $50, per month it will be over $5 000 000 per year!Which will double current SENS budget. So, united we can change the world. We cannot and should not wait whengovernments and big pharma will fund rejuvenation research. (In fact theywon’t, they will wait and see the first results.) We can do it ourselves! Whatcan you say to our readers to encourage them?

de Grey: You are saying itreally well. One way to say it is to calculate how many dollars it would taketo save a life by donating to SENS. I estimate that a budget of $50M per year would let us go three times faster than nowand would bring forward the defeat of aging by about a decade(骗钱的真相终露). About 400 million people dieof aging in a decade, so that means donating to SENS has a bang-for-the-buckof roughly one life per dollar.No other cause comes anywhere near that.

Feinerman: Another doubt thatpeople usually express is how does SENS Research Foundation do anythingmeaningful with such a small budget? While NIH and many others have hundreds ofmillions per year and cannot cope with aging, SENS has only $5 000 000 peryear. I answer that SENS is a highlyefficient organization, goal-directed and result-oriented rather thanprocess-oriented. Everyone can go through SENS web page and read last yearsannual report.

de Grey: Thank you! – That isindeed correct. Almost all research that is funded by governments is almostuseless, because its effects on health will be tiny. SENS is different because it is a coherent, comprehensive plan forbring aging under complete medical control. (继续忽悠)……

Note: Unfortunately, I[Feinerman] agree with Dr de Grey. If you take a close look at NIH funded work…well… You will find hundreds of publications about obesity, lifestyle, airpollution and their impact on longevity. Don’t you know that obesity,smoking and much drinking of alcohol is bad for you? How can this informationmay help us create a new cure against cancer, Alzheimer or atherosclerosis? Dowe really need another one work on it? Also you can find many publicationsabout calorie restriction and various genetic manipulations on worms and othermodel organisms that mimic it. Calorie restriction is everywhere! While weknow for twenty years that CR does not work for humans. In 2015, $500,000was given to projects like “A Large Randomized Trial of Vitamin D, Omega-3Fatty Acids and Cognitive Decline”. It’s not a joke, it’s a real research work.You can find more here. All that is useless because you cannot use it toproduce working rejuvenation therapies. Only small part of thesepublications are useful in the sense of defeating aging. Do you know what isthe most interesting? It’s all your taxes, all you money! Now you know that. Atthe same time really important research projects like work on glucosepanebreaker therapy (which will end manyaging pathologies like arterial stiffness, chronic inflammation, hypertension,strokes, and will save many lives) in Spiegel Lab at Yale is permanentlyunderfunded and would be closed last year without financial support from SENSResearch Foundation and German entrepreneur Michael Greve. Finally, the cost ofimplementing the working rejuvenation treatments in old mice would by currentestimates be only 1-2% of the Apollo Program. And the same amount of money and time was already spend on Sirtuinswhich have obviously produced nothing.

Feinerman: Can you say whatProject|21 is, why it is so important and how people can help?

de Grey: Project|21 is ourname for our appeal to wealthy individuals. We of course welcome donationsof any size, but at present it remains the case that most of our income isdonated by a small number of wealthy donors, so it stands to reason that weare doing all we can to attract more of those. What other people can do to helpis easy – donate what you can, and encourage donations by friends who arewealthier than you! Note: Project|21 is a new initiative created by SENSResearch Foundation to end age-related disease through human clinical trials, starting in 2021, through investment inrejuvenation biotechnology. Through three new programs, the Bridge fund, The Center of Excellence, andThe Alliance Program, Project|21 will deliver the perfect environment forthis fusion of opportunity and investment. $50 million in total funding isrequired for Project|21, at least half of which will come from the members ofSENS Research Foundation’s Group|21. Group|21 will bring together 21philanthropists, each donating between $500,000 and $5 million. Grants,grassroots efforts, and matching-fund strategies will provide the remainingsupport. $5 millions was already donated by German Internet entrepreneurMichael Greve. Thank you, Mr Greve! You are our hero!

Feinerman: Some people preferto donate not to the whole organisation, but rather to concrete project or lab.Of course, it is not among the most convenient and efficient ways to managemoney but anyway do you consider such an option?

de Grey: Certainly yes. Wesometimes have projects that cannot be funded because there is too little“unrestricted” money to go around, but for the most part we are able to make itwork, so absolutely, if anyone wants to restrict a donation to a particularproject, we are totally happy to work with that. (怎样给钱都欢迎)

Feinerman: Nowcryptocurrencies and blockchain technologies allow completely new and efficientways for crowdfunding and investment. We can see as various no-name companieseasily raise tens of millions dollars via ICO for clearly doubtful projects.While really important areas like generative medicine, rejuvenationbiotechnology or bionics are permanently experiencing an acute thirst ofmoney. Do you consider ICO for Project|21? I believe it perfectly fits intoICO conditions and requirements!

de Grey: It’s definitelyimportant for us, and we are working closely with various people who areexperts in cryptocurrencies. Vitalik Buterin, who created Ethereum, is actuallya donor. We very much hope to bring in substantial funding via that route. Human psychology not the science is the keyissue in defeating aging.

Feinerman: When I ask people,do they want to live hundreds of years? Many of them say “no”, but when I ask them, Do they want to look andfeel like 30 being 70? They say “yes,ofcourse!” I hope, you got my idea: people are afraid of big numbers.People don’t want to live forever. They just want not to be sick forever,even though big numbers logically emerge from not being sick. Have you everregret about your claims about big numbers and 1000 years lifespan? Peopleusually understand them in the wrong way. Someyour colleagues say that without such claims your ideas would be much morepopular.

de Grey: It has always been adifficult decision. Yes, people are afraid of big numbers and they are reallybad at reasoning about the distant future. But the most important thing, inthe long term, is that I am saying what I believe to be true and that I canalways give very thorough, logical answers to any challenges. If I had gone out in 2005 saying that wecould live to 150 with rejuvenation tech, and people had said why not 250, I would not have had a good answer, andpeople would not have trusted me. In the end it always works best if you tellthe truth.

Feinerman: What do you thinkof 2013 workThe hallmarks of aging”, which is obviously inspired by your seventypes of damage? They look more sophisticated, and harder to deal with. Anyway,does it mean that researches finally demystified aging and recognised it as asolvable problem?

de Grey: You’re right, it was definitely a reinvention of SENS. Ithad quite a few mistakes, but the basic idea of divide-and-conquer damagerepair is identical. It is not at allmore sophisticated, it’s the same. And yes, it means that mainstream researchers have finally accepted thataging is now pretty well understood and is solvable. !!!

Feinerman: Although, biomedical gerontologists do not afraid tospeak about aging any more, as it was 10 or even 5 years ago, which itself is avery big step, they are still very sceptical – at least publicly – aboutour ability to put aging under medical control in a foreseeable future. Youknow many of them in person, is it their real opinion? Maybe, face toface, they are more optimistic? Note: I think that gerontologists should take alesson from physicists and engineers. Whenphysicists realised that our Sun uses nuclear fusion reaction they was excitedby the idea to build a fusion reactor. Being full of courage theystarted to work and immediately came across many obstacles. Although reactionitself is very simple, the processes behind it are complex. However, engineershaven’t given up and said: “We don’t fully understand these processes solet’s stop working and study the Sun for 100 years.” They continued to workas hard as they can, built many working prototypes, and now we are much closerto commercial nuclear fusion reactor than ever before. And they are full ofoptimism! If you ask any physicist, is it possible to build such a reactor? He answer: “Yes, of course!” And ifyou ask an engineer, when can we build it? He probably says: “20 – 25 years, andit can be much sooner, if we have enough funding.” Sounds similar, doesn’t it?Aging is the same. But when you ask a gerontologist, can we defeat aging, helikely calls you a crazy. Why? They areboth engineering problems!

de Grey: Well, maybe some of themare slightly more optimistic in private than they are in public, but really no– the problem is that they are basic scientists, so they are trained not to believe anything for which they do not havedirect evidence. They just don’t like to speculate about time frames, evenin private.

Feinerman: Yeah. With currentpace of progress anything beyond 2030 isuncertainty. However, what I know exactly is that if we want to havesomething working in 2030 we should work very hard in the right direction justnow. So why do many [anti]aging researches consciously or unconsciouslychoose the most inefficient and ineffective way – altering metabolism viagenetic manipulations or medications to only slightly possibly modestly slowdown aging – and use that as a proof (!) that we cannot radically extend humanhealth and lifespan? Such an example is ridiculous by itself and nearlyimpossible in any research or engineering area, except biomedical gerontology!

de Grey: That is not somethingspecific to anti-aging research. In all research areas, the leaders alwaysthink they are right and take a long time to understand radically new ideas.

Feinerman: Maybe, that is thereason? Maybe we need to have lessgerontologists who merely study aging and more biomedical engineers who repairdamage? In other words we should switch our focus from agingresearch to rejuvenation engineering. Since aging is an engineeringproblem, then from the gerontologists’ point of view it looks like “not my job”to reverse it.

de Grey: Exactly. The mainproblem is that until “only” 17 years ago no one had any coherent plan forfixing aging, so it made sense to carry on treating gerontology as a basicscience in which the priority was to discover more about it rather than tomanipulate it. And 17 years is not very long in science, so the people whoare most senior and influential are still the people who formed their mindsetin the pre-rejuvenation era.

Feinerman: Unfortunately, thevast majority of biomedical engineers, those who do actual rejuvenationresearch, do not want to be associated with any [anti]aging business and life extension, are not involved inlongevity discussions and usually keep silence. When pressed, they,however, are not very optimistic about life extension. It’s quite surprisinglyto hear such claims from cutting-edge researchers, especially from those whorecently promised to print or grow all vascularised human organs to 2035 andgrow new limbs to 2030. If it is not about life extension, so what is it allabout? Why do they behave in such a manner? Because of pro-aging trans? Orbecause they are too specialised and cannot see the whole picture? For example,cell engineers make predictions as though there will be no progress in bionics,and bionics engineers make predictions as though there will be no progress incell engineering. Each technology alone unlikely will be game changer but whencombined their impact will be enormous!

de Grey: You’ve got it. Thesetechnologies are developed largely independently of each other, so theirleaders are largely unaware of how much progress is being made in the otherareas. Since SENS is a divide-and-conquer approach, one cannot be optimisticabout the overall outcome unless one is informed about all the components.That’s the main reason why I ran the Cambridge conference series starting in2003, which is being revived in Berlin in March 2018 – to bring the leaders ofthese fields together.

Feinerman: Thank you very muchfor your amazing interview! Our conversation was wonderful! I wish you all yourwishes come true as soon as possible. When we succeed, I hope we will shake ourhands one hundreds years from now, walking along the waterfront of Mars Citywhich Elon Musk has promised to start to building in 2020s. Ah, and when you meetwith him, remind him, please, that we will not be able to colonise Mars untilwe defeat aging! Because microgravity and cosmic radiation have the sameimplications on human organism as premature aging.

de Grey: Thank you for yoursupport!

Afterwords

We live in the exciting era,The Era of Very Rapid Progress in science and technology – era when many thingswhich were merely a science fiction only five years ago are common now, andthings that are no more than a science fiction now will be common in next fiveyears. At the same time we live in The Era of Great Uncertainty – era when oursmall everyday life decisions may have a huge impact on next several decades.One step to the right – and we may defeat aging in twenty years. One step tothe left – and the whole research areas will stagnate for another twenty years(like it was in the case of glucosepane research).

New rejuvenation medicine isstill very young and fragile like the first spring flower after dry and coldwinter. In these days it especially needs our support! Even in such relativelyadvanced fields like stem cell or cancer research there are grey underfundedand under-researched areas we need to care of.

Of course, you wish to knowthe time frames – when will we defeat aging? You wish to know, will youpersonally benefit? Nobody knows. I intentionally did not ask Dr Aubrey de Greyabout the time frames and predictions. There will be no more time frames.Enough. Because they give you an illusion that some good clever guy will do allthe work needed, while you may just relax, wait when he finish and “live longenough to live forever”. But he won’t! It is too big, too ambiguous project forone person. Now you know – your future only in your hands. Not “live longenough…” but “work long enough…”! I always say that scientific andtechnological progress is a function of efforts – not of the time. The only wayto get rid of a painful uncertainty and get to the definitive answer is tosupport meaningful rejuvenation research just now!

How can you help? Well, if youare a researcher yourself, then spend your time and money on the meaningfulrepair-based approach which will produce working rejuvenation therapies in theforeseeable future. If you are a businessman – donate money to SENS ResearchFoundation and allies – Project|21, Methuselah Foundation, Forever HealthyFoundation, Life Extension Advocacy Foundation or directly support research groups.Invest in the associated rejuvenation companies or found your own. If you are acelebrity 知名人士, then use your fame to give attention to the problemand such a research. If you are an ordinary person, well, you can encourageyour more influential friends and do almost the same – just scale yourabilities!

Some of you may ask: is itreal? I hope we gave you enough evidence. Yes, of course, it’s real. Mover,it’s already happening! The right question, however, is it happening fastenough to help us – currently living adult persons? And the answer is,probably, no. Of course, there may (and likely will) be many unexpectedbreakthroughs but we should not rely on probability and scientific serendipity (幸运者) when we talk about human lives (especially our own). We should rely onwell-written plan, reasonable budgeted and our efforts.

So the next question is can wespeed up the progress? Yes, we can! All we need to do is what Dr Aubrey de Greysaid many times before and what I have just said above – unit against our mainenemy and help researchers. But will we? Although, people rarely think andbehave rationally I prefer to be cautiously optimistic! See you on Mars!




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