Fight Aging!

Aubrey de Grey of the SENS Research Foundation took a few hours from his packed schedule yesterday to answer questions from the community at /r/futurology. It is a pity that we can't get a full day of his time at some point - clearly there are way too many interested folk with questions and not enough hours to answer more than half of them. It is a sign of progress, I hope, that ever more people recognize that the SENS approach to the development of rejuvenation therapies is promising, and understand enough of the science to ask intelligent questions about the details.

SENS is simple enough to explain at the high level: identify the cell and tissue damage that (a) appears in old tissues but not in young tissues, and (b) is caused by the normal operation of metabolism, not by some other form of damage. The resulting short list includes the causes of aging. It may include some other things as well, that in the end turn out not to need fixing, but why take the chance? In modern biotechnology and life science research, it is faster and cheaper to develop a repair therapy and see what happens than it is to painstakingly figure out how everything fits together.

When de Grey first evaluated the field of aging research, back before the turn of the century, he found that the causes of aging by the above definition were largely known, with a good deal of evidence in support of each one. Yet next to no-one was working on fixing them. Since then, he has campaigned tirelessly to build organisations, assemble allies, raise funding, and persuade researchers, and all of that to ensure that the scientific and biotechnology communities do in fact move ahead with a repair-based approach to building functional rejuvenation therapies. It has been surprisingly hard work, given a research community that was hostile towards the idea of treating aging as a medical condition versus merely observing it, and a public at large who seem disinterested in living longer in good health. Nonetheless, here we are today, on the verge of the first rejuvenation therapies making it into the clinic, and with a growing number of research, investment, and business interests showing great interest in treating aging.

Aubrey de Grey, AMA, December 7th at /r/futurology

I've noticed in the last year you seem a lot more optimistic about the timeline.

I wouldn't say a LOT, but yeah, it's been a good year. Basically just the cumulative progress, both on the science and on the public attitude and funding stream. I'm still cautious, because for sure we are still really struggling for funds, but I'm hopeful.

If you were to find all the funding you'd ever need, how long until you make major breakthroughs in all 7 areas and essentially completely remove aging?

50% chance: 20 years.

What do you think were the biggest wins of the last couple of years in SENS-relevant advocacy, research, and development? What has moved the needle?

There have been lots. On the research I would highlight our paper in Science two years ago showing how to synthesize glucosepane and our paper in Nucleic Acids Research one year ago showing simultaneous allotopic expression of two of the 13 mitochondrial genes. Both those projects have greatly accelerated in the meantime as a result of those key enabling breakthroughs; watch this space. On advocacy I think the main win has been the arrival of private capital; I would especially highlight Jim Mellon and his Juvenescence initiative, because he is not only a successful and energetic and visionary investor, he is also a highly vocal giver of investment advice.

Can give your thoughts on Mark Zuckerberg's plan to "cure all diseases" within his child's lifetime? I suspect there's a lot you could talk about regarding that.

Mark is (as far as I can tell) not well-informed about this area. Unlike Page and Brin, who were quite assiduous more than a decade ago in educating themselves on matters technovisionary including medical (I first met them both in that era), Zuckerberg seems to be reluctant to reach out to those who actually know stuff. Anyone who can get me an hour of his time, you could save a lot of lives.

Is there anything new you are able to say about the breaking of cross-links in the extracellular matrix?

Absolutely. Short story, we now have a bunch of glucosepane-breaking enzymes, and we are within a few months of spinning the work out into a startup.

The SENS strategy to migrate mitochondrial DNA (mtDNA) into the nucleus seems to be preventive engineering approach rather than a maintenance approach. In light of new techniques like killing senescent cells, why wouldn't killing off cells that have given in to mutant mitochondria make more sense?

Great question - see my early papers on the subject. Basically the issue is that the majority of mutant mtDNA in an aged body is in muscle fibres, which do not get completely taken over, only segments a millimeter or so long, so we would do much more harm than good if we zapped the whole fibre.

RepleniSENS describes the thymus rejuvenation project. How does this approach compare to directly injecting stem cells into the recipient's thymus?

Actually we have discontinued that work, mostly because we were basically overtaken. A raft of approaches seem to be working: our approach of building a new one, or growth factors to regrow the old one, or even tricks to repopulate the T cell pool by proliferation in the periphery (i.e. without a thymus).

Some researchers attempt to eliminate mutated mitochondrial genomes from the cell. Would you reckon these approaches have a chance of success?

The work you referenced is terrific, but it is intrinsically limited to mitochondriopathies that are caused by inherited, single mutations, whereas in aging we have different ones in different cells. There are some ideas out there for tipping (reversing) the selective advantage enjoyed by mutant mtDNA without being sequence-specific, but they are not all that promising yet.

Once we have an efficient senolytic drug and we can get rid of a significant number of senescent cells in the body, do we also have to clear the senescence associated secretory phenotype (SASP) that has been secreted over the years or is it something that the metabolism can naturally get rid of?

The latter. The SASP molecules have a short half-life.

Aside from funding, what do you consider to be a burden or delay for your type of research?

Nothing. Seriously, nothing at all. We have the plan and we have the people. It's all about enabling those people, giving them the resources to get on with the job.

How come the epigenetic changes and changes to our microbiome that accumulate with age are not a part of the categories of damage? When do you predict that rejuvenation approach as a solution to the problem of aging will become accepted by clear majority of scientists?

The microbiome is basically a highly dynamic population of cells, hence it is virtually certain to become right on its own when we fix everything else (even assuming that there is anything suboptimal about it in old age in the first place). For epigenetic changes, this is also the case if you mean coordinated ones that happen across all cells of a given type. If you mean drift, i.e. epimutations, my explanation for that is protagonistic pleiotropy (see my 2007 paper with that title). Rejuvenation is already accepted as a solution by most scientists, and it is being reinvented by other people. See for example the 2013 "Hallmarks of aging" paper.

How confident are you still in your previous prediction that humans will be able to control aging by 2029?

I think we've slipped a few years, entirely because of lack of funding. The tipping point will be when results in mice convince a critical mass of my curmudgeonly, reputation-protecting expert colleagues that rejuvenation will eventually work, such that they start to feel able to say so publicly. I think that's on the order of five years away.

Given current funding, how far away from robust mouse rejuvenation do you think you are?

My estimate is 5-7 years, but that's not quite "given current funding". My overoptimism in saying "10 years" 13 years ago consisted entirely of overoptimism about funding - the science itself has not thrown up any nasty surprises whatsoever - but nonetheless I am quite optimistic as of now about funding, simply because the progress we have made has led to a whole new world of startups (including spinouts from the SENS Research Foundation) and investors, so it's not only philanthropy any more. Plus, the increase in overall credibility of the approach is also helping to nurture the philanthropic side. We are still struggling, that's for sure, but I'm feeling a lot surer that the funding drought's days are numbered than I felt even two or three years ago.

It was some time ago that you guys published your paper on inserting the enzyme into white blood cells to help them break down 7-ketocholesterol, I know a company was spun out not to long after that. Are they making good progress?

Actually, of all our (so far five) spinouts, that's the one that has rather lost its way. We are working to reboot that work and get it moving more promisingly. A lot of the problem was that it was bankrolled by one wealthy person, so that (rather like Calico) it had no incentive to let the world (or even me) know what it was doing.

When would you guess that we will have the first, direct evidence of human rejuvenation through removal of senescent cells (also considering self-experimenting individuals, which could get there first)?

To start at the end: if it works, the first evidence will indeed quite probably be from self-experimentation. Of course it will be n=1 so it will be very provisional evidence, but you knew that. So, when? - that mostly depend on the extent to which humans reproduce what has been seen in rodents, where the benefits of removing senescent cells were a lot broader than I (or anyone, I think) would have anticipated. We just don't know.

You have recently accepted a position as Vice-President of New Technology Discovery at BioTime Subsidiary AgeX Therapeutics. Can you give an overview of why you accepted this position and how it affects your current work at SENS?

I'm still defining my role there, but it is a big deal. I am there 30% so my primary affiliation remains SENS Research Foundation. But the emergence of the private-sector component of the rejuvenation biotech effort is a hugely important recent advance, and for me to have an official foot in both camps makes a strong statement. Also, it is a huge thing for me to be finally working closely with Mike West, who has been a hero of mine for 20 years. The two roles will certainly dovetail a lot: at AgeX my basic task is to come up with new therapeutic ideas, and naturally that will feed off what we are doing and have done at SRF.

Given that cells can reverse their age through induced pluripotency, do you see this as a viable strategy for reversing aging in humans, or is it too difficult and dangerous to do in vivo?

As of now it's definitely dangerous in terms of its carcinogenicity. However, we may be able to reduce that soon. I am particularly excited by the recent work of the awesome researcher Vera Gorbunova on the difficulty of dedifferentiating cells from naked mole rats; I suspect that that work may uncover ways to be more selective and controlled with in vivo dedifferentiation.

Has your position on the relative importance of the stem cell side of aging changed over the years? I know that in earlier years I was somewhat convinced that stem cell decline was fairly secondary to other parts of SENS.

It very much remains to be seen. In some tissues, like the substantia nigra where cell loss causes Parkinson's disease, I'm pretty sure we will indeed need stem cell therapy. In other places, the failure of stem cells to maintain their numbers and/or their proliferative vigour seems to be quite largely determined by the systemic environment, i.e. by what is and is not present in the circulation, and there I agree that recovery is quite likely to be largely spontaneous once we fix other stuff.

It seems likely that artificial intelligence will be a necessary tool in order to reach longevity escape velocity. I was wondering how much of a role does artificial intelligence play in your research? Is this something you devote many resources to?

We don't, but that is because other major players in this field (and good friends of mine), such as Alex Zhavoronkov and Kristen Fortney, are doing it so well already (with Insilico Medicine and BioAge respectively). They are both awesome and massively committed crusaders for this mission. Check out the BioData West conference that will occur in San Francisco a couple of days before our Undoing Aging conference in Berlin; I will be chairing a session on this.

With the recent departure of Calico's Head of R&D for GSK, do you think that there is a chance that Calico might now redirect its efforts in a more productive direction?

No. A good approximation to how Calico operates is as two entities: one that is essentially Genentech 2.0, setting itself up to make massive money from big deals with other traditional pharma, and one that is to pursue its actual remit, namely to defeat aging. Barron was squarely on the former side. The latter side is led by David Botstein, who is as pure a basic scientist as they come and has no time whatsoever for "dreamers" who think we might actually know enough already to be able to develop therapies. His philosophy is unfortunately permanent: no amount of progress will make him become translational and cease to be 100% discovery-focused. I don't remotely blame him - he is who he is. I only slightly blame Levinson: there was nothing wrong with hiring a chief science officer to do discovery, the only thing he got wrong was not also to hire a chief technology officer (me, obviously) alongside him. The people who have all the blame are Larry and Sergey, for allowing their billions to be wasted like this and not having the guts to step in and impose a change of direction.

Given that it's such an emotionally charged field how do you personally, and SENS in general, remain objective and keep hope from interfering with your work?

That's not so hard as you might think. Ultimately, we are driven by the desire to increase the chance of success, or equivalently to reduce the likely time until success - but from what to what is secondary. If we hasten the defeat of aging by a year, who cares whether it's from 2050 to 2049 or from 2030 to 2029? - it's still 40 million lives.

You have been wrong in the past with your expectation of peoples willingness to get onto this idea. Thus I can easily see a path where this technology is proven enough to be clearly happening but most people just don't care and the funding is still very hard to come by. Have you given much thought to this potential scenario?

You're right that I was overoptimistic in the past about the willingness of other high net worth individuals to follow in the wake of Peter Thiel, who started funding us in 2006. However, when it comes to support from scientists, I have never made such a mistake - I always knew it would take robust mouse rejuvenation. I have the advantage in that regard that the community in question is just the most credentialed, authoritative biogerontologists - no one else. Thus, they are (a) really few in number (truly, we are talking about something like a dozen people), (b) scientists (hence I know how they think, unlike billionaires) and (c) people I know well, personally. So I have very strong confidence regarding what determines what they say publicly.

Many wealthy celebrities and smart individuals can easily afford to invest into SENS. How come they are not?

Everyone has rationalisations. The key thing to remember is that humanity has been hoping against hope for a cure for aging since the dawn of civilisation, and it has been suckered time and time again into believing we had one, so there is a rather strong incentive not to get hopes up. And if something is impossible, its desirability is irrelevant: there is still no basis for funding it. So it falls to the small minority of wealthy people who are also truly independent-minded to support this work. Yes, people like Elon Musk may well feel rather ashamed a decade or two from now that they didn't do more earlier. But we're working on it.

How do you feel about the impact of groups like LEAF advocating and reporting on rejuvenation biotech? Has the advocacy and reporting of these groups made your life any easier?

Massively! A huge thing that I say all the time is that advocacy is one thing that absolutely relies upon diversity of messenger. Different people listen to different forms of words, different styles of messaging, etc. The more the better.