Aubrey de Grey, who should need little introduction here, is cofounder of the SENS Research Foundation, while Matthew O'Connor leads the foundation's in-house research efforts. O'Connor's focus is on the allotopic expression of mitochondrial genes, the complicated form of gene therapy needed to copy versions of these genes from the vulnerable mitochondrial genome into the much more secure nuclear genome, but altered in such a way that the resulting proteins can find their way back to the mitochondria where they are needed. Earlier today de Grey and O'Connor stopped by /r/futurology at Reddit to answer questions on this and other SENS rejuvenation research initiatives. One of the many benefits brought by this modern age of near zero cost communication is the way in which the barrier between researchers, supporters, and the public at large has faded to the point of non-existence. Any interested party can in a few minutes find out who is working in any specific areas of interest and reach out with questions or offers of support. Any researcher can find out where the interested parties congregate to talk about their research and join in. That was science fiction just a few decades ago. The world moves at a fast pace.
Once allotopic expression of the thirteen crucial mitochondrial genes involved in oxidative phosphorylation is realized, undergoing this gene therapy will ensure that the accumulation of mitochondrial DNA damage that occurs over the years no longer contributes to degenerative aging as it does today. It will be an actual, working narrowly focused rejuvenation therapy. As an incidental benefit, this technology will also provide cures for a range of inherited mitochondrial diseases. This work has been underway both at the SENS Research Foundation and in allied labs for some years now, and the biotech company Gensight has been founded on success in allotopic expression of the gene ND4. The SENS Research Foundation in-house team recently achieved success for the mitochondrial genes ATP6 and ATP8, and had a paper accepted by a noted journal, which all in all is a great step forward in a field that has proven to be quite challenging. I've pulled out some of the questions and answers from the AMA for posterity:
What is the updated timeline for when a MitoSENS-based therapy could be available for humans, and what would be its impact?
I think we're still several years away, which means any prediction of a timeline is pure speculation - but it's definitely accelerating.
For those that want to be alive when SENS 1.0 is here, what else can we do besides caloric restriction? Brisk walking?
Raise money for SENS Research Foundation! Seriously. The difference you can make to your own chances by hastening the arrival of SENS far exceeds what you can do with lifestyle etc. The less wealthy you are, the more people you probably know who are wealthier than you are. So, sure, it'll be the money of the people you persuade, rather than your own money, but that doesn't change what I said. Everyone can make a difference if they put real effort into advocacy.
Could you please tell what will be the next stage of the MitoSENS project, are you going to try to reproduce mitochondrial gene relocation in animals?
Yes we want to take this into animals next and yes we are starting now. I don't have any results to share yet but we are in the very earliest stages of pre-mouse work now. We are working in mouse cells to make sure that we can get our process working in cells before we move into whole mice.
Are you guys considering or taking advantage of the power of deep learning to accelerate your research into aging?
Now we have great results how long do you think it will be before we can do the same with the other 11 genes and are these genes technically any more or less challenging than the two already done?
Yes, there is reason to believe that some of the other 11 will be harder than ATP8 and ATP6. In fact, ATP6 is itself much harder than ATP8 and our results with that aren't as strong as with ATP8. We have some technologies that we've tested already that seem to work a bit with the harder genes and we're layering on additional levels of mitochondrial targeting and import. The hard thing is how complicated it gets when we start combining multiple targeting strategies together and quantifying their affects. We are building a rigorous system so that we can test variables in a matrix and clearly determine what works and what doesn't.
How long do you think it will take before we can reverse surface level aging : hair loss, gray hair and wrinkles? Which of the 7 damages types do we need to solve to make it happen?
Wrinkles are mainly from crosslinking, an area that was pretty much stalled for 20 years until our breakthrough publication in Science last October; still a way to go but we're now making rapid progress. Hair loss and grey hair are mostly a cell loss problem, and rejuvenating the epidermal stem cell population (as well as melanocytes specifically) is something a lot of people are making good progress on; check out the work of Elaine Fuchs and Fiona Watt and Colin Jahoda especially. The main thing to keep in mind here on the science side is that the technologies needed to rejuvenate appearance and to rejuvenate internal organs are broadly the same. And on the broader picture, just as we don't care whether people give us money for selfish reasons or for humanitarian reasons just so long as they give it, we also appreciate that changing the zeitgeist of the longevity quest is inextricably linked with hastening the science.
How can grassroots activism most effectively be leveraged to hasten the defeat of aging?
The key thing is to tackle both feasibility and desirability together, which paradoxically means tackling them separately. People are scared to get their hopes up, and they dismiss the feasibility issue because they have already decided that success would be a bad idea, and at the same time they dismiss the desirability issue because they have already decided that the whole concept is a pipe dream. So, first force your interlocutor into understanding that that linkage is logically absurd and thus into addressing the two questions separately. Then, give them the best arguments.
What about mitochondrial diseases that are caused by point mutations in the mitochondrial DNA? Won't these misfolded proteins still being produced compete with the corrected proteins now being produced by your imported RNA?
This is a hard question. We don't really know how effectively our engineered genes will compete with existing mutant (or non-mutant for that matter) proteins. We and others have done some work on it, but the answers aren't satisfying for me yet. We are at the conceptual stages of designing a rigorous method of quantifying this. It is not clear that mutant proteins much exist in "normal" aging though, so it might be a non-issue for aging but a very important question for inherited mitochondrial disease. Recently a new mouse model has been developed that accumulates deletions at an accelerated rate. It is a "binary system" that allows the problem to be activated in a tissue-specific manner by crossing with specific other mice, so it's very versatile. I expect that it will be quite useful.
Robert K. Naviaux, mitochondrial expert, asserts that their dual (or even primary) function is as an exquisitely sensitive alarm system, triggering the 'cell danger response' to chemical or microbial threats. How does this sit with the understanding so far in the MitoSENS project?
I'm going to give a snap reply that our mitoSENS project might not help this kind of "homeostasis" problem, if that problem isn't caused by the loss of mitochondrially encoded genes. Mitochondrial are indeed complex organelles with much cross-talk with the rest of the cell so our philosophy is always that the underlying problem needs to be addressed. If the problem is in the nuclear genes then that's what needs to be fixed. If the problem is in the lysosome - resulting in reduced mitochondrial turnover - then we need to fix the lysosome rather than the mitochondria. It is often forgotten that mitochondria are constantly recycled even in non-dividing cells, and thus that the only damage they can possibly accumulate other than as a side-effect of something extramitochondrial is DNA damage, and only then if somehow mutant mitochondrial DNA is selected for. Historical aside: after Harman first suggested the role of mitochondria in aging in 1972, the only published reaction by anyone prominent was that Alex Comfort in 1976 rejected it on exactly this basis. He did not, of course, consider the bizarre possibility that mutant mitochondrial DNA could be selected for, which was only shown in 1993.
You've mentioned that SENS 1.0 therapies, when perfected, will add maybe around 30 years of healthy lifespan. Does that mean that it's impossible for them to work indefinitely long without needing any improvements? If so, why?
Yes, that's what it means. Here's an example that may explain it: crosslinking. Once we are able to break glucosepane, we'll be able to reduce crosslinking by a big factor - for sake of argument let's say 50% - but we won't be breaking any other crosslinks. Thus, eventually the total amount of crosslinking will return to old-age levels even if we blitz the glucosepane every year. So, we need to carry on with the introduction of therapies that hit the next most abundant link, and the next, etc.
Do you think we will see major steps and results in mice in the next 5 years?
Yess, there's a chance of that; I'd say in 6-8 years there's at least a 50% chance. And by "major" I mean robust mouse rejuvenation, i.e. seriously life-extending interventions that start in middle age. For first generation human therapies my current 50% prediction is 20-25 years. We might see human gene therapies in patients with mitochondria disease in much shorter periods of time. If these work the chances of it working on aging increase dramatically!
I want to ask about the potential for CRISPR to impact longevity research. Could CRISPR potentially do this? If so, is CRISPR accurate enough?
CRISPR is getting very, very error-free now, so I am sure it will be a big tool in implementing SENS. We have developed a way to use it in combination with a bacterial virus; our method allows the insertion of lots of DNA (even up to 100kb potentially) in one go, into a defined location on the chromosome, so we would aim to do all the aspects of SENS that require new genes that way - mitochondrial DNA backups of course, but also enzymes to degrade waste products, and suicide genes to eliminate death-resistant toxic cells. Increased accuracy means a lower probability that a given CRISPR construct will do a bad thing, which in turn means that we can introduce more constructs (whether all at the same time or over repeated administrations) while remaining at an acceptable risk of bad things, which in turn means we can hit more cells.
Is it ever too late to start studying microbiology? What are some things an aspiring longevity researcher should take into account before dedicating themselves to such a cause?
No, never too late - whether microbiology, molecular biology, or any other biology. The main thing to take into account when starting out is that you shouldn't specialise too soon, because aging affects the body at every level of organisation, hence to have the best insighhts you need a god grounding in every area of biology.
How old do you think the youngest person is today that will never have a chance to benefit from the coming longevity revolution?
I prefer to answer the converse question, how old is the oldest person who will benefit! I still think that person could be in their 60s, or even 70 now. Remember, though, that will be a person who would naturally live to 110 without SENS.
Since you began your public mission to now, has progression of our knowledge in the field of gerontology progress exceeded your expectations?
It's gone more slowly than I expected, but only because it has continued to be crippled by lack of funding. We're doing our best, but another digit on our pathetic $4M annual budget would probably treble our rate of progress.
It seems that recently there's been a bit more attention into anti-aging/gerentology research from mainstream research institutions. How has that affected the work you do at SENS?
It's huge that really respected people like Craig Venter and Peter Diamandis are in this now, as well as really respected companies like Google. It's making a lot of previously skeptical people take notice, and we are hopeful that it will soon translate into better funding - we really need that. As for variety of lines of thought, the more the better: the main problem SENS had in years past in gaining general expert acceptance was that too many experts had already become wedded to particular prior ideas.
Given that yeast cells don't have some of the seven classes of SENS damage to worry about, wouldn't it be easier to first create a line of yeast cells that can be kept indefinitely youthful? Or is this in fact more difficult than creating an indefinitely youthful multi-cellular organism as intra cellular damage can no longer be continually spread between daughter cells?
Much easier, yes, but that's exactly what makes it not informative for translation to the clinic. The second half of your question makes less sense though, because multicellular organisms that matter, i.e. complex ones, have plenty of long-lived non-dividing cells as well as dividing ones. Only simple ones like Hydra can combat aging in the way you describe.
Has Calico reached out to you and your team at all?
We reached out to Calico very energetically when they were getting going but they basically blew us off. We are dismayed that they are not taking advantage of our expertise. Maybe they will start to do so eventually.
Any plans to translate the research into a gene therapy for a specific inherited mitochondrial disease?
Well to get into the nitty gritty a little bit, there are exceedingly few patients who have been discovered to have mutations specific to ATP8, less than 5 that I know of. ATP6 has more, but still very few. The gene therapy advancement that needs to happen is to get gene therapy technology approved that can be used outside of the eye. Then it will be easier to get these individual mitochondrial gene therapies approved.
What increase in health and lifespan can we expect from solving just mitoSENS out of the seven SENS fields?
Maybe there will be synergistic health affects of applying more than one, but less than seven fundamental rejuvenations, but we won't know until we try. There is some evidence that just tampering with mitochondria can improve the health of old rodents.
Back at the outset of the SENS research programs, the estimated cost to prototype allotopic expression of all 13 oxidative phosphorylation mitochondrial genes in mice was ~$150M and ten years. MitoSENS has had probably something like a $10-15M investment (very fuzzy number). What is your current thinking on remaining costs and time now that the project is 20-25% of the way towards a prototype?
We've spent a lot less than $10M on this project so far. Total from all groups working in the field must be much much more than $15M. I will get it working in mice for much less than $150M.
If I understand correctly, the CYB protein is about 50% larger than ATP6. After your "many failed attempts", do you now have an understanding of what is preventing its import into the mitochondria, and, if so, what can be done to work around it?
CYB is both bigger and thought to be more "hydrophobic" than other mitochrondial proteins. I really like working on CYB though for two reasons: One is that I think that once we solve CYB we will have solved all 13 genes. The other is that CYB is the only mitochondrially encoded subunit of OxPhos complex III, which makes it a very simple system to study. We have cells that are null for CYB (similar to, but more simple than the cells that we used in the current publication) so we have a great system to test our innovations in.
Do you think that allotopically expressing ATP6 and ATP8 could have a measurable life extension effect in mice? Or it's more probable that all 13 genes must be allotopically expresed in order to see some improvement?
I think we would need to do all 13 to get some health affect in normal wild type animals, but there might be some tricks we can use to get it to work on some mutant mouse models.
With the advent of CRISPR, would it make more sense now than it did previously to code the cell to make catalase and target it to regularly be delivered to the mitochondria?
Catalase (and other anti-oxidants) can prevent some damage, but not reverse it. I'm more excited about the current generation of mitochondrially-targeted drugs that can act as anti-oxidants and/or mitochondrial activity boosters (in various ways). I'm betting that these next generation drugs will be even more effective than "natural" methods of preventing mitochondrial damage transgenically and we know that they will be easier to get approved by the FDA.