Aubrey de Grey AMA at /r/Futurology: the SENS Approach to Cancer and More

Today, July 19th, Aubrey de Grey of the SENS Research Foundation and Haroldo Silva, lead SENS cancer researcher, are hosting an AMA - Ask Me Anything - event at /r/futurology. They will be there for a few hours to answer questions on rejuvenation research, fundraising for work on aging and cancer, and other aspects of the work of the SENS Research Foundation. This is a chance to ask about the SENS approach to a universal cancer therapy, one that targets the common mechanism of telomere lengthening that all cancers must employ to grow. The SENS researchers are focused on alternative lengthening of telomeres, ALT, a collection of processes that are still comparatively unexplored, yet essential to this approach to cancer therapies. The AMA started at 1PM EST and is ongoing at the time of posting, so if you jump in there is still the chance to have questions answered.

Below, I've digested a number of the questions and responses, with some light editing for clarity where necessary. As you can see, quite the range of topics are covered, from the cancer research that is the subject of the present SENS crowdfunding initiative at Lifespan.io to the newly announced large-scale funding initiative Project|21, from present day politics and economics relevant to research to the personal organization of future longevity assurance therapies, and more besides.

Aubrey de Grey AMA! Ask about the quest to cure cancer's root causes, increasing healthy human longevity, or anything else!

Would the anti-ALT small molecules just prevent the cancer cells from dividing eventually, or would they actually kill the cancer cells?

It really depends on how exactly the small molecules we find inhibit the ALT pathway. They could just prevent telomere elongation which will eventually result in complete cessation of tumor growth as you pointed out. On the other hand, these molecules can interfere in the process in such a way as to cause abnormal chromosome fusions which will actually kill cancer cells.

How can you be certain that telomeric C-circles are the only method for cancer cells to achieve ALT? Or that there are a finite number of ways for cells to achieve ALT?

C-circles are currently the best biomarker identified to date that is most closely associated with ALT activity. It represents our best chance to help us develop ALT-specific cancer therapies as well as demystify how this mechanism of telomere maintenance works. However, we do not know which specific role(s) C-circles are playing in the ALT pathway. We also do not know how cancer cells initiate ALT activity.

Given small molecules often have side effects, why not use an intra-cellular method such as DRACO to target telomeric C-circles and induce apotosis? Or alternatively, do telomeric C-circles present material on major histocompatibility complexes (MHCs) that could be targeted with genetically engineered T cells?

C-circles are composed of DNA with the repetitive sequences found at telomeres. Targeting C-circles directly and specifically is not feasible since there is no way to differentiate between C-circles and regular telomeres. Additionally, there is no evidence at present that targeting C-circles would actually inhibit ALT activity. Since C-circles are just DNA strands, they cannot be presented on MHCs for T cell signaling or other stimulation of the immune system.

Given that an anti ALT therapy will probably be given along with an anti-telomerase therapy, won't this affect cell replacement by regular stem cells that can no longer replace tissues for the duration of the treatment? We produce a million new T cells per second, how long can a dual therapy be endured before damaging the subject?

We envision that the side-effects associated with telomerase inhibition will be worked out in the current clinical trials by the time that ALT-specific experimental treatments reach such advanced stages in development. The ALT-specific therapy will of course have no effect on stem cells.

Will the human clinical trials resulting from Project|21 address all 7 categories of aging damage? If not, what is their goal?

No. The goal of Project|21 is to clear the path to the first genuine clinical trials in rejuvenation biotechnology. This will involve building better collaborations, better regulatory frameworks for rejuvenation clinical work, and pushing the first technologies specific to rejuvenation that are available and at a stage where early clinical work is truly feasible. We think this will involve technologies in intracellular damage repair, and technologies in senescent cell work, and other likely candidates for the first clinical work. The comprehensive solution, however, will require a larger selection of technologies and the investment and development power of more industrial partners (and the early successes of Project|21 will be used to precipitate that).

Robust mouse rejuvenation (RMR) will probably require simultaneous, high-quality implementation of all the SENS strands in mice, because the omission of any one strand will probably cause the mice to die on schedule. Project|21, on the other hand, is only about getting part-way to the equivalent stage in humans: first of all we would only be implementing a subset of the SENS therapies, and secondly we'd only be beginning the experiment (the clinical trial), whereas RMR is defined in terms of the outcome.

How satisfied are you with the progression of science in regards to human longevity?

We're about where I thought we'd be in the context of the funding that has been available, but that's only about 1/3 as far forward from 2005 as I'd have expected to be with even 10x more funding, i.e. with on the order of 30 to 100 million per year. We really need to ramp up that funding!

An important question would be what we can actively do to convince our leaders to give the billions of dollars from our national budget not to neverending wars and killing people, but instead to curing aging medical and scientific research?

Political leaders don't lead, they follow, in order to get re-elected. So, the sequence is painfully clear: first convince the mainstream biogerontologists. Once they are on board it's easy: they convince the likes of Oprah, they convince the public, and they in turn convince the politicians. Or we could just convince one billionaire...

How does Liz Parrish's work at BioViva impact what you are accomplishing at SENS?

There are a lot of strong feelings about BioViva swirling around the net at the moment, but it's really not as alarming as is being suggested. To address the various aspects of this issue: Stimulating expression of telomerase and follistatin are plausible ways to derive some aspects of rejuvenation; if I were to choose two genes with which to do what Liz has done, those would be quite high on my list. Yes, the SENS strategy for addressing cancer is the opposite of stimulating telomerase, but that doesn't take away from the fact that such stimulation can have beneficial effects. Gene therapy is certainly highly experimental still, so there is a definite risk to doing what Liz did. However, we must also remember that the public's attitude to medical risk is way over-conservative; for illustration, Mary Ruwart calculated that at least 50x more people die from slow approval of good drugs than from approval of bad drugs. Self-administration has a long and distinguished history in biology research. Even such luminaries as Haldane used to do it. The tests that have been done thus far to determine the effect of the therapy are certainly very inadequate, but I'm guessing that that is mainly because of budget limitations. As far as I know, BioViva has not thus far offered this therapy (or any other) to the public for money.

What you do guys think about all this Nicotinamide Riboside business? Will this have an impact on longevity in humans?

I'm generally pessimistic about the human longevity potential for any intervention that seeks to mimic calorie restriction, i.e. to induce the same changes of gene expression that CR induces, because the best that can be expected from such an approach is what CR itself gives, and that seems to be much less in long-lived species than in short-lived ones. But there may nonetheless be good health benefits, so I'm all for this research.

Are there any well-known people who support human longevity? Couldn't the support of people like Bill Gates or Elon Musk considerably boost funding of any projects?

We have support from a few celebrities, such as Steve Aoki and Edward James Olmos, but we definitely need more. Yes, any billionaire would do!

I'm concerned that there will be a mad rush for volunteers or a price gauge for treatments. How can I become a volunteer? How may the average human being access early treatments?

I'm quite sure that the arrival of these therapies will be preceded by at least a decade by the widespread realisation that they are coming. During that decade, society will do whatever is necessary to ensure universal access.

I am among the minority of people who have said at a every young age that I want to live a very long time, 150+, but all my friends and family all say they would never want to live that long. How do we change people's perception of growing old and make them think long term?

That's the wrong thing to try to convince people of. Instead, convince them that the diseases of old age are inseparable from the aspects of age-related ill-health that we don't label as diseases, so that the only way we'll ever "cure" Alzheimer's, etc, is by defeating the whole lot together. Then they won't be distracted by the unnerving side-effect that they might end up living a long time.

What's your take on why parabiosis seems to rejuvenate mice? Is damage cleared or what's going on? If not, why do the aged mice seem to perform better?

It presumably works by a combination of restoring good things that are less abundant in old blood and removing bad things that are more abundant in old blood. What those things are is still a huge research area. Damage in the SENS sense is probably not cleared except that there may be some stimulation of stem cell division and thus restoration of cell number, though "pre-damage" may well be cleared somewhat via shifts in the kinetics of its creation and repair. There are bound to be epigenetic mediators of the effect.

Recently, there seems to be an uptick in startups focused on reversing aging. Does that seem to be the case to you?

Yes, there certainly are more such startups around, including ones spun out of our own work such as Ichor Therapeutics. It's happening simply because more and more rejuvenation research is getting to a stage of sufficient proof of concept that the more visionary investors are seeing the light at the end of the commercial tunnel.

Comments

Very straightforward, as of today, do you think you will die? Or will these technologies come in time to prevent it?

Posted by: Miladin Sinik at July 19th, 2016 2:12 PM

Don't ask when it will happen, ask what can you do to make it happen.

Posted by: Antonio at July 19th, 2016 3:17 PM

Human rejuvenation isn't about never dying.

It's about taking our present lifespans and adding a few more zeroes at the end.

Posted by: Slicer at July 19th, 2016 4:13 PM

If you can a few more zeroes, probably you can continue adding them until the Universe permits it. But anyway, that's another question.

Posted by: Antonio at July 19th, 2016 5:35 PM

Hi there ! Billions?, oh no... AdG, it's getting bigger and hungrier. Let's do our best to convince the (billions owning rich individuals) infinitely rich few of them. But others on other website challenge the infinite cost do not translate as rejuvenation when other infinite-like costs have been alread injected to no avail :

(On another website discussing SENS I found this as a general mood ) :

''I'm really really skeptical of the claim that SENS can give every person on earth 30 additional years of healthy life for a billion dollars. Billions are spent annually on cancer research, and we still haven't cured cancer.''

''Lila mentions cancer, which I think is very instructive in this context. A "war on cancer" was declared about 45 years ago. Since then,

100-300 billion dollars have been spent on cancer R&D.
Very little progress has been made. Why should we expect a SENS-inspired "war on aging" to make lots of progress, on all seven causes of aging (of which cancer is just one), in one third of that time,
with one hundredth of that budget?''

Joon Yun (California Palo Alto Prize of Longevity) said the we have spent 2 to 3 trillion dollars on health care in last something years and people still die. Of course, it was not targeted towards rejuvenation and the best thérapies that SENS offer (and work since they really do target the important things) but I wonder if this same of money (2 trillion dollars) will translate into completing RHR and reach LEV by SENS.

And this :

''If SENS needs one billion dollars to ensure that rejuvenation technologies that give individuals 30 extra years of healthy life are available to the public in 30 years, we might (completely arbitrarily) assume that someone else will come along and fund SENS in ten years if we don't contribute to funding SENS today. This means that if we fund SENS today instead waiting for it to be hypothetically funded in ten years from now, about ten times the number of people who die each year would live 30 years of healthy life that they wouldn't have lived otherwise. Given that there are about 57 million deaths per year worldwide, this translates to about 17 billion YLLs lost by waiting ten years to fund SENS; since SENS ostensibly requires only 1 billion of philanthropic funding, this implies that $0.059 of funding for SENS produces a YLL.

Of course, regenerative medicine won't be free to the people receiving it, and I have no idea how to account for this, given that I don't have a good idea of how much regenerative therapies will initially cost. The above estimate hasn't been adjusted to account for the fact that there is a time-delay between when funding is provided, and when the benefits of regenerative therapies are available to the public. Perhaps Aubrey isn't well-calibrated, and the "$100 million per year for ten years" figure is entirely wrong. It may be the case that starting work on SENS's research agenda earlier rather than later would allow certain people who would have otherwise died to live until aging escape velocity is reached, which would have lots of utility. There are plenty of other issues with this cost-effectiveness estimate which I am sure that readers could point out.
''

Posted by: CANanonymity at July 19th, 2016 6:48 PM

The most interesting answer I saw Aubrey give was to say that they are using CRISPR to create a line of mice in which somatic gene therapy is much easier. This could go a long way towards RMR as one of the biggest challenges will be genetically editing/modifying every cell in the body of an adult mouse. I'd love to hear more about what this technology actually involves.

Posted by: jim at July 20th, 2016 12:41 AM

Human rejuvenation isn't about never dying. According to Aubrey it is about never dying (of old age).

Posted by: Martin S. at July 21st, 2016 6:39 AM

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