No.221
(Minor edits: comments directed to specific people have been knocked off.)
A cell needs to alter the methylation of the promoters for many genes in order to change the expression of many genes, so any change in the cell's internal or external environment to which the cell responds will lead to changes in its DNA methylation pattern; aging causes a massive amount of change in every cell, in its neighbors, and in the systemic environment (viz. parabiosis work, etc), so it's entirely to be expected that DNA methylation status will change sweepingly with age. Most obviously, when looking at blood cells: as "everybody knows," inflammation and oxidative stress in the blood rises with age for a variety of reasons (senescent cell accumulation, accumulation of cells homoplasmic for large mitochondrial DNA deletions, unresolved injury, age-related autoimmunity, rising burden of atherosclerotic lesions, etc, plus a variety of specific diseases of aging); oxidative stress both dysregulates expression of many genes, and elicits adaptive gene expression responses, while inflammation is itself mediated by gene expression (most clearly and consistently of interleukin-6). And we also know that levels of multiple hormones and other blood-borne signaling factors (TGF-β, GDF-11, etc) are also altered by aging damage; their signaling effects, too, are often mediated by changes in methylation of genes. At the same time, blood cells themselves are suffering damage that leads to changes in gene expression and accompanying methylation status, such as cellular senescence (driven by telomere attrition, oxidative stress, aberrant oncogene expression, etc) and involving in many cases demethylation of the p16 promoter) and the accumulation of anergic T-cells. (Contrariwise, there is now rather strong evidence that p16 hypermethylation can be detected in DNA in the blood of patients with some cancers (especially esophageal cancer): this is because tumor DNA escapes into the blood, and reflects the true mutations and epimutations that allow the cancer to escape senescence).
While some quick headline-generating results would be useful for fundraising, especially in the short term, the extension of lifespan of a model organism simply can't be achieved in the short term through the SENS "damage-repair" strategy. This is because multiple kinds of aging damage contribute to the degenerative aging process, and in order for the rejuvenation biotechnologies that SENS Research Foundation is working to develop to effect lifespan extension, we will require the development of a suite of rejuvenation biotechnologies: one each to remove, repair, replace, or render harmless one of the particular forms of aging damage whose accumulation plays an important role in setting a currently-normal lifespan. But the suite as a whole must be sufficiently comprehensive, or it will exert only a modest effect on lifespan. If you only rehabilitate foam cells in atherosclerotic lesions, or only reverse the age-related stiffening of major arteries, or only reverse thymic involution by developing engineered thymus tissue to restore naïve T-cell production, you will benefit the great majority aging people (or rodents) a little bit (and a very small number of people quite dramatically), but the average person (or mouse) won't actually live much longer, simply because of the "weakest link in the chain" problem. If heart attack doesn't get you, then it's cancer, or stroke, or Alzheimer's disease — or a hip fracture brought when your central vision is so blocked by the early stages ofmacular degeneration that you don't see the cat, trip across it, and then send your osteoporosis-weakened bones crashing to the floor.
Olshansky, for instance, has calculated that a complete and final cure for all ischemic heart disease would only gain an average person who has already made it to age 50 (and thus avoided death in childhood etc) ≤ 3.55 years of life.(1) Similarly, eradicating cancer nets ≤ 3.2 years; both together ("if one doesn't get you, the other will") ≤ 7.83 years; and both, plus ALL circulatory diseases and diabetes, 15.3 years (1). Dr. de Grey subsequently zeroed in on the key point in the specific context of development of rejuvenation biotechnologies:
No.222
[Critics] note that no SENS intervention — in isolation — has ever been shown to extend any organism's lifespan. I do not recall Henry Ford alerting potential customers that the components of a car — in isolation — remain obstinately stationary when burning petrol is poured on them, nor do I recall his being castigated for this omission. Similarly, if engineers followed scientists’ lead in regarding the most direct evidence as the most valuable, we would still be trying to fly by flapping.
Thus, there is no quick-and-easy lifespan headline in the offing: to have a convincing impact on lifespan using SENS "damage-repair" therapeutics will require the assembly of not one therapy, but a sufficiently comprehensive panel of rejuvenation biotechnologies that have first been validated individually in rodent proof-of-principle studies, then tweaked as necessary to allow for joint administration to mice, and finally tested in mice as a combination rejuvenation protocol. Of course, only a limited subset of such therapies exist at present, and a lot of them are still undergoing the first steps of development in cell models, so that first goal is the immediate focus of SENS Research Foundation's work.
Once we have a comprehensive panel of rejuvenation biotechnologies assembled and ready to administer them all to mice, it will (by definition) take up to four years to show life extension — although, for reasons scientific, practical, PR-related, and political, we will in practice want to use mice that are already in early seniority, to effect the goal of "Robust Mouse Rejuvenation" (RMR). The actual testing will therefore take more like 2-3 years: on the one hand, the mice will only have 1 year of "naturally" remaining life expectancy, but on the other hand, the goal of RMR will only really be demonstrated with a doubling or trebling of that remainder, as a small (10-30%) lifespan extension will be compared unfavorably to CR or rapamycin, nullifying its power as a demonstration of the potential of the "damage-repair" approach.
No.223
Let me remind everyone that from the very first days of cofounding the Methulselah Foundation, Dr. de Grey has always estimated that it would take at least a decade of research with adequtate funding to achieve this goal — meaning, dedicated investment of $10 million annually for 10 years, for a total of $1 bn. A more detailed analysis has now revised that estimate to more like $4.5 bn. Now, let there be no misunderstanding or slack-jawed incredulity: this does not mean that the SENS Research Foundation budget has to be raised by an order of magnitude to achieve RMR in ten years! It is perfectly fine if much of the research is done (and much of the investment flows) through government health research institutes like the NIH, and/or through universities, and/or through other biomedical charities that are not focused on the degenerative aging process, and/or pharmaceutical companies and biotech startups (such as those developing vaccines against intracellular aggregates including beta-amyloid and α-synuclein, which are now in human clinical trials, and now moving into vaccines against aberrant tau species). Strategically, much of our focus is on critical path investments into exactly those planks in the SENS platform that are not being actively pursued by industry or government sources (and thus usually in their most preliminary stages), so as to bring them closer to the stage of development of the planks that are nearest to the clinic; this allows us to make the most efficient (least redundant) investments, and mitigates the risk that the success of the platform as a whole stymied by the inavailability of some single, neglected element when the rest of it is already ready to be rolled out.
Of course, this focus on making investments in cash-starved, early-stage rejuvenation research also comes with the downside that those aspects of SENS are (by definition) statistically going to be the farthest from even proof-of-principle in rodents — and thus, the least least likely to garner us headlines, except by dint of being the first and at least initially sole mover in a space. (A lot of these issues were explored in a previous dialog with members of the FA! community).
To be proleptic: I expect that someone may wonder if it would be better to drop the relatively longevous laboratory mouse as a test subject and shoot for quick results in something with the courtesy to develop age-related disease and die much more quickly — nematode worms, for instance, or fruitflies. These organisms are both fast-aging and genetically very tractable, and are thus useful for basic science exploration of some of the the genetic determinants of "normal" species-specific lifespan and the organism's dynamic range of modulation of the rate of aging by Calorie restriction (CR) and similar manipulations. However, invertebrate species are wholly inappropriate for actual testing of rejuvenation biotechnologies, because they age so much differently from mammals. Fruit flies, for instance, don't develop cancer (no WILT or any other cancer therapy); their entire bodies (aside for the gonads) are composed of postmitotic cells, so no endogenous stem cell pools to rejuvenate or repopulate; they lack hearts or circulatory systems as they occur in mammals, and thus don't have large arteries to de-stiffen or foam cells to rehabilitate; they don't accumulate mitochondrial mutations as they age that can be rescued with allotopic expression; etc. In other words, since many of the key forms of damage targeted by rejuvenation biotechnologies — including the main ones we're attacking at the moment! — don't occur in these organisms or can't be repaired in them.
No.224
Moreover, even when it comes to old-school, "messing-with-metabolism" biogerontology, you always have to wait for validation in mice before you assume that the results can be translated to mammals. both Drosophila and C. elegans have a single, unified insulin/insulin-like growth factor signaling system, whereas the two pathways are separated in mammals, and while CR extends life in invertebrates just as it does in mammals, the reasons why it works are quite different: CR affects the initial mortality rate immediately on implementation in Drosophila, whereas in mice and rats, CR retards the rate of acceleration of mortality with age. As the linked paper notes, this fact "indicates that the biology underlying the life-extending effect of DR in rodents likely involves attenuated accumulation of damage, which contrasts with the acute effect of DR on mortality reported for Drosophila." And there are a zillion things along these lines (including many dietary and genetic antioxidant manipulations, or even putting the little pests in the 'fridge!) that extend the lives of simple model organisms that just don't work in mammals. So there are an awful lot of premature, breathless headlines about such research in the press.
On another point, I'd also be cautious about making comparisons between philanthropic investments in SENS Research Foundation and business investments in companies working with pathways involved in the regulation of aging. As we have seen over and over again for the last decade and a half (Geron, Eukarion, Elixir, Sirtris, Genescient, Centagenetix (HLI, take heed!), Rejuvenon, etc), most of the early investment flowing into these companies rests on hopes of a quick and profitable IPO rather than any real desire to see the therapies actually intervene in the human degenerative aging process, and rapidly lose patience with the company's original vision. This impatience rapidly leads to a "strategic repositioning" into metabolic therapies (in most cases against diabetes), and soon thereafter the company shuttes due to investor impatience, or because the very nature of the metabolism-modulation approach makes them unable to deliver. Aging damage accumulates gradually; "gerontological" therapies can only retard but not reverse its accumulation; disease is a late indication, and geriatrics do not interface with gerontology. (There has been one rather dramatic exception on the IPO front, of course, but it's no secret that the prominent buyer did fare well from the purchase and no further development is under way).
As to what SENS Research Foundation delivered in the last five years, I'd encourage you to read our Annual Reports. SRF/MF funded research (a bit more than 5 years ago, just prior to the formal institutional division) led to reversal of blindness induced by allotopic mitochondrial DNA mutations in mice, and subsequently our sponsored research has developed candidate rejuvenation therapies that alleviate the cytotoxicity of the key oxysterol 7-ketocholesterol; has brought us close to development of the Maximally-Modifiable Mouse; has gone a substantial way toward development of engineered thymus tissue to restore naïve T-cell production; and has had substantial success (quite recently, and still unreported) in allotopic expression of up to two new mitochondrial DNA genes. With the support of our donors, David Spiegel's group at Yale have successfully completed the first-ever synthesis of glucosepane (and anticipates the ability to use the same approach to synthesize its biologically-significant isomers and pentosinane, another AGE crosslink that may have been mistakenly neglected), which will in turn enable the development of synthetic glucosepane-crosslinked peptides that can be used to develop antibodies against glucosepane, which will make it orders of magnitude faster and cheaper to look for it in biological tissues, as well as to do high-throughput screening of potential crosslink-breakers and to test potential glucosepane crosslink breakers in vivo.
But (again) this is long-term work, and we are grossly underfunded relative to the amount of neglected work there is to do: headlines attracted is not the appropriate metric to evaluate efficacy. This is expensive, time-consuming work, and maddening as it is, it just requires (and I'm genuinely sorry to say it) patience and ongoing support from donors and supporters of SENS, SENS Research Foundation, and rejuvenation biotechnology. (Relatedly, Mr. Thiel remains one of the biggest and most enthusiastic donors to the Foundation).
No.225
Longevity is a tiny, tiny fraction of human improvement, but it's necessary if you want to long enough to get anything else.
If this is tl;dr for you, you'll never be transhuman.
No.230
>>225Jesus fucking christ. Im going to go through it and cross reference everything, but gee thanks for giving me a shit ton of work to do. I WAS going to fap.
No.231
>>230Take your time. This is deep, deep science he's referencing here.
By the way, SENS needs your fucking money, because they're doing the research that Calico and other VC-funded organizations aren't talking about.
No.234
>>230You can watch Aubrey De Gray's videos for a more beginner-friendly breakdown. Anon did a great job by providing in-depth technical details, but that can be tough for a beginner to grok.
>>231Absolutely, SENS is fighting the good fight. Their approaches will empower and enable all other forms of life-extension.
No.250
>>221Wow. That's a lot. Screencapping this thread now, based science anon!
No.270
>>223>meaning, dedicated investment of $10 million annually for 10 years, for a total of $1 bnSomeone is an order of magnitude off somewhere in there.
No.271
>>270Good catch. Pretty sure he missed a zero in the investment.
No.294
No.297
(Straight from the bearded mouth itself. As before, comments directed to a specific person have been edited out.)
It's most gratifying to see an actually thoughtful challenge to the LEV concept - one of my biggest frustrations is that it is so ubiquitously dismissed out of hand as farcical without any actual analysis of the argument.
However, there are some aspects of the LEV idea that I think might make people more optimistic. First and foremost is that, even though design-wise life is indeed about as Rube-Goldberg-esque as can be imagined, robustness-wise it is not: the unpredictability and variety of the circumstances that an organism must survive in order to maximise its ability to contribute to the next generation is vast, and has driven evolution to develop exceptionally powerful homeodynamic tools that recover the organism from all manner of insults. This applies to internally-derived insults (i.e. aging) as well as environmental ones: even though the body creates a huge variety of types of damage in the course of its normal operation, nearly all of them are automatically repaired as they arise. The only ones that aren't are those that accumulate too slowly to impair function until middle age or later, when evolution no longer cares.
Secondly, it seems that the number of types of damage that start to impair function at age N does not actually rise exponentially with N. Why this is is perhaps just inherent in the underlying biochemistry of life - but the fact seems to be that the extremely elderly, who through luck or judgement avoid the major diseases that kill most of us, seem to have not many more things wrong with them than the average person. Indeed, maybe it's not even peculiar to biochemistry: going with your mention of cars, it simply doesn't seem to be appreciably harder to get a car that was designed to last 10 years to last 100 years than it is to get it to last 50. Perhaps the exponential relationship is in fact a sigmoidal one, being exponential at first but then levelling off.
Third and very importantly, the LEV concept rests on the classification of damage that is the starting-point of SENS. That classification exists not just for discursive convenience, but because for each category there is a generic therapeutic approach that is claimed to be likely to work for each example within the category. Thus, as long as the classification remains supported and we don't discover an eighth deadly thing, but only additional examples within the existing categories, our therapeutic challenge reduces to retooling the details of the therapies we already developed for the first example within the category, to work for the new ones. And retooling details is a great deal easier and quicker than developing a new therapy from scratch.
Taking these considerations into account, I conclude that LEV is indeed very nearly certain to be exceeded and maintained following the development of "SENS 1.0", i.e. the therapies that we're already working on and that I have discussed in Ending Aging and elsewhere.
No.299
File: 1429382285294.png (394.94 KB, 720x404, 180:101, so where are your great de….png)
>>297
>In my TED talk (the one I gave at TED itself, in Monterey in 2006, not the one at ted.com that I gave in Oxford in 2005) I made this point the centrepiece of my presentation, actually - I talked about how success would empower us by curing our fatalism and lack of ambition.>Posted by: Aubrey de Grey at April 18, 2015 11:34 AMI love the guy, really I do, but… Aubrey….
No.300
Absolutely titanic slapfight going on between the big names in anti-aging and some anonymous motherfucker regarding SENS getting more money:
https://www.fightaging.org/archives/2015/04/tomorrow-will-be-different-from-today.php#comments No.309
Work on encouraging older cells to act like younger ones is actually getting done. Expect some serious anti-aging drugs to come down the pipe soon, although they're not repair and replacement.
No.334
HEY RICH ASSHOLE YA CAN'T SPEND IT WHEN YA DEAD