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Michael R

CR & Biogerontology in "The Economist"

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All:

 

I was a bit disappointed with this, as it covers much ground that has been covered before, and focuses very heavily on old-school biogerontology; it only begins to enter into the SENS strategy of direct repair of cellular and molecular damage well into the article, after having early on suggesting that anti-aging therapies would have to work through altering metabolism. And then, the talk is all about cell therapy, with no discussion of other regenerative therapies. Also, no mention of the CR Society. Still, pretty good, and nice to have CR proper in the headlines again — and from a quite respectable venue. (Later: unfortunately, it appears alongside a much more problematic companion article).

 

Adding ages

The fight to cheat death is hotting up

Natasha Loder

 

MICHAEL RAE eats 1,900 calories a day, 600 fewer than recommended. [Grr ... I was very explicit about the "recommended" Calorie intake being too generic to apply to any given individual and never intended to do so -MR]. Breakfast is a large salad, yogurt and a “precisely engineered” muffin. In a mere 100 calories this miracle of modern gastronomy delivers 10% of Mr Rae’s essential nutrients. Lunch is a legume-based stew and another muffin. Dinner varies. Today he is looking forward to Portobello mushroom with aubergine and sage. There will be a small glass of red wine. He has been constraining his diet this way for 15 years.

 

In some animals calorie restriction (CR) of this kind seems to lessen the risk of cancer and heart disease, to slow the degeneration of nerves and to lengthen life. Mr Rae, who works at an anti-ageing foundation in California, thinks that if what holds for rodents holds for humans CR could offer him an extra seven to 15 years of healthy life. No clinical trials have yet proved this to be the case. But Mr Rae says CR dieters have the blood pressure of ten-year-olds and arteries that are clean as a whistle.

 

The “profound sense of well-being” Mr Rae reports might seem reward enough for his privations. [Nah ;) . But it sure is nice, and reinforcing -MR]. But his diet, and the life extension he thinks it might bring, are also a means to an end. Mr Rae, who is 45, thinks radical medical advances that might not merely slow but stop, or reverse, ageing will be available in the not-too-distant future. If CR gets him far enough to benefit from these marvels then a few decades of deprivation might translate into additional centuries of life. He might even reach what Dave Gobel, boss of the Methuselah Foundation, an ageing-research charity, calls “longevity escape velocity”, ...

 

That all remains wildly speculative. But CR is more than just an as-yet-unproven road to longer human life. Its effects in animals, along with evidence from genetics and pharmacology, suggest that ageing may not be simply an accumulation of defects but a phenomenon in its own right. [Heh? -MR]. ...[ I]t might in principle be manipulated, either through changes to the environment (which is what CR amounts to) or by getting in among those genes, and the metabolic pathways that they are responsible for, with drugs. [Or by repairing the damage!! -MR].

 

A treatment based on such manipulation might improve the prospects of longer and healthier life in ways that drugs aimed at specific diseases cannot match.  ... And if it delays the onset of a range of diseases it might also go some way to reducing the disability that comes with age. An ongoing long-term study at Newcastle University has been looking at the health and ageing of nearly 1,000 subjects now aged 85. At this point they have an average of four to five health problems. None of them is free from disease. Most researchers in the field scoff at talk of escape velocities and immortality. But they take seriously the prospect of healthier 85 year olds and lifespans lengthened by a decade or so, and that is boon enough. [Hardly! But it would be a start. -MR]

 

Indications of immortality

Before discovering whether anti-ageing drugs might be able to deliver such things, though, researchers need to solve a daunting regulatory conundrum. At the moment the agencies that allow drugs to be sold do not consider ageing per se to be an “indication” that merits therapy. ... Unless ageing is treated as an indication, anti-ageing drugs can’t get regulatory approval. And there’s little incentive to work on drugs you can’t sell. [Not necessarily true -MR]. ...

 

 there are hints that the stance may indeed be changing. Two existing drugs approved for other purposes—metformin, ..., and rapamycin ... In 2014 a study of 90,000 elderly patients with type 2 diabetes found that those receiving metformin had higher survival rates than matched non-diabetic controls. [Not really. And it has repeatedly failed to exert more than a very modest effect on mean/median LS only in normal, healthy rodents -MR]. Other work has shown its use is associated with a decreased risk of cancer. [but these studies are conducted in diabetic patients, and are confounded by cancer-promoting effects of alternative treatments -MR]. ...

 

[Nir Barzilai] want to mount a trial of metformin in elderly subjects to see whether it delays various maladies (and also death). If that turns out to be the case, it will go a long way to showing that there is a generalised ageing process that can be modulated with drugs ... [and] have an indication against which next-generation ageing drugs can be assessed by regulators.

 

... Food and Drug Administration ... is thinking about when a broad, and so far unprecedented, claim of anti-ageing might be considered to be supported by the evidence; it is “looking forward to seeing this area of science evolve”. In the dry language of a government agency these are encouraging words.

 

If an unregulated diet can do the trick, why does the world need drugs? Three reasons. One is that taking a few pills a day will be easier for most than subsisting on low-calorie muffins and salad. [Happily, no hyperbolic descent into globalizing generalizations about the misery of practicing CR. -MR]. A second is that companies can make money making pills and will compete to create them. A third is that pills may work better than diets. Dr Barzilai, who is in the pill camp, points out that CR works less well in primates than other mammals, and that people with low body-mass indices, a natural condition for those restricting their calories, are in general more likely to die. Those who do well on CR, he says, are likely to be a subset benefiting from the right genetic make-up. His hope is that a range of targeted therapies might allow everyone to get the benefits. [This does, however, wind up being a somewhat internally inconsistent argument to the extent that such drugs are developed as CR mimetics. And testing age-retarding, metabolically-based therapies is hard enough, without adding the difficulty and expense of personalized medicine into the testing process. -MR]

 

If they do, it will be by inducing changes in metabolism. [.Unless they don't!! -MR.] Again, disappointed no discussion of the alternative strategy -MR] [DAF2/FOXO; DAF16/IGF-1; mTOR; ...

 

Alexander Zhavoronkov, the boss of Insilico Medicine, a longevity firm, says he is testing rapamycin on himself (self experimentation does not seem uncommon in the field). But he warns it is necessary to have a significant knowledge of biomedicine to do so safely. [Not clear how such knowledge would enable safer self-experimentation -MR] ... One idea is that low doses might preserve the drug’s benefits while limiting its side-effects. [unfortunately not, if like Mr. Zhavoronkov you're male (1). 14 ppm was the dose in the original study, and yields blood levels similar to trough levels targeted for human patients taking it for kidney transplants -MR]]

 

acel12194-fig-0001.png?v=1&t=irs4ipia942

[The miserable failure of resveratrol and the SIRT1 story is laid out as less complete than it has proven -MR]...

 

João Passos, also at Newcastle University, says cells from which mitochondria are removed start to look more like young cells and stop secreting cytokines. [This is a highly distorted summary of (2) -MR]. Other work has shown that killing off mitochondria can mimic some of the effects of drugs that activate mitochondrial renewal—such as rapamycin. Faster turnover of mitochondria seems to improve their functioning. [strong evidence against this, too, as a generalization (eg. (3,4) -MR] ...

 

[some are looking at "longevity genes" for targets, including Dr Zhavoronkov’s Insilico Medicine and Craig Venter's  Human Longevity Inc (HLI)] ...For those who cannot wait for drugs, HLI has a high-end “wellness” service called the Health Nucleus. At prices starting from $25,000 it will give a customer a constellation of cutting-edge tests, including a full sequence of both his genome and a battery of tests for the signs of cancer, Alzheimer’s and heart disease. [skeptical that they can do this much better than fairly ordinary blood tests plus the most rock-solid of SNP genotyping -MR] Lots of tests means lots of possibilities for “false-positive” results; but the affluent clients of Health Nucleus may worry less about follow-ups that reveal false alarms than other people do. [Which is foolish, as most people already don't take this problem seriously enough -MR].

 

In 2013 Google (now Alphabet) started a venture called the California Life Company, or Calico, to take a “moonshot” approach to anti-ageing; the company has said it will invest up to $750m in the venture. ... But it has announced a series of collaborations, the most significant of which is a ten-year R&D deal with AbbVie, a pharma company based in Chicago, focused on cancers and degenerative nerve conditions. [Granted the way they're pursuing them, these are arguably a step back from the company's stated core mission -MR].

Degeneration leads to thoughts of regeneration. Even the most enthusiastic adherents of slowing down ageing by means of diet or pharmacology have to admit that it will not keep people going forever. At best it might allow them to age as slowly as the slowest-ageing people do naturally. ... To do something about this means not just slowing ageing but stopping or reversing it, either by causing bits of the body to rejuvenate themselves or by removing and replacing them. This is where stem cells come in. ...

 

[Parabiosis ... BioViva ...]

 

The idea that radical biotechnology can lead to longer lifespans than that of Jeanne Calment... seems at best a plausible speculation. To say—as Aubrey de Grey, a noted cheerleader for immortality, has done—that the first person to live to 1,000 has probably already been born seems utterly outlandish. But thinking through Calment’s life might give you pause. When she was born, in 1875, the germ theory of disease was still a novelty and no one had ever uttered the word “gene”. When she died in 1997 the human genome was almost sequenced. All of modern medicine and psychiatry, barring general-purpose anaesthesia, was developed during her lifetime. If a little girl born today were to live as long—and why should she not?—she would see the world of 2138. The capabilities of medicine at that point will surely still be limited. But no one can guess what those limits will be.[/i]

 

 

Reference

1: Miller RA, Harrison DE, Astle CM, Fernandez E, Flurkey K, Han M, Javors MA, Li X, Nadon NL, Nelson JF, Pletcher S, Salmon AB, Sharp ZD, Van Roekel S, Winkleman L, Strong R. Rapamycin-mediated lifespan increase in mice is dose and sex dependent and metabolically distinct from dietary restriction. Aging Cell. 2014 Jun;13(3):468-77. doi: 10.1111/acel.12194. Epub 2014 Feb 9. PubMed PMID: 24341993; PubMed Central PMCID: PMC4032600.

 

2: Correia-Melo C, Marques FD, Anderson R, Hewitt G, Hewitt R, Cole J, CarrollBM, Miwa S, Birch J, Merz A, Rushton MD, Charles M, Jurk D, Tait SW, CzapiewskiR, Greaves L, Nelson G, Bohlooly-Y M, Rodriguez-Cuenca S, Vidal-Puig A, Mann D,Saretzki G, Quarato G, Green DR, Adams PD, von Zglinicki T, Korolchuk VI, PassosJF. Mitochondria are required for pro-ageing features of the senescent phenotype. EMBO J. 2016 Apr 1;35(7):724-42. doi: 10.15252/embj.201592862. Epub 2016 Feb 4.PubMed PMID: 26848154; PubMed Central PMCID: PMC4818766.

 

3: Herbst A, Johnson CJ, Hynes K, McKenzie D, Aiken JM. Mitochondrial biogenesis drives a vicious cycle of metabolic insufficiency and mitochondrial DNA deletion mutation accumulation in aged rat skeletal muscle fibers. PLoS One. 2013;8(3):e59006. doi: 10.1371/journal.pone.0059006. Epub 2013 Mar 13. PubMed PMID: 23516592; PubMed Central PMCID: PMC3596334.

 

4: Dumont M, Stack C, Elipenahli C, Jainuddin S, Launay N, Gerges M, Starkova N,Starkov AA, Calingasan NY, Tampellini D, Pujol A, Beal MF. PGC-1α overexpressionexacerbates β-amyloid and tau deposition in a transgenic mouse model ofAlzheimer's disease. FASEB J. 2014 Apr;28(4):1745-55. doi: 10.1096/fj.13-236331.Epub 2014 Jan 7. PubMed PMID: 24398293; PubMed Central PMCID: PMC3963016.

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Michael,

 

Thanks for posting this, and your insightful commentary about it's shortcomings. Reason over at FightAging.org was also disappointed, saying in his commentary on the coverage:

 

For advocates who are trying to ensure that the research community adopts damage repair as the dominant strategy, it is frustrating to have the press telling the public that slowing aging is all there is, or painting specific efforts to slow aging (capable of extending life only a little) as being equivalent to specific efforts to reverse aging (capable of extending life greatly). The article linked here is a particularly egregious example of this sort of thing. It starts out and ends with quotes from people long involved in advocating and funding SENS rejuvenation research, and then completely fails to mention the SENS Research Foundation or the SENS approaches to repairing the damage that causes aging. 

 

It is rather ironic and unfortunate that they talk about you, but not your affiliation with the SENS Foundation, or all the great research you folks are doing to combat aging.

 

--Dean

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Michael,

 

Thanks for posting this, and your insightful commentary about it's shortcomings. Reason over at FightAging.org was also disappointed, saying in his commentary on the coverage:

 

For advocates who are trying to ensure that the research community adopts damage repair as the dominant strategy, it is frustrating  ... It starts out and ends with quotes from people long involved in advocating and funding SENS rejuvenation research, and then completely fails to mention the SENS Research Foundation or the SENS approaches to repairing the damage that causes aging. 

 

It is rather ironic and unfortunate that they talk about you, but not your affiliation with the SENS Foundation, or all the great research you folks are doing to combat aging.

 

Indeed. It does actually allude to "an anti-ageing foundation in California" for which Mr. Rae works, but doesn't name it, link it, or explain what it does. Annoying. Ditto for CR Society: no mention we even exist, and only the briefest of mention of the known beneficial effects of CR or how esential our group has been  to documenting same.

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All:

 

I was a bit disappointed with this,

Wait, what? You're "disappointed" about being featured and quoted in The Economist? Haha... Your mom has this framed on her wall by now, centerpiece, and she shouted out the window over her organic chard to the neighbors about how proud she is, Michael this, Michael that, and she's framing the article again twice in expensive forest wood to give it to you next holiday... That is, it's always the same problem with you: what do we give Michael THIS year for Xmas, he already has everything....

 

Disappointed my ass. You're proud as a panther, man, strut with it -- you deserve some goodness just like we all deserve some goodness before we're frozen by Alcor... https://www.buzzfeed.com/theangryluddite/25-animals-that-are-incredibly-proud-of-themselves-5dn9?utm_term=.qsMOqYLMv1#.tj9PgbZBx9

 

Now get back to solving the idiocy of aging, woo I mean ageing wtf... Y'all can't even agree on how to spell the word

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It's good that Michael has an opportunity to criticize in this public-accessible forum (the old mailing List format was dysfunctional in that aspect!)

 

The distortions in the Economist article are not surprising.

The choppiness and capriciousness of that (and the companion) articles indicate a kind of quickie hack job: that the author(s) superficially Googled topical keywords and came up with a mix of DATED content (videos, blogs, old Yahoo List, old media articles). Copy n' paste ... limit to 2000 words (or whatever), etc.

Not that accurate reporting of scientific topics is easy; and the Economist is hardly a respected science authority (nor should one expect it to be).

 

Indeed. It does actually allude to "an anti-ageing foundation in California" for which Mr. Rae works, but doesn't name it, link it, or explain what it does. Annoying. Ditto for CR Society: no mention we even exist, and only the briefest of mention of the known beneficial effects of CR or how esential our group has been  to documenting same.

 

Probably a high-level editorial decision. SENS and CRS are not "financial" or elite enough (see below) for an outfit as big as The Economist to openly "support". But the topic is hot because of outfits such as Google/Calico -- hence, a lotta nuances/hedging in its political prose.

 

E.g., for linking, you could look at the Alexa score:

SENS (328,899)

calicolabs.com (318,000)

CRS (626,247)

The Economist (1,886)

Facebook (3)

Instagram (16)

 

That's one metric out of several to consider. E.g., organizations' financial statements, temporal length of existence, etc. Even "image": Aubrey may have to lose that beard ;) And some of us emaciated ones --especially young females -- may have to gain a few pounds, and pose for photo ops in swimwear.

 

Noam Chomsky once refered to mainstream publishers such as the NY Times, Business Week, etc. this way:

1. "The major media-particularly, the elite media that set the agenda that others generally follow-are corporations “selling” privileged audiences to other businesses. It would hardly come as a surprise if the picture of the world they present were to reflect the perspectives and interests of the sellers, the buyers, and the product. 

 

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I'll add my nitpick:

 

A third is that pills may work better than diets. Dr Barzilai, who is in the pill camp, points out that CR works less well in primates than other mammals, and that people with low body-mass indices, a natural condition for those restricting their calories, are in general more likely to die.

 

For those restricting calories - for health - low body mass is likely an unnatural condition and potential confounder.
 

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