Most Brain Aging Decline Can Be Fixed Overnight

There are two huge aspects to a new antiaging drug. The first aspect is that a large portion of age-related brain decline is not permanent damage. This non-permanent damage is repaired overnight by a new antiaging drug. The Google-back antiaging company, Calico, has licensed the drug.

A new University of San Francisco antiaging drug, called ISRIB, has already been shown in laboratory studies to restore memory function months after traumatic brain injury (TBI), reverse cognitive impairments in Down Syndrome, prevent noise-related hearing loss, fight certain types of prostate cancer, and even enhance cognition in healthy animals.

The extremely rapid effects prove that a significant amount of age-related cognitive losses is caused by a kind of reversible physiological blockage rather than more permanent degradation.

ISRIB, discovered in 2013 in Peter Walter’s lab, works by rebooting cells’ protein production machinery after it gets throttled by one of these stress responses – a cellular quality control mechanism called the integrated stress response (ISR; ISRIB stands for ISR InhiBitor).

Improves Cognition, Boosts Neuron and Immune Cell Function

In the new study, researchers led by Rosi lab postdoc Karen Krukowski, PhD, trained aged animals to escape from a watery maze by finding a hidden platform, a task that is typically hard for older animals to learn. But animals who received small daily doses of ISRIB during the three-day training process were able to accomplish the task as well as youthful mice, much better than animals of the same age who didn’t receive the drug.

The researchers then tested how long this cognitive rejuvenation lasted and whether it could generalize to other cognitive skills. Several weeks after the initial ISRIB treatment, they trained the same mice to find their way out of a maze whose exit changed daily – a test of mental flexibility for aged mice who, like humans, tend to get increasingly stuck in their ways. The mice who had received brief ISRIB treatment three weeks before still performed at youthful levels, while untreated mice continued to struggle.

Common signs of neuronal aging disappeared literally overnight: neurons’ electrical activity became more sprightly and responsive to stimulation, and cells showed more robust connectivity with cells around them while also showing an ability to form stable connections with one another usually only seen in younger mice.

ELife – Small molecule cognitive enhancer reverses age-related memory decline in mice

With increased life expectancy age-associated cognitive decline becomes a growing concern, even in the absence of recognizable neurodegenerative disease. The integrated stress response (ISR) is activated during aging and contributes to age-related brain phenotypes. We demonstrate that treatment with the drug-like small-molecule ISR inhibitor ISRIB reverses ISR activation in the brain, as indicated by decreased levels of activating transcription factor 4 (ATF4) and phosphorylated eukaryotic translation initiation factor eIF2. Furthermore, ISRIB treatment reverses spatial memory deficits and ameliorates working memory in old mice. At the cellular level in the hippocampus, ISR inhibition
i) rescues intrinsic neuronal electrophysiological properties,
ii) restores spine density and
iii) reduces immune profiles, specifically interferon and T cell-mediated responses.

Thus, pharmacological interference with the ISR emerges as a promising intervention strategy for combating age-related cognitive decline in otherwise healthy individuals.

77 thoughts on “Most Brain Aging Decline Can Be Fixed Overnight”

  1. Not into monster stuff. You may be interested that Janov expressed fear that someone would use his findings to make movies so disturbing that they would cause damage.

  2. There is something wrong in chess as it is. We need torpedo
    chess 960 with random symmetrical traffic cones.

  3. Study highlights:
    -Administration of "drug-like "ISR" inhibitor" appears to decrease "ISR" as evidenced by a reduction in circulating surrogate biomarkers, ATF4 and eIF2 in aged mice but not young mice.
    -The reduction in ATF4 and eIF2 surrogate biomarkers was accompanied by a 50% improvement in a validated spatial memory test for mice in old mice as compared to young mice.
    -This reduction in ATF4 and eIF2 as well as the 50% improvement in spatial memory performance persisted for at least 2 weeks after administration or the treatment medications.
    -Treatment effects were significantly different from placebo/sham treatment effects

    Questions I have:
    -What exactly is this mystery compound? they never say. Appears to be some kind of immuno-modulator that can cross the blood brain barrier.
    -it does appear to be better than placebo but I'd be interested to see if there were similar reductions in ATF4 and eIF2 plus improvements in memory performance tests for ISR inhibitor treatment as compared to existing treatments for cognitive decline such as donepezil or memantine…heck, even amphetamines.

    My Conclusion:
    -promising results that appear to validate the efficacy of targeting ISR to treat age related cognitive impairment. Definitely warrants further study.
    -I suspect the "drug-like ISR inhibitor" is an existing drug or treatment and not some new and unique chemical entity otherwise they would not be so secretive about what the actual treatment entity is.

  4. I should probably reiterate that it's not pharma grade (nor food grade), so the usual warnings and disclaimers apply.

  5. Well, first, the title already feels like it's trying to sell you something. And it's somewhat click-baity: you're left wondering what "Secret compound"?

    The 2nd hint is the length of the article (you can see by the scroll bar even before scrolling down).

    At this point (once I suspect a sales pitch), I immediately scroll down to check for numbered section titles. That's an your 2nd-to-main sign. Brian never numbers his sections.

    If you happen to spot what looks like stock symbols (like "CSE:LOBE", "OTC:GTSIF", etc) or market estimates ("could be a $6.9 billion market by 2027"), that's another hint. That one has both.

    And finally, you find the "By [author]" and disclaimer, which gives the final confirmation.

    The more NBF you read, the more you'll be able to recognize these before you even read them.

    PS: Also, the writing style is much cleaner and more structured than Brian's. Brian's tends to be more of a messy mash of quotes and streams of consciousness.

  6. 3 downvotes? Either from pharma researchers who disagree with my amateur dose scaling, or people who DO want Brett to poison himself and then become a vengeful spirit plotting my demise.
    I guess we'll never know…

  7. Of course, at this point, most of this is pretty academic as far as I'm concerned: Plastic lenses now, after cataract surgery. (The cataracts were a side effect of chemo, I went from better than 20-20 while wearing my (Coke bottle!) glasses to effectively blind in a few months. Fastest onset of cataracts my eye doctor had ever seen.)

    These days I'm strictly fixed focus.

  8. A more wild idea of mine, following Bates, is that increased movement of the eye shape and lens will flush out the lens and fluid of the eye, helping with both cataracts and glaucoma. Not wearing glasses will increase this movement, as will intentional exercises. Just an idea, but keeping things from moving, such as eyes, seems a bad idea in general.

  9. Bates has theories of stress that are almost up to Janov, but very local to the eyes. I was having great success with Bates before even reading Janov, however, in the '70s, so cannot say it was only Janov's much more effective stress removal that worked. The theories both stand, however, as the *wrong shape* theory is false by counterexample. Failure to do Primal Therapy correctly, as is common, does not disprove Primal Science. I can prove Bates is correct by looking out the window now. Remember, there is great money to made selling glasses.

  10. FWIW I tried Bates methods for a year or two a few decades ago. I eventually decided that it was not working.

  11. it just goes to show you how humor impaired people have gotten that you have three downvotes for what is a rather witty joke.

    i mean republicans – really, are you that brittle that you can't take a little joke at your own expense?

  12. It's not just that. In my case, a cataract patient, my eyesight goes to pot as soon as the light level goes down. Part of it is pinhole effect, and part of it is the larger pupil letting some light in around the edges where things don't get focused.

  13. Yes, in the days when each lens had to be hand blown and ground from glass, it was probably something only limited to the professional and upper classes.

    Prescription glasses cost several hundred dollars as recently as when I started wearing them. Now they cost several 10s of dollars, about as much as a bottle of bourbon.

  14. These factors are not exclusive. Eyes are important. Cool. edit: in my case, I was looking distance, same overall otherwise.

  15. When the eye focuses, there is also pupil movement, they are not completely independent systems. The pupil gets smaller in bright light, and that is in the direction of the lens becoming more convex which is the direction we are trying to go to look close.

  16. He is somewhat right, the smaller pupil in bright light will create a somewhat sharper image, but nothing like what you and I experience, a TOTAL clarity, in my case going from myopia to distance capabilities. But not always, all the time.

  17. When I was first experimenting with Bates, I was walking up a very bright path and could barely open my eyes, they were so painful. BUT I could see perfectly clearly, for a few moments. For the first time ever. Sunlight sends a power *focus* demand that can *cause* movement, disproving conclusively that the wrong shape or such is the cause. The goal of the sight exercises is to relax this stress caused cramping, bringing us full circle to the blog topic.

  18. This should be interesting for the chess world. A lot of washed up players might surge in strength. The best players might not all be 19-39 with a few 40-55 year old ex-World Champions in 15-20th places:
    The top 5 players in the World currently are all between 28-30 years old.
    There is a guy who is 59 who is in 49th place…but he was caught cheating with a computer and is now banned:

  19. So tell me how I suppose to know I'm reading an ad with the  "Medicine Could Be Big Pharma’s Dream article?"

    It's is even listed as under the Medicine subdirectory.


  20. Heck, it may do positive things for a number of brain conditions they haven't even mentioned. Fixing Autism would be fantastic, and any special skills would likely be retained. Curing schizophrenia would also be fantastic. Depression and anxiety affect many millions. Fixing that would be beyond fantastic.

    I have intense ringing in one ear from blowing out an eardrum when I was 14, it would be wonderful to have that gone.

    It is all a wish list though. We have to wait and see.

  21. Look up "Pinhole Camera".
    In bright light the iris contracts leading to everything being less blurred for the degree to which the eye lens is out of focus.

  22. There is a long way to go on this one. The obvious is that stuff that has worked on mouse brains hasn't fared so well on human brains. Another issue that jumps out at me is the possibility that it is resetting the brain…making you forget a lot of stuff, so you have more room. If so, that is a serious drawback. What about personality change? Would I still be me? Could there be aspects that it does not address that because they are not addressed leave you just as addled. Then there is sanity, long term effects, and effects on other organs.
    Though, I am perfectly open to this being everything it promises to be. Chances are this is going to be pricey…unless you get it black market or in another country.
    I am also hopeful this will actually work on Down Syndrome. That would be great for those with Down Syndrome and society. It is a major burden on parents to care for a Down Syndrome child. If regular doses, say once a year, allows these kids to live a normal life, that would be fantastic. Then it should just be a mater of a little surgery to shorten their tongues so they can talk clearly. They probably will still have shortened lives, but they should be higher quality lives.
    If it is a small molecule, I wonder if it is found in nature anywhere. If it is in some plant or fungus maybe we can get it cheap as a supplement. We probably would already have found it, if it was in a normal food or herb…unless it was at very low concentration like that Nicotinamide riboside in milk.

  23. Actually I have found something different than that with my eyesight. I started needed reading glasses around 48 yrs old, had better than 20/20 even though I am a lifelong heavy reader.
    I am now 52 and of course still need them, unless I am in direct sunlight. In direct sunlight I can read even very small text, which would be nothing but a blur under artificial light without my glasses. Even text small enough to have trouble reading with my glasses, I can read no problem with my naked eyes in bright sun.
    That is leading me to think that it is not an issue with the lenses of my eyes but how the eye collects and uses light itself, and that a broader range of light gives me the ability to see things that a problem with the lens would not let me see no matter what the light source.
    Does anyone else notice this as well?

  24. Roughly speaking, you'd start by chlorinating phenol to 4-chlorophenol. Next you need to make 1,4-diaminocyclohexane, probably by hydrogenating para-phenylene diamine (which you need to synthesize first – see Wikipedia).
    Either separate the stereoisomers, or you may be able to hydrogenate stereoselectively.
    Then you need to make chloroacetic anhydride. I'm not quite sure how that is done, there's probably more than one way. And finally, react those three components to get ISRIB.

    You could also go via chloroacetic acid instead of its anhydride, with an extra step to convert to the acyl chloride after reacting it with the chlorophenol.

  25. HPLC grade is not pharmaceutical grade. IIRC, pharma grade usually is more expensive. OTOH, SigmaAldrich doesn't show bulk price on the main product page, and some stuff is expensive due to low-demand (hence low manufacturing volume). This looks like a good example.

    It may be fine for personal use, but doesn't give much indication of likely mass-production price.

    The molecule isn't very complex, but it's still a multi-step synthesis. If the stereochemistry matters (likely), it's more complicated. If either one of the stereoisomers works, it should be simpler (and cheaper).

  26. Well, but in the case you give, people eating a normal diet didn't get scurvy, only people forced to eat unusually restricted diets. The vitamin C wasn't fixing a general problem, it was correcting an unusual dietary deficiency.

    The usual rule when we find something that affects an age related miracle on lower, shorter lived organisms, it that it turns out to be something our own bodies already implement, and we're only bringing the mouse or whatever up to par with us. There are exceptions, like the enhanced ribosomal fidelity of naked mole rats. But they're not easy to do fixes.

    Since we're a long lived organism already, the general expectation is that easy tweaks would already have been evolved by us.

    But there are counter-arguments; Evolution hasn't done a lot of work on things that go wrong only beyond our 20-30's, because for most of evolutionary history most people wouldn't have lived that long anyway. And you CAN point to simple nutritional fixes that help a lot in your later years, but are meaningless earlier in your lives, like SAMe.

    This stuff, if it works in humans as it does in mice, would be miraculous. Sure, it probably won't extend overall lifespan much, but I personally hate the fact that my mental acuity is declining, and am horrified by the likely prospect that I'll be mentally incompetent in my last few years.

  27. One problem: if you reverse common cognitive decline, who will be left to vote republican?

    Just kidding, just kidding. There are impaired brains on both sides of the aisle.

    I want to try this now. And will want it much more in a few years. Family history of Alzheimer's and early neurodegeneration.

  28. I can personally testify to the fact that, even when you still retain enough acuity to pick out needed details, declining acuity slows down how fast you pick them out.

  29. The lens grows as it ages. As it grows, the growth uses up the range of travel of the ring of muscle that pulls it flatter, and you lose accommodation. They can restore accommodation by implanting a ring to stretch the anchorage. Not an approach that gets used much, the surgery is enormously more expensive than bifocals.

  30. That would be my expectation, that it was just diluted for measurement purposes. And it was injected into the body cavity, not into a tissue.

    It's a fairly small molecule, and readily crosses the blood brain barrier, so I'd expect that with a bit of DMSO it would penetrate skin, too.

    The mouse research shows long term effects from short term dosing, so getting it as an IV drip wouldn't be silly. Depending on how it behaves, it could also be administered as a patch.

    At current prices 25mg is available for about $400. I'm not sure what the purchase restrictions are. I wonder how hard it is to synthesize?

    This seems like it could actually be affordable if approved, depending on how much they jack up the price.

  31. I wonder how much glasses would cost in the middleages, – presumeably not much compared to 20 more years of work.
    Learning to read is a much bigger investment.

  32. The mix is loaded with DMSO, you can probably just rub in on your skin.

    More seriously, my first guess (only a guess) is that it's diluted down to 0.1 mg/mL so that you can physically make and use a 0.05 mg dose for a mouse without needing a microscope to see how tiny the syringe needs to be.
    I've never done any work dosing animals (well, not animals smaller than me, with cattle and horses the problems go in the other direction) but I DO deal with microgram doses of chemicals all the time. And it's so much easier to deal with a human sized volume of a very dilute solution than trying to measure out microlitres of fluid.

  33. All of the ad posts I've seen here (or at least recognized) have the same format. This isn't it.
    Also, this has a clearly marked abstract and links to the source material. That should tell you it's reporting a scientific study.

  34. At 0.1mg/ml, 240ml. 24 of those little 10ml syringes.

    IV drip I suppose…only a quarter liter, not so bad.

  35. The problem with this site not disclosing "Paid Advertisement" until the bottom of ads makes me now wonder if this is also an ad and just has a buried disclosure.

    So hard to have credibility now.

  36. The lens can only *fine tune* the accomodation that I have, for instance. Only making the eye longer will allow me to focus as close as I can, yet still see *pretty* well distance, compared to glasses days. And the colors are sooooo much better.

  37. I love it.
    I wouldn't have picked agricultural workers as a profession that this would seriously move the needle on, but there you go.

  38. Trying to avoid writing (another) thesis on prescription lenses, but:
    Yes, the lens in your eye changes shape, and hence focal distance, as the muscles around your cornea tighten or relax. But there are limits to the range of shapes that a given lens/muscle system can reach. Hence we have limits to the range of focal lengths that our eye can adjust to.
    Some (common) things can limit this range in a way that affects our usable vision.

    1. The base, or resting shape of your eye, can be sufficiently far away from "ideal" that even at the extreme end of the muscle movement, your lens still doesn't focus at either the short distances (long sighted) or at long distances (short sighted). In which case, adding a fixed corrective lens will shift the entire range so that it now covers the range you wanted. A short sighted person wearing their glasses will find that their focus at 10 cm is now not as good as before, but they accept that in return for being able to read street signs.
    2. As we age, the lens in our eyes tends to stiffen up. It is no longer as flexible and so it's no longer able to thicken and focus in on close things any more. So the range, rather than being offset, is actually shrinking because the lens has less range of movement. Hence older people tend to go long sighted. They can get focusing lenses for close vision and take them off, or look over them for long distance where their rigid lenses are still OK.
    3. Yes, the muscles in the eyes can stop working so well too.
  39. From the paper:

    Stock ISRIB solution was at 0.1 mg/ml and injections were at 2.5 mg/kg. Each animal received an intraperitoneal injection of 2.5x their body weight.

    So those sentences seem to be saying the same thing in different words, but the second sentence leaves out one detail.

    The number given is 2.5 mg/kg. So that is 2.5x bodyweight, and then divided by a million. I guess that to a pharma scientist that may well be said to be 2.5 x B.W. as shorthand because everyone knows about the factor of a million. Everyone who counts.
    When everyone works with the same units, you tend to make shorthand cuts in the language like that.

    Which is a fairly believable sort of number for a drug. So a 75kg human would get 187.5 mg. Except that you don't just scale linearly from mice to men, there is a whole scaling science that you can read up about on wikipedia.

    Depending on details of the drug pharmakinetics, you get a different amount, but my first guess is that it's about

    0.319 mg/kg or about 24 mg for a 75 kg person.

    Visit the above scaling page to calculate your own dose.

    #I'm not a physician
    #This is not a prescription
    #if you poison yourself don't come and haunt me

  40. Not to say that glasses don't do exactly as you describe, but the *science* behind eyesight is quite surprising. Turns out that eyes focus by changing shape, like a camera lens moving in and out, rather than being *a* shape that needs correcting with glasses. Unless! there are cramps in the eye muscles, caused by the very sort of stress response ISR is. After I get my dose, I'll remember the guy's name. edit William Horatio Bates. I am proof of the theory, but have advantage of PT at same time, so far more likely to succeed in relaxing eye muscles than mere exercises. The colors are incredible compared to my college days, wearing glasses. Eye sees color by vibrating, and cramps stop that.

  41. Interesting historical theory.

    You only need look at modern studies to know your general hypothesis is well supported. Glasses improved the productivity of tea pickers by 21.7% and 31.6% for those over age 50.

    "DOI: 10.1016/S2214-109X(18)30329-2
    Effect of providing near glasses on productivity among rural Indian tea workers with presbyopia (PROSPER): a randomised trial"

  42. "a kind of reversible physiological blockage rather than more permanent degradation" "after it gets throttled by one of these stress responses – a cellular
    quality control mechanism called the integrated stress response (ISR;
    ISRIB stands for ISR InhiBitor)." Just as Janov sez.

  43. I think when it comes to this sort of stuff, our intuition as to what is "likely", "unlikely", "too good to be true" etc. is not a good guide at all.

    After all, after a billion years of bacterial diseases being a matter of "suck it up and rest while your body might get better on its own, or die, who knows?" in a couple of decades it was largely fixed by a bunch of miracle, too-good-to-be-true drugs. Largely fixed is not the same as completely fixed, and there has been some backsliding since, then, but it's still amazing compared to 100 years ago.

    Long ocean voyages, even on fast, well run, latest technology ships, had a death rate we would consider a national disaster. Then vitamin C came along (or at first, "this unknown thing that is in this list of foods") and now scurvy is a historical note.

    Topically, we have gone from "mysterious new disease" to "multiple vaccines approved for use" in under a year. Did anyone really think that was likely?

    On the other hand, we've still got stuff like malaria and cancer where we are still struggling to improve, despite vast fortunes being poured into it, and (cancer especially) imminent cures being promised as long ago as the 1970s.

    It's just complicated, and our intuition is not a good guide.

  44. I'm generally interested in the protocol used in these things; What sort of dose are we looking at?

    In this case I'm a little unclear about that yet. Line 471 in the paper: "Each animal received an intraperitoneal injection of 2.5x their body weight." That sounds pretty brutal, I assume it's a typo.

    The list of positive effects this stuff has reminds me a bit of aspirin. And apparently you don't need to take it on a daily basis. I hate to say it, but it sounds almost too good to be true.

  45. IIRC the story of Limitless is that if a really effective super-IQ drug is found… you won't hear about it.
    It will be too valuable for the few people who get to keep it to themselves.

    All we'll see is a couple of biomedical researchers somehow manage to quietly retire as billionaires. And maybe the trickle of science and tech breakthroughs get's bumped up an order of magnitude.

    My personal historical theory is that we already saw this happen once in history. In the late 1200s when eyeglasses were developed in middleages Italy. In one step, society doubled or tripled the lifetime productivity of every fine smith, scientist, artist, scribe, lawyer, tailor, doctor… anyone who did anything more detailed than making horseshoes or standing there and telling other people what to do. Instead of the most productive period of life being maybe 20 years, from 20 to 40, at which point you started having to give up the fine detail work and move into administration, you instead had another 20 to 40 years of being able to keep doing the advanced work. These days we consider 40 to be about the point where a craftsman or professional starts to be really good, before eyeglasses you were about ready for retirement.
    Hence, middle ages Italy turned into Renaissance Italy within a couple of generations.

    It's not a perfect analogy to a smart drug, because everyone else can see you wearing glasses. They can't be kept secret.

Comments are closed.