| ▲ | A_D_E_P_T 19 hours ago |
| The authors report that restoring NAD+ balance in the brain -- using a compound called P7C3-A20 -- completely reversed Alzheimer's pathology and recovered cognitive function in two different transgenic mouse models (one amyloid-based, one tau-based). The mice had advanced disease before treatment began. Three comments: - You can actually buy the drug here: https://focusbiomolecules.com/p7c3-a20-nampt-activator-prone...
It's a simple small molecule. If this stuff works, expect it to be everywhere within just a couple of years. - There's room for skepticism. As Derek Lowe once wrote: "Alzheimer's therapies have, for the most part, been a cliff over which people push bales of money. There are plenty of good reasons for this: we don't really know what the cause of Alzheimer's is, when you get down to it, and we're the only animal that we know of that gets it. Mouse models of the disease would be extremely useful – you wouldn't even have to know what the problem was to do some sort of phenotypic screen – but the transgenic mice used for these experiments clearly don't recapitulate the human disease. The hope for the last 25 years or so has been that they'd be close enough to get somewhere, but look where we are." > https://www.science.org/content/blog-post/just-how-worthless... - If the drug's mechanism of action has been correctly assigned, it's very plausible that simply supplementing with NMN, NR, or NADH would work equally well. The authors caution against this on, IMO, extremely shaky and unjustified grounds. "Pieper emphasized that current over-the-counter NAD+-precursors have been shown in animal models to raise cellular NAD+ to dangerously high levels that promote cancer." |
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| ▲ | Aurornis 13 hours ago | parent | next [-] |
| > - You can actually buy the drug here: https://focusbiomolecules.com/p7c3-a20-nampt-activator-prone... It's a simple small molecule. If this stuff works, expect it to be everywhere within just a couple of years. There are numerous chemical supply companies that will list chemicals like this “for sale”. They might not have it in stock but they hope they’ll get your search traffic and be able to synthesize it if you place an order. If you look at the amounts, they’re tiny. I don’t know the doses that would be used in humans but typically ordering from chemical supply shops would be economically infeasible for just about any drug. These are meant for one-off studies and experiments, not ongoing human use. There have been a growing number of online groups arranging to do group buys of synthesized experimental drugs based on studies. I’ve followed a few of them and the results range from people losing their money, receiving product that is too contaminated to use, or in some cases they go to great lengths to verify the chemical but then discover it doesn’t do what the original study promised it would do. In some of the more horrifying cases I’ve seen forum posts from people reporting long lasting chest pains from one chemical, and another chemical was sending people into psychosis. So if (when) these chemicals start appearing on group buy sites I suggest ignoring it until more research is done. Making yourself into a lab rat is not a good idea. |
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| ▲ | RobotToaster an hour ago | parent | next [-] | | There have been a growing number of online groups arranging to do group buys of synthesized experimental drugs based on studies... There's also a good number of cases of people getting exactly what they ordered. There's been a thriving market for Retatrutide, ozempic's more powerful younger brother, for years despite it not being approved yet. Also, people with Alzheimer's don't have the luxury of being able to wait 20 years for it to be approved. | |
| ▲ | esperent 7 hours ago | parent | prev | next [-] | | > If you look at the amounts, they’re tiny. I don’t know the doses that would be used in humans but typically ordering from chemical supply shops would be economically infeasible for just about any drug. These are meant for one-off studies and experiments, not ongoing human use I didn't get the impression that the person above was suggesting actually buying it here, but rather just pointing out that if it does prove effective in human trials, it's going to become cheaply and easily available since it's already possible to order online for research. | |
| ▲ | jokowueu 6 hours ago | parent | prev | next [-] | | I was actually researching this yesterday for a groupbuy, the synth is chromatography-free which means gram scale production is possible with much less cost than expected . https://utsouthwestern.elsevierpure.com/en/publications/deve... | |
| ▲ | chasil 13 hours ago | parent | prev [-] | | There appears to be some danger in using NAD+ without the supervision of an experienced physician. "Pieper emphasized that current over-the-counter NAD+-precursors have been shown in animal models to raise cellular NAD+ to dangerously high levels that promote cancer." | | |
| ▲ | digitaltrees 12 hours ago | parent | next [-] | | Most people with Alzheimer’s are older and would probably trade having their cognitive abilities back even with increased risk of cancer | | |
| ▲ | timr 10 hours ago | parent [-] | | Depends entirely on the stage of the disease and the aggressiveness of the cancer! Getting an aggressive brain cancer when you had early stage Alzheimer’s [1] would be tragic. The tradeoff would be years of life. For the record, I have no idea what the actual risk tradeoff is, but the point of regulation is that nobody does. You can’t have informed consent when you can’t be informed. [1] Aside: Alzheimer’s is relatively early stage, as dementias go. It’s frequently diagnosed by onset in younger people. |
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| ▲ | Aurornis 9 hours ago | parent | prev [-] | | The chemical the parent comment linked is different. NAD itself isn’t usually supplemented because it’s broken down by your digestive system. So NAD precursor supplements have been available for a while: NR and NMN specifically. These are the precursors they were talking about. The actual drug used in this study has a different mechanism of action. It’s not directly available as a supplement, but like the parent commenter discovered you could technically find a chemical supply house to synthesize a tiny quantity of it. |
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| ▲ | mmooss 18 hours ago | parent | prev | next [-] |
| > There's room for skepticism. And there's room for thinking there's water in the ocean. We have no idea whether this would work at all or how it would work at all in humans. We have one experiment in mice, which as you say can't have Alzheimer's. This is a nice step, like developments in fusion energy. That's part of research, and let's hope and investigate it, but it's absurd to think about it as anything but a science project right now. |
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| ▲ | reissbaker 14 hours ago | parent | next [-] | | Sadly, it's worse. We don't have one experiment that works in mice: we have dozens, if not hundreds. We've cured "Alzheimer's in mice" many times over. The treatments never work in humans, because it's not the same disease. We don't know the root cause of the human disease and so we can't model it accurately in mice. | | |
| ▲ | esperent 7 hours ago | parent | next [-] | | > We don't know the root cause of the human disease It's increasingly likely that there is no "root cause" to find in humans, but rather, that Alzheimer's is what happens when there's enough external stressors acting on the brain. I've seen an analogy of a leaky roof being used: the leaks are things like age, stress, heavy metals, mold, bad sleep, bad diet. Genetics defines the original building materials (resilience) of the roof. You can put buckets under a certain number of leaks but if there are too many your ability to repair gets overwhelmed and the result is diseases like dementia. I think something similar applies to other diseases of aging like heart disease, arthritis, osteoporosis, diabetes, perhaps even cancer. The downside of this is that's it's hard to imagine a miracle drug being the solution. But the upside is that a combination therapy that identifies the "leaks" and works on reducing or eliminating them will likely be effective against a wide range of age related diseases. The therapy will likely consist of drugs and supplements in combination with lifestyle changes. | |
| ▲ | everdrive 14 hours ago | parent | prev [-] | | I totally get that people are not mice, however animals studies have been useful for all sorts of diseases. Are they really uniquely bad for Alzheimer's? | | |
| ▲ | greygoo222 13 hours ago | parent | next [-] | | To put it simply, mice don't get Alzheimer's. We're not studying mice with Alzheimer's, we're studying mice with an mutation chosen for resembling Alzheimer's. But we don't know whether this model replicates the actual mechanisms of the disease, or if it's superficial. | |
| ▲ | adinb 13 hours ago | parent | prev [-] | | No. I believe the problem is with our artificial models of Alzheimer’s in mice. |
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| ▲ | thisislife2 17 hours ago | parent | prev [-] | | And the author of the paper has disclosed that they have patent on the drug being tested. Let's see if the results can be reproduced by others. Then let's see how it tests with humans. | | |
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| ▲ | scarmig 16 hours ago | parent | prev | next [-] |
| > Pieper emphasized that current over-the-counter NAD+-precursors have been shown in animal models to raise cellular NAD+ to dangerously high levels that promote cancer. As someone who's seen both cancer and Alzheimer's up close, that would be a very easy choice. |
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| ▲ | JumpCrisscross 15 hours ago | parent | next [-] | | > current over-the-counter NAD+-precursors have been shown in animal models to raise cellular NAD+ to dangerously high levels Is this a problem with the molecule or the dose? | |
| ▲ | kingofmen 16 hours ago | parent | prev | next [-] | | Uh... which one? Choice is not obvious to me, and I think it would depend on the type of cancer. | | |
| ▲ | shepardrtc 15 hours ago | parent | next [-] | | From multiple personal experiences, including both of my parents, dementia is a slow, horrible death where you are robbed of your dignity and end up dragging all of your relatives through a very long, very torturous hell. You will be drooling, pissing, and shitting yourself, all while slowly reverting back to a low IQ childhood mentality where you're very likely to have outbursts and verbally or physically attack the people around you. Your loved ones will be tormented, and if you don't have loved ones then if you're lucky you'll be tossed into a room and forgotten about by underpaid, overworked staff at some run-down nursing home. If you're not lucky you'll be laying in a gutter on the street until you die. | | |
| ▲ | PaulHoule 14 hours ago | parent | next [-] | | Interestingly my wife helped a friend whose father had the disease during the pandemic. He had worked as a professor and after retirement had suffered with AD for years but had stayed "independent" because his wife was high functioning mentally but low functioning physically and formed a good team. He'd bought long term care insurance so he had the resources to afford both a room at a care home but also personal help from home aides, including my wife. He didn't really know what was going on most of the time but he never got angry or flustered and was always pleasant to deal with. We had trouble with certain homes having a way they want to do things or requiring things that weren't really necessary, one insisted that he get a pacemaker because he had bradycardia. When he lived with his son between homes probably the most difficult thing was that he got up in the night to use the bathroom and would end up urinating in the wrong place. He got much better care than many residents because people were always coming around to see him and the staff knew that we cared and would advocate for him. He passed away at 92 and outlived many of the people who knew him at work so he had just a small memorial ceremony. I saw it as an example of healthy aging and talked about it a lot with my wife -- and it made me think about myself and my own fear that my ability to compensate for my schizotaxia may degrade when my brain degrades and I can picture myself becoming really nasty and it gives me all the more incentive to rewrite my habits while I still can. | |
| ▲ | Aurornis 14 hours ago | parent | prev [-] | | Sadly, cancer isn’t one singular disease. Types of cancer can be excruciatingly painful for many years, which is also tormenting to everyone around you. I wouldn’t wish either on anyone. |
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| ▲ | ramencentral 16 hours ago | parent | prev | next [-] | | Cancer is better than Alzheimer’s. There is no comparison. I wouldn’t wish Alzheimer’s or dementia on my worst enemy. | |
| ▲ | scarmig 15 hours ago | parent | prev | next [-] | | Cancer. The worst types of it have the advantage of killing quickly. Alzheimer's destroys the self, and you survive a long time with it, leading to much more suffering, both to you (to the extent you continue to exist) and to your family. | | |
| ▲ | deepspace 14 hours ago | parent [-] | | I have a different perspective. The worst types of cancer kill slowly and cause agonizing suffering. Alzheimer's leads to negative outcomes for your caregivers, but by many accounts many affected individuals do not suffer all that much, if at all, due to their lack of awareness. |
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| ▲ | Workaccount2 15 hours ago | parent | prev | next [-] | | Seeing my grandmother go through dementia for 10 years made me incredibly angry that we don't have assisted suicide available for people. People with the emotional and compassionate depth of a child are the ones keeping us from allowing people to die with dignity. | | |
| ▲ | scarmig 15 hours ago | parent | next [-] | | If I were diagnosed with Alzheimer's, I would seek out assisted suicide. But I think it's more complicated than that: its existence incentivizes pushing people toward assisted suicide. The government finds a way to help with bloated medical care budgets; unscrupulous family members guilt trip the sick to choose the option to keep the inheritance intact. The best solution allows it for severe cases, while still investing money in research and spending money for palliative care so it remains an option and not a demand. But that's a tricky line to maintain. | | |
| ▲ | Workaccount2 15 hours ago | parent | next [-] | | My grandmother's case ended up bankrupting my grandfather and seriously straining the rest of the family. Which ultimately put my grandfather in a pennyless position when he was in his 90's, and poor state care when he was declining - not what he or my grandmother worked their entire lives for. Our family couldn't replace what was lost in the years of care for my grandmother's body, long after she herself was gone. Never something she would have wanted, but you don't really have a choice and dignified death is never given as an option. | | | |
| ▲ | tim-tday 11 hours ago | parent | prev [-] | | Not me, I’d hire someone to take really good notes and test all the promising potential treatments one after the other. No need for lengthy approvals or a drug trial if you’re giving it to yourself. I’d want to go out doing some mfing science. |
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| ▲ | snapplebobapple 8 hours ago | parent | prev [-] | | Its the slippery slope proved real by places like my home country of canada keeping other people from having it. I am a huge supporter of assisted suicide but what my country has gone way too far. find a way credibly Keep it to impending death with lots of pain and alzeimers like disease and you would have strong majority acceptance. |
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| ▲ | idiotsecant 16 hours ago | parent | prev [-] | | Cancer times a million |
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| ▲ | tsoukase 14 hours ago | parent | prev [-] | | Except that time of death comes on average many years later for Alzheimer's than cancer. In the same thought, better die from heart attack instantly but unfortunately much earlier, which would be devastating for the relatives. |
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| ▲ | Palomides 18 hours ago | parent | prev | next [-] |
| >expect it to be everywhere within just a couple of years. there are studies about this compound from a decade ago, kinda doubt it's going to be a breakthrough at this point |
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| ▲ | SoftTalker 16 hours ago | parent [-] | | Searching for "P7C3-A20" just now, looks like it's readily available now from multiple sources. | | |
| ▲ | cj 16 hours ago | parent [-] | | Is this the same NAD+ that’s prescribed by longevity / hormone clinics? Edit: after some googling, sounds like NAD+ (which you can get from real doctors) is the “building blocks” similar to how protein is the building blocks for muscle, while the experimental compound changes/enhances how the building blocks are used inside your cells. | | |
| ▲ | andy_ppp 15 hours ago | parent [-] | | So you might need some NAD+ precursor like NMN and this compound for it to work in humans because by the time you’re old it’s much harder for your body to make. Was the experiment done in older mice or younger ones that have NAD+ but artificial Alzheimer’s ? | | |
| ▲ | JumpCrisscross 15 hours ago | parent [-] | | What’s the current state of between NMN, NR and straight-up niacin? | | |
| ▲ | storus 11 hours ago | parent [-] | | NMN and NR are both good but NMN might not be available anymore as some company decided to repurpose it as a drug instead of supplement. Best combo nowadays looks to be liposomal NR with pterostilbene, a sirtuin activator. NR boosts NAD+ (the main electron transporter in mitochondria), pterostilbene activates sirtuin SIRT1 that regulates aging. B2/Riboflavin might be a good idea as well as it is a FADH donor, secondary electron transport carrier especially in nerves/brain. B1 to the mix as every single metabolic reaction needs it and it's depleted by consuming lots of carbs or drinking alcohol, a common western diet. Niacin is less effective in raising NAD+ but the flush can open up veins and flood hard to reach extremities of the body with blood so it's probably good from time to time. Slow B3 seems to be even worse for raising NAD+. | | |
| ▲ | JumpCrisscross 11 hours ago | parent [-] | | > the flush can open up veins and flood hard to reach extremities of the body What does it mean if I don’t flush? Is the supplement a dud? | | |
| ▲ | storus 11 hours ago | parent [-] | | I know of three possible reasons: - your supplement is a dud - you took niacin too often (best to do it once a few days as body adapts quickly) - you have a gene mutation that prevents you from absorbing enough B3 (common in some schizophrenia cases that can be managed by huge doses of daily B3, like 4-10g) | | |
| ▲ | JumpCrisscross 10 hours ago | parent [-] | | > you took niacin too often Oh yeah, I was taking it daily when I stopped flushing. Makes sense. |
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| ▲ | hnlmorg 18 hours ago | parent | prev | next [-] |
| > and we're the only animal that we know of that gets it. Is this actually true? I thought it was pretty common for elderly pets |
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| ▲ | xenospn 17 hours ago | parent [-] | | Elderly pets have loss of cognitive function/memory, but I don't think it's the same disease. | | |
| ▲ | anonym29 17 hours ago | parent [-] | | What's the objective, clearly disambiguated, empirically demonstrable difference between memory loss, dementia, and Alzheimer's? | | |
| ▲ | tsimionescu 16 hours ago | parent [-] | | Alzheimer's is, by definition, dementia with associated amyloid plaques in the brain. Since you can't detect the plaques without cutting into the brain, the diagnosis is normally given based on symptoms of dementia (significant loss of memory or other cognitive functions) without other clear reasons (no evidence of vascular events, head trauma, brain tumors or other neurological diseases etc). | | |
| ▲ | armadsen 15 hours ago | parent | next [-] | | My understanding is that amyloid plaques can actually be seen with a specialized PET scan now, so it can be more definitively diagnosed in living people. | |
| ▲ | anonym29 15 hours ago | parent | prev [-] | | You mentioned amyloid plaques. What about tau tangles? I thought Alzheimer's required both. If someone (or some dog, for that matter) has amyloid plaques but no tau tangles, is that Alzheimer's? If they have tau tangles but no amyloid plaques, what is it? And what about the brains that show amyloid plaques, tau tangles, and Lewy bodies? Or plaques plus vascular lesions? At autopsy, most elderly brains show mixed pathology. Does that person have Alzheimer's plus Lewy body dementia plus vascular dementia? Three diseases? Or one brain failing in multiple correlated ways that we've artificially carved into separate categories? It sounds like we have at least five different pathological markers that correlate with cognitive decline, often co-occurring, with inconsistent symptom mapping. What makes 'Alzheimer's' a disease rather than a region we've named in a high-dimensional space we don't really understand all that well? | | |
| ▲ | tsimionescu 14 hours ago | parent [-] | | > What makes 'Alzheimer's' a disease rather than a region we've named in a high-dimensional space we don't really understand all that well? Nothing. I think it's sometimes in fact called a syndrome, not a disease per se. Since we don't really understand the mechanism of action, it remains more of a diagnosis by exclusion rather than anything else. |
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| ▲ | bossyTeacher 18 hours ago | parent | prev [-] |
| > Pieper emphasized that current over-the-counter NAD+-precursors have been shown in animal models to raise cellular NAD+ to dangerously high levels that promote cancer. Does this mean that people are having to trade Alzheimer in exchange for high risk of cancer? Or does this mean that we need better precursors that don't require that trade off? |
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| ▲ | A_D_E_P_T 18 hours ago | parent | next [-] | | There's no good evidence that supplementation with NMN, NR, etc. increases the risk of cancer in healthy people. There's some speculation that it might be risky for people with cancer to take those supplements, but the picture is far from clear. Some papers even suggest that they can be beneficial. (e.g., https://pmc.ncbi.nlm.nih.gov/articles/PMC10177531/ ) In terms of risk-benefit analysis, if this stuff actually cures Alzheimer's, then even a 10x increased risk of cancer (all types) is acceptable, as Alzheimer's is frequently a fate worse than death whereas cancer can be managed whilst keeping your personality and sanity intact. In reality, the increased risk of cancer from something like NMN is perhaps 1.005x. To all appearances, totally negligible. The problem, for Pieper, is that NMN/NR/NADH are ubiquitous and cost pennies per dose. So, if they work (big if), this new research is unmonetizable. The team leads would win a Nobel Prize, but Big Pharma gigabucks are out of the question. Let's see what happens. | | |
| ▲ | nkmnz 17 hours ago | parent | next [-] | | Could explain how a compound that's already on the market and has been patented for (some) medical use at least once in 2015 (expiring 2035) might make a good case for "Big Pharma gigabucks"? I thought one reason for a lack of research into "repurposablity" of existing small molecule drugs is the fact that new applications cannot be independently patented? | | |
| ▲ | cyberax 16 hours ago | parent [-] | | You absolutely can patent existing drugs. There's a whole scummy pharma industry that takes existing drugs that are widely used off-label and patents that off-label use. | | |
| ▲ | directevolve 15 hours ago | parent | next [-] | | I think it’s worth addressing this with more nuance. Companies can get a METHOD-OF-USE PATENT (MOU) on an old drug for a new INDICATION. This gives them the exclusive right to LABEL AND MARKET that drug for that indication for a period of time. I however, doctors can prescribe and pharmacists can substitute generics for the new indication, regardless of the MOU. For a company to profit off an MOU, they strategically need to create a new FORMULATION. This is a new dose or delivery mechanism (extended release, topical, etc). A new formulation can be protected with conventional patents that go beyond an MOU. With an MOU + patent on a new formulation, the company has a brand where they are the only ones allowed to make the new formulation and the only ones with a product approved to be marketed for the new indication. Getting FDA approval for the new brand is not the main hurdle for the company. To get insurers to pay the premium they want over the cost of existing treatment options, they have to show it’s safer or more effective than those existing options. Otherwise insurance will block it. In principle, this means that repurposing should only enable companies to profitably repurpose off patent off label applications if they can provide a real patient benefit. Whether this is the best or most efficient way to promote this kind of innovation, or whether it works as well in practice as it would seem in theory, is a separate question. | |
| ▲ | nkmnz 11 hours ago | parent | prev | next [-] | | Could you name some examples so that I can read more about this? | |
| ▲ | rockskon 14 hours ago | parent | prev [-] | | You don't patent a use. You're thinking trademark. |
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| ▲ | FooBarWidget 17 hours ago | parent | prev [-] | | Furthermore, we don't even know whether NAD precursor supplementation works. They raise intracellular NAD+ levels, but unclear whether they raise intercellular NAD+, which is what really matters. There are also those that say NAD+ recycling matters more than we think, and precursors don't address that. | | |
| ▲ | JumpCrisscross 15 hours ago | parent [-] | | > raise intracellular NAD+ levels, but unclear whether they raise intercellular NAD+, which is what really matters Why? | | |
| ▲ | FooBarWidget 13 hours ago | parent [-] | | Urgh I made a mistake. I meant the other way around: intracellular matters more, but intercellular is easier to measure. |
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| ▲ | shawnz 18 hours ago | parent | prev | next [-] | | Keep reading: > Pieper emphasized that current over-the-counter NAD+-precursors have been shown in animal models to raise cellular NAD+ to dangerously high levels that promote cancer. The pharmacological approach in this study, however, uses a pharmacologic agent (P7C3-A20) that enables cells to maintain their proper balance of NAD+ under conditions of otherwise overwhelming stress, without elevating NAD+ to supraphysiologic levels. | |
| ▲ | luma 18 hours ago | parent | prev | next [-] | | I think it means one should read the very next sentence: > Pieper emphasized that current over-the-counter NAD+-precursors have been shown in animal models to raise cellular NAD+ to dangerously high levels that promote cancer. The pharmacological approach in this study, however, uses a pharmacologic agent (P7C3-A20) that enables cells to maintain their proper balance of NAD+ under conditions of otherwise overwhelming stress, without elevating NAD+ to supraphysiologic levels. | |
| ▲ | mmooss 18 hours ago | parent | prev | next [-] | | It means we have no idea if this would work or how it would work, and discussing it as a treatment for humans is badly mistaken. | |
| ▲ | juujian 18 hours ago | parent | prev | next [-] | | It's a quality of life vs years left calculation you have to make on a case by case basis. | | |
| ▲ | mmooss 18 hours ago | parent [-] | | You can't make calculations without data, and in this case you have none: we have no idea of the effects on humans. |
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| ▲ | banq 8 hours ago | parent | prev [-] | | [dead] |
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