> "The use of this peptide in patients is a long way away. It requires careful consideration about safety, about the appropriate group of patients for whom this peptide can be beneficial in a reasonable period of time so that positive effects can be easily measured at an affordable cost."
My bet: this drug will be for sale on the internet illegally within a year (and probably fake half of the time). The demand for this exact thing is just too high. It doesn't even matter if it's shown to not work on humans, people will still try it "just in case".
As long as people are aware of the risks and are willing to take the chance, I actually support this.
It doesn't make sense that society doesn't blink an eye when we send our youth off to war to die, but heaven forbid if someone dies in the pursuit of knowledge, everybody goes batshit insane. At least if someone dies taking this stuff, we learn a lot. And if it actually ends up working, it benefits society tremendously.
> At least if someone dies taking this stuff, we learn a lot.
We'd learn a lot more if they were being monitored as they took the stuff, though. And yet it's still considered unethical to run human trials without preceding animal trials, even when the alternative is people off doing those same trials to themselves without your assistance.
We understand this problem in other domains—that's why "safe injection sites" for drug-addicts exist. So why has pharmaceutical research not cottoned on and begun offering "safe self-experimentation sites", complete with medical researchers + monitoring equipment to capture data, and nurses to help with bad reactions?
Safe injection sites don't create a moral hazard: they are a response to a public health and safety crisis that exists whether or not you have them. Your neighborhood drug dealer won't convince anyone to start abusing drugs just because there's a safe injection site nearby.
Charging for any FDA regulated drug or therapeutic (or anything) before marketing approval, however, is a cardinal sin in the pharmaceutical industry because it incentivizes the exact kind of snake oil salesman behavior that the FDA was created to curtail. Gathering any kind of useful data (let alone keeping patients safe) for a few self-experimenters will be extremely expensive so unless this infrastructure is publicly funded, you're just recreating the conditions of the 1800s, except now with entire businesses built on finding gullible people who will try literally anything because... "science". Even if it's publicly funded, it will almost certainly end in disaster.
All it takes is a few desperate parents, a dead autistic kid, and some clickbait for an entire generation to lose trust in our pharmaceutical and healthcare industries. That loss of trust will lead to orders of magnitude more death and suffering than would be prevented by letting desperate people play Russian Roulette with what is essentially a fully loaded gun (that they think is empty).
The first phase of human clinical trials is literally giving a small group of healthy patients under constant supervision a steadily increasing dosage until more than half of them can no longer safely handle it. That's only after a safe dose has been established in animal trials so we're talking about serious complications or death in the single digits percent of cases after tens of millions of dollars have already been spent. Individuals hoping for a positive outcome have a better chance of winning the lottery.
I can think of a number of reasons why this isn't done:
* You can't run a randomized control trial in this fashion, which makes it harder to collect meaningful data.
* You can't select the populations of people who are in your test groups. It's possible the drug will only work well in certain populations.
* You can't monitor people as well for things like adherence or control their other behaviors. Perhaps they are taking 5 other compounds simultaneously which are having an effect or interfering with your compound of interest.
* You can't screen for toxicity or determine dosing meaning the drug could kill people en masse before the ideal dose is determined.
I think it's fine for people to take any compound they want as long as it's an educated decision, but I don't think what you're describing is a great source of data or a good substitute for animal trials.
> You can't run a randomized control trial in this fashion, which makes it harder to collect meaningful data.
You can, it just needs to be organized properly. You sign up for a test of a new drug/nootropic online, you get the pills, but you don't know if they work or not.
Then, you have to report the results.
> * You can't select the populations of people who are in your test groups. It's possible the drug will only work well in certain populations.
First of all, you can. Require filling a questionaire (or even genotyping) before sending the drug. Not only you will be able to analyse the statistics across populations, but you will no longer have problems with many drugs being only tested on white males.
If certain populations are missing from the data, the company could afford the therapy to them for free, or even pay them.
> * You can't monitor people as well for things like adherence or control their other behaviors. Perhaps they are taking 5 other compounds simultaneously which are having an effect or interfering with your compound of interest.
What has a higher chance - experiment subject lying about other meds he's taking, because he wants to get the drug (or money for participation in experiment), or a person who stands nothing to gain or lose from filling in the questionnaire truthfully?
> * You can't screen for toxicity or determine dosing meaning the drug could kill people en masse before the ideal dose is determined.
The idea would be to allow only drugs that passed initial trials to estimate toxicity and safety. But open the drug to public before efficacy is established.
By the way, every single day doctors prescribe drugs with "unproven" efficacy. While every drug had to be proven that it's good for "something", many of them have off-label use, which is currently totally not tracked.
I was prescribed Modafinil for ADHD. It's off-label, and there is some research proving that it helps. I feel it's helping me too.
Unfortunately, I have no way of filling any kind of detailed description of perceived effects, or my history. Nobody offered me an option for participation in double-blind study. There is so much lost potential there.
"The drug gave me a headache and made me feel moody, and increased my cravings for white chocolate and potato crisps."
That's what you're likely to get from self-reporting in that sort of trial. Especially given the scale implied by the interest in an anti-ageing agent, you can expect to gather bazoodles[1] of data, most of which will be absolute garbarge.
Sure, I'd support "self-experimentation sites" where experimental subjects bring their own drugs and get better supervision/instrumentation. Just like self-injection sites let people who already have heroin inject it there but don't provide it on-site.
Volunteering and bringing your own drugs with you is a much stronger signal of intent and capability than just volunteering. You don't need a large cohort to find exceptional effects, negative or positive, so the bias toward stronger filtering seems fine to me. If you're looking for subtler effects, self-selection won't work anyway; you'd need double blinded clinical trials like usual.
Er, the context of this subthread is about people who already do experiment on themselves. People in the "nootropics community." There are a lot of them.
You could try teaching these individuals experimental protocols if you like, but if you enforce them, that means you're the experimenter. You're not allowed to be the experimenter. You just have to hope they're doing something useful. Probably you'd point a lot of automated instrumentation at each room, rather than having any human observers giving anyone (costly) individual attention, because most of the experiments would be too mired in sources of error to tell you much.
But keep in mind that the point wouldn't be to capture subtle things like drug efficacy. The point would be to find out about side-effects that might otherwise not be found, by having people around when they suffer adverse reactions to the drug to help the person not-die, and then being able to pull reports directly from the people who helped the person not-die, to find out (in clear medical terms) what the adverse reaction was.
> Er, the context of this subthread is about people who already do experiment on themselves. People in the "nootropics community." There are a lot of them
They are not "experimenting" on themselves, they are simply engaging in a chemically-mediated attempt at wish fulfillment. There are few, if any, actual experimentation protocols being used and whenever I check out the scene to see if it is any better Instill find a random collection of anecdotes and poorly gathered "data points." I see no baseline data, no blinding or controls, the worst sorts of confirmation bias in data gathering and assessment, and people entering these "experiments" with a random selection of pre-exisiting conditions for which they are attempting self-medication. This is just an exercise in generating noise, not data.
Yes, that is exactly why it was proposed by ~derefr to
> [offer] "safe self-experimentation sites", complete with medical researchers + monitoring equipment to capture data, and nurses to help with bad reactions?
The point is that there would be no useful data captured at such sites beyond 'what is the LD50 of this random shit someone ordered from China?' Such a site would possibly increase safety for individuals, but not much else.
I've read my share of gwern reviews, and he does double-blind testing on himself and all, but there's an obvious bias that all the tests are done on gwern. Similarly, if you let people submit their own data you're still only getting data from those people, and in this case it wouldn't even be blinded.
A real experiment has access to much better populations, tendency of psych experiments to be done on psych students aside.
It doesn't make sense that society doesn't blink an eye when we send our youth off to war to die, but heaven forbid if someone dies in the pursuit of knowledge, everybody goes batshit insane.
That's a great soundbite, but it rather ignores the long and continuing history of exploitation via the sales of snake-oil cures and "enhancements". I absolutely have problems with the existing pharmaceutical industry and the economics around that. But it's foolishness to fail to understand how we got here: countless centuries of people peddling fake cures (and even outright poison) to people in need.
Likewise, it's mostly really hard to do actual, legitimate human-studies science that has a solid chance of advancing human knowledge. Thus the presence of things like experiment design as a discipline, ethics review committees around studies on human subjects, etc. This article specifically mentions that human studies are in the works, by teams that presumably conduct them in ways that are 1) ethical and 2) have a hope in hell of yielding useful long-term knowledge. OTOH, I have about zero confidence that random internet self-experimenting yahoos will produce any knowledge ROI on their risk investment.
I agree with you. I also think that the current balance of pharmaceutical regulation and ways to circumvent it is pretty good. I wouldn't want anyone to be able to hawk novel drugs to the general public without full FDA approved clinical testing. But if there is a self-selected population of risk-tolerant, educated, affluent people who want to experiment on themselves using concepts from scientific papers and manufacturing from contract labs... I wish them all the best of luck, and I look forward to any exceptional results (beneficial or harmful).
>> At least if someone dies taking this stuff, we learn a lot.
The expectation of course is that someone else will die. From my experience, very few people [edit: who know what they're doing] are willing to actually kill themselves for science, or, say, endanger their children on the off chance it would "benefit society tremendously".
That's just not morally tenable, if I may be so bold. If there is some sort of benefit to be had, society will benefit in the long run and it doesn't make any difference if the benefits come right now or in a couple of generations. Dropping safety procedures is only ever going to benefit individuals- and probably not the ones who willingly (and foolishly) step up to be human guniea pigs for unregulated "trials".
I support the notion that the government shouldn't control what we put into our bodies, but the counter is the burden to society because of the medical costs.
I'd bet insurance companies would fight hard to reject coverage for anyone who publicly takes a non-FDA drug. If society supported the use of them, then they'd also have to support the aftermath, just like veterans.
There are going to be side effects and probably severe ones. We just don't know them yet. Most newly invented drugs of various types never get approved because of either side effects or they are not actually effective in humans.
Agreed... And its not just war but all the stuff that has proven to be bad for your health like tobacco, liquor, sugar etc is available for people to use at their own discretion, why not something that might actually help in the long run.
There is an overwhelming chance that a drug based on this will never see the light of day, and not just because medical professionals by and large hate the very idea of life extension, although they do. It's an unspecified peptide that purportedly triggers apoptosis in senescent cells to make room for new ones. There are places in the body where you absolutely do not want this, most importantly: nerve cells. If you trigger apoptosis in senescent nerve cells, they're just gone (with very few exceptions). You might have a shiny coat, but you'll be vegetative.
Also, this effect has not even been reproduced, and they seem to be playing their cards very close to the chest, which is almost always a massive warning sign. Even the researchers themselves don't seem overly sure they're seeing a statistically significant effect, citing it works on some mice and not on others.
on the other hand, kudos to the researchers not joining the hype train - it might be their best interest to 'hype up' their research, but they stood fast to their honesty
Or you could try navitoclax, dasatinib, fisetin, piperlongumine, or any of the others tested so far in animal models and human cancer trials with well-understood pharmacology and that are easily purchased.
The trick here is that the current state of assays for senescent cell presence in samples is pretty terrible if you're outside a lab, and there is little point in doing this without measuring the outcome.
Because chemical analysis is a solved problem, peptide synthesis is commercially trivial, and black market sellers live and die by their reputation.
Additionally, grey-market supply is guaranteed to be real, because anyone can sell it for nonpatented use cases and there will be a huge demand by researchers for it, as biochemists don't often do their own peptide synthesis.
It's also filled with a lot of garbage. How many people are going to be able to verify that the "modified FOXO4-p53 interfering peptide filled brownies" they got from Silk Road are genuine? The effect isn't going to be immediate, and the placebo effect alone might make it seem as if it works.
Probably the same way they verify their drugs potency. There are a lot of 3rd parties in these market places that provide services such as chemical analysis of vendors products and make these results available. In fact, it goes as far as the very vendors selling the drugs pay to have their goods independently verified and issued with a "certificate" of how good their quality is which they display on the product listing.
These black markets or silk roads are not just a bunch of drug swinging deviants. A lot of the processes are very well thought out. As someone already mentioned their business relies heavily on their reputation so they tend to take care of it quite closely.
> There are a lot of 3rd parties in these market places that provide services such as chemical analysis of vendors products and make these results available. In fact, it goes as far as the very vendors selling the drugs pay to have their goods independently verified
Who verifies the "independence" of the "3rd parties" and/or the reliability or honesty of their results?
> As someone already mentioned their business relies heavily on their reputation so they tend to take care of it quite closely.
Reputation is important to any business. Hence the practice of dishonest/insincere/bought and paid for reviews or endorsements.
With these sorts of things you have no idea how to tell a real from a fake. Which is why even the supplements on Walmart's shelves are often altered. Nobody knows if the drug they get is real or is a gelcap filled with flour.
"He tested it on mice that were just old (the equivalent of 90 in mouse years), those genetically programmed to age very rapidly and those aged by chemotherapy."
Great! Too many results have been previously reported just in genetically modified mice that weren't aging normally in the first place.
Many of the current methods of killing senescent cells hinge on apoptosis in some way.
UNITY Biotechnology: using repurposed chemotherapeutic drugs like navitoclax to selectively drive senescent cells into apoptosis by suppressing on the mechanisms that prevents that fate. They also have antibodies and immunotherapies in their backlog of patents, but if they haven't got it to work by now, not likely to be a direction they take in favor of the drugs.
Oisin Biotechnologies: programmed gene therapy that assesses p16 levels in the cell and then induces caspase expression and apoptosis if it looks senescent.
SIWA Therapeutics: monoclonal antibodies.
Everon Biosciences: small molecule drugs and related immunotherapies.
There is a lot of money sloshing into the field of senescent cell clearance at the moment, and given that the target market is ultimately every adult human for a treatment undertaken every few years, I think there is plenty of room for more players.
I'm not clear on exactly what happens once the senescent cells are cleared.
Can an elderly body body replace these cells on its own, or would senescent cell clearing generally need to be paired with a stem-cell replacement protocol of some kind?
Yes, the cells can be replaced. In old people, with their declining stem cell populations, that replacement will be slower and less effective. So give them lower doses over longer periods of time.
Stem cell replacement is something that should be developed for use in old people anyway; the more of that going on the better.
We'll find out in the next 12-24 months. UNITY is starting trials this year, and Oisin won't be too far behind.
If they don't work in humans it will be a great surprise given the science to date - an unlikely outcome. The open question is the degree to which specific diseases are rolled back and life extended, given that this is only one of a number of mechanisms causing aging.
In theory, yes. But that depends on how many healthy cells or stem cells that change to replace them there are. It's a big complex problem really that I think people understate. It's part of why we heal so well up to a certain point in our lives (the ability to remove and kill off faulty or old cells). This wouldn't be a fountain of youth but more like a fountain of "not needing a nurse to wipe your ass when you're 95."
I may be misremembering, but I think senescence is often induced as a response to damage -- a protective measure, since damaged cells are liable to become cancerous if allowed to continue to divide.
As for why the cells become senescent rather than merely dying -- well, even senescent cells retain some function. If damaged cells died rather than becoming senescent, it would presumably result in more deaths in situations where a large number of cells are damaged.
It may be that a drug which kills senescent cells results in a decrease in chronic disability but an increase in deaths... an interesting trade-off!
Well, all cells convert oxygen and sugar into energy, including old cells and cancer cells.
Like you said, cellular senescence is a trade-off -- the body doesn't want these damaged cells to keep dividing per se, yet they are still useful for continuing to covert sugar and oxygen into energy to use as needed.
We do have a mechanism for getting rid of damaged cells in general: autophagy. However, autophagy seems to be mostly triggered when there is an energy deficit, for instance during fasting or during intense exercise.
This is probably why fasting and exercise are proven over and over to be beneficial to health, they essentially trigger a "cleaning cycle" of cellular autophagy within the body. I'm not sure autophagy typically includes senescent cells, my understanding is that it's primarily targeted towards cells that have damaged mitochondria.
Even if autophagy eats cells randomly, it will reduce the proportion of senescent cells, since the removed cells will eventually be replaced by newly divided (and non-senescent) cells.
Lots of people wonder that, from science fiction authors to sociologists to random yahoos on HN.
We've got some historical modelling available - as life expectancy has increased family sizes have dropped accordingly. Maybe we'll have entire villages with a couple communally raised children every decade.
Could this be the first "real" result in anti-aging? It sounds plausible but we can only hope...I've been expecting something like this at any time for the last ten years at least. There must be at least a little bit of low-hanging fruit in this area!!
Wikipedia has quite a bit of information about p53. [1] It seems to have an important role as a suppressor for cancer. So maybe the comment was referring to that, you probably don't want to mess that up.
When apoptosis fails, it's might be because p53 binds to foxo4 and gets stuck in the nucleus which prevents the p53 from getting to the mitochondria. In the experiment p53 in the paper, p53 unbound from foxo4 in the nuclease and bound to foxo4-dri and successfully flowed down the mitochondria so apoptosis could occur.
The point of my answer was to imply that no-one knows the outcomes or if it's safe for humans. After it's been tested in humans for safety I'd give it a go for sure. I suppose if you are 90 it's worth a punt ;-)
There's quite a few societies where old people live great active lives up until the day they die and take care of themselves. They're healthier. So shouldn't we try to be healthier and less reliant on the young people too?
Granted stronger social bonds has often been linked to better health so maybe a bit more relying on each other is a good thing.
This is a good question, I don't have a tidy answer, it just feels like that is the way of things, born, grow old and die, if we change the die bit I do feel like something is lost, if I could freeze time, no more births, no more deaths, would I, no, I don't think so, and we are still evolving, so perhaps that is a good reason to let things run their 'natural' course?
This line of thinking comes up a lot in longevity discussion. Pretty much all medicine is "unnatural" and extending life. People evolve all the time even while being alive, we change our opinions on things, we learn things, and we make impact on our surroundings. Usually the question of social progress comes up, but there are still quite a lot of people alive today who dealt with segregation in schools, it wasn't just the deaths of people with those beliefs that moved that progress forward. I could even argue that the fact that people have to focus so hard on survival is slowing down a lot of progress.
I'd also argue that a lot of the reasons people think death is "necessary" are actually symptoms of senescence. Decreased neuroplasticity, for example, is likely one of the reasons that old people tend to get "stuck in their ways" and are unwilling to accept new ideas. Clearly, part of solving the aging problem involves solving that too.
A lot of anti-immortality arguments reduce to this problem. Folks who advocate ending aging do not want us to just live forever as progressively more decrepit and cranky old codgers. The point is not to keep you at 90. It's to keep you at 25 (and put you back there if necessary).
Even in the off chance that this is a path to reversing aging, there is no way of knowing what the impact would be. Looking at cumulative the trends over the past decades overall life expectancy increased while disabled life expectancy has dropped. So if this has impact, and if that impact is typical, there would be less young people needed to care for the people whose aging was "reversed".
Older people can care for themselves, if they are physiologically more able again. I'd happily work 20 years more if I also got another 20 years of able-bodied life.
My bet: this drug will be for sale on the internet illegally within a year (and probably fake half of the time). The demand for this exact thing is just too high. It doesn't even matter if it's shown to not work on humans, people will still try it "just in case".