Phase 0: exploration of effectiveness
Phase I: is the treatment safe?
Phase II: does the treatment work?
Phase III: is the treatment better than existing alternatives?
Phase IV: After approval, monitor the long term effects of the treatment.
Phase I: Will this treatment immediately kill people?
Phase II: Does this methodology seem like the right methodology to show some sort of result in larger trials?
Phase III: Does the treatment work better than some type of placebo for at least a few weeks without causing obvious and unjustifiable harms during those few weeks.
Phase IV: Let's shift our marketing budget into R&D so that we can claim to be unprofitable to congress.
Yeah but they (usually) don't have to be tested against the existing standard of care, or tested longer than a few weeks. So really it's misleading to claim that Phase III trials guarantee anything other than the extremely minimal standard of safety and efficacy that they actually guarantee.
"A research study in which one or more human subjects are prospectively assigned to one or more interventions (which may include placebo or other control) to evaluate the effects of those interventions on health-related biomedical or behavioral outcomes."
A phase 1 clinical trial is used to determine safety (including dosage) and involves far fewer people than a stage III clinical trial.
For Biotech startups, the companies value usually increases with each successfully completed trial. Conversely, the cost of conducting a trail also increases at each stage.
The book Lifespan by Dr David Sinclair is really interesting. Sinclair is a professor at Harvard. He's highly optimistic that something will come of the various ideas looking at slowing aging.
This fallacy that the only way to fix the world is to make kids of your own that will make it better is ridiculous.
I imagine people with access to anti aging therapies would postpone having children further and further.
Today's real world requires you to practice before saying "I know kung fu".
I'm seriously considering it in a few years after it has more time to be proven safe enough.
For now I'm planning to measure DNA methylation in my body to understand the reason for my chronic illnesses better. I already got my DNA sequenced, but now that methylation can be measured cheaply as well, I don't see a reason why not to.
If you have any ready-researched and outlined sources or links for this, please post them here for reference. I know that we all can google, but I think linking here will help a lot of people, me included. HN articles are sometimes used as an online notepad of sorts, a repository of well researched and compiled information with built-in peer review from (hopefully, since they are on HN) somewhat competent even if amateur internet researchers.
That being said, if you have reason to believe that the knowledge will help, or are just curious, feel free
I already found multiple papers published in the last few years that identified the important locations with methylation changes, and those targets map to known illneses.
I tried to go to many doctors, but as they couldn’t measure any important changes with their toolboxes, they all sent me to psychologists.
Thanks for offering help, I’m always interested in learning more about genomics, though right now my plan is to learn by reproducing some articles that I read that contain methylation data sets (after the Harvard course).
A lot of genuine promising research in animals, but you also have this animal cancer model that suggests at least a little caution...
In hindsight doctors say that might have been what triggered my chronic auto immune hepatitis (immune system attacks my own liver). They say basically they don't know and will probably never know, but it has been put forth as a possible trigger.
Are they just quantifying how many methyl groups are attached to a piece of DNA? Methylation is a mechanism for site-specific in/activation, so I'm unclear (and curious) how this would be useful.
This also means that it may be the most important thing to learn to manipulate to defeat aging.
Also it's the cause of many non-genetic chronic diseases that come with age.
In summary it's a really really important thing to study.
There are other hallmarks of aging though:
I'm guessing I'll wait 20 years until they are off patent?
(Assuming they actually work. I'm skeptical.)
(Not doing what you actually want to.)
Others mentioned include HGH, which has been around for decades. Only problem there is that it's a controlled substance so getting a prescription for anti-aging purposes may be difficult.
And I second the NMN being expensive. I use about 800mg a day and it is by far the most expensive thing I take.
So if you supplement with HGH for years or even months, your body stops making it and the ability to produce more may take a very long time to come back. It may never come back.
Also, there are many types of tumors that have HGH receptors, and HGH has an even bigger impact on the tumor than it does on the rest of your body. So you're basically supercharging your cancer.
I remember a professor in law school saying that during the big tobacco trials, someone mentioned that people dying younger from smoking meant lower healthcare costs overall, because the major predictor of healthcare costs is age. Basically everyone dies, and the older you are when you die, the more expensive it will be.
Obviously that's not a good reason to die early, but preventative care is mostly good for quality of life, rather than from a financial perspective.
something like "You gave $50 a month for 20 yrs to unlock the treatment, but now it costs $10000 and you cannot afford that? Too bad."
You will die. And you ain't ready for it. But Mother nature is.
And no, it is not hopeless or futile. There are animals that live 300 years, what basic biology class did you miss in order for you to think that it would be futile to modify humans which are biological machines with genetic programming to make them live at least that long?
you can age gracefully or you can age terribly. there are many things entirely in your control that can shift you one way or the other.
there's dozens of studies that show very strong correlation between calorie restriction and longevity.
Remember, it's not only about lengthening the lifespan, but healthspan.
You shouldn't look at doing anything else until you've at minimum mastered all of the listed items above. Nothing else will have as much outsized impact.
We are discussing drugs(or other systemic measures or therapies) that make people younger. The only thing that you can manage to do if you do all those things you listed perfectly is to come close to your theoretical maximum lifespan that is already preset in your biology/genetics. What we are trying to do with these drugs is to increase that biological span, the base span that you are currently always limited at, regardless of how many broccoli you eat or how many steps you make each day. Those are not the same endeavors, they don't work in the same way (although sometimes they will overlap of course).
Please see this quote from Aubrey de Grey: https://www.youtube.com/watch?v=fPyObli0ezA
It is not enough to just recommend people to have a good lifestyle. That is a plus, but that will not get humanity to regular 100+ of healthy life years. We need actual new biological or genetic technology to do this.
Increasing lifespan more than that requires an entirely new paradigm or class of therapeutics. Like you said, we'll need entirely new biological/genetic technology to address the system-wide mutation and degradation of the body that inevitably occurs through the progression of time. That requires going into the realm of biotech/nanotechnology/etc. which as of now, we are still very far away from being able to produce. It will require many more years of basic research in a plethora of different fields before we can even begin to think about it in fact. Your best bet if you want to make it all the way to then is to follow the steps listed above.
Lots of drugs do things that your body is not capable of, and many drugs augment the way your body works in a way that is not possible without an external compound.
I can’t quite see how drugs which modulate existing biochemical pathways can stop, let alone reverse the processes I’ve named.
I'm honestly mystified why this would be a mystery. Your cells have the blueprint to grow a whole new body, but clearly many of these pathways are dormant. Is it really so far fetched that a drug could reactivate some of these pathways?
Like, why is there a loss of hair in the ear when for the first few years of life, that hair grows instead of dies? There is even evidence that age reversal can and has been done:
DNA is not enough. There was coordination in time and space to construct the body during development, and the growing body has no damaged cells and structures to deal with.
Also, the cornea does heal from some damage, so clearly it's not just passive tissue.
You have to engineer new machinery to replace/repair the failing processes for any chance at real longevity. The kind of things that will be capable of doing something like that will be extraordinarily complex, and to compare the drugs we have available today is akin to comparing an abacus to a modern supercomputer.
Why do you do that? Why would you think it is correct?
To my knowledge that's a wrong interpretation.
Yes there is constant continuous damage to DNA and cells etc. But the body has mechanisms to repair that damage. It is the repairment that slows down during aging, and that is programmed by genetic and biological processes, like everything else in the body. Biologically, a cell can keep reproducing over and over again, it is no problem.
Similarly, you can reverse other negative effects with other drugs. One thing at a time.
That's exactly what the drugs being discussed in this thread purportedly do. For instance, NMN allegedly repairs epigenetic factors that repair DNA damage, but which degrade as we age.
Oh then I guess the body is perfectly capable of having lucid trips for hours like users report from a simple little molecule such as LSD. Good to know. /s
Yes, but the problem is this is such a broad brush stroke.
For example, most people who are chronically stressed will generally never be able to obtain relief. There is a common joke about abs being made in the kitchen not in the weight room, and another one about not being able to outrun a poor diet. The truth is the best diet in the world, cardio and strength training will never overcome the damaging effects of cortisol as a result of chronic stress.
The same for proper sleep. Its not just about 6-8 hours, its about quality. If you aren't getting quality sleep, most people don't have a solution. Then when they look for solutions its generally a bombardment of sleep products (from beds, to pillows, to supplements) that are backed by million/billion dollar companies that are targeting you when you perform a search for information/help.
As to intermittent fasting, that has become a major fad since the Nobel Prize for Autophagy (with the most popular implementation being a 8/16 time restricted eating "fast"). In other words the goal is to trigger the body to begin consuming/recycling dead cells and other cellular waste; however, this typically isn't triggered by time restricted eating, but requires longer periods of fasting (usually kicking in around after 20-24 hours of fasting).
Finally "a complete diet", not only is there no general consensus what that is, you generally can't even have a conversation about diet without triggering a flame war. It doesn't matter if you are WFPB, keto, vegan, vegetarian, paleo, carnivore...not only will people oppose your diet, they will aggressively attack it. I remember I once mentioned "detoxing" and couldn't believe people referring to it as voodoo, and telling me there is no such thing as detoxing the body, but then when I ask them what the function of the liver and kidneys are, and they had no idea.
I can't comment on how long it takes to achieve autophagy - I am happy to stipulate that you are correct.
However, digestion is a very all-encompassing, rigorous and expensive activity for your body. If we believe that there are more "cleanup" mechanisms than just autophagy, it's not much of a reach to suggest that we engage in extra digestion at the expense of these maintenance tasks.
Make no mistake I think there are potential benefits to IF fasting such as these. For most people yes it will let their digestive system rest and even potentially reduce the overall intake of calories. Again it is all potential though, obviously not everyone needs to do IF to restrict calories if that is their goal, and there are ways to consume calories while simultaneously not digesting solid foods (that are typically outside the accepted scope of IF or fasting).
My point is the reason IF became a phenomena so widely discussed and implemented (edit: for increasing life span/expectancy) is directly related to the Nobel Prize in 2016; however, that work is related to autogaphy and fasting, not IF and IF related benefits. Edit:
There's always OMAD (one meal a day). I generally fast 23 hours out of every 24. I rarely think about my next meal until I get home from work and it's time to cook something.
Also, how did you go about detoxing, in your case?
This really stood out to me. If this is how you feel, I strongly recommend trying out meditation. I at one point in my studies while in college felt the same, and it really is night versus day in being able to experience a life without constant stress/anxiety.
> The same for proper sleep. Its not just about 6-8 hours, its about quality. If you aren't getting quality sleep, most people don't have a solution.
Stress/anxiety from above is generally the most common cause of poor sleep. Fixing that will give quality sleep for the majority of people. The next thing to try is to check with your doctor whether you have sleep apnea as that's probably the second most common trigger. For some, sleep apnea is treatable with better sleeping posture and for others it will require more active work to resolve. A note that obesity is the most common cause of sleep apnea. The third most common cause is likely some kind of thyroid condition. More than that is probably going to be a case by case basis where you'll have to individually look at your genetic profile through something like SNPedia (https://www.snpedia.com/index.php/SNPedia) to try and pinpoint your underlying issue. Usually though, the first three things will cover the vast majority of people looking for better sleep.
> In other words the goal is to trigger the body to begin consuming/recycling dead cells and other cellular waste; however, this typically isn't triggered by time restricted eating, but requires longer periods of fasting (usually kicking in around after 20-24 hours of fasting
For most normal people, it's unrealistic to be able to do day fasts. That's why the 8/16 method is so popular. You'll still see benefits as you are incorrect that, there has to be a strict limit of precisely 20 hours to get beneficial effects. Autophagy like any other biological process in the body is a series of continuous interlinking upregulating and downregulating mechanisms that ensure homeostasis. Autophagy is always happening. It's just that the longer you fast, the more your body gets tilted towards consuming/recycling until of course you end up in starvation which is effectively just extreme autophagy.
> Finally "a complete diet", not only is there no general consensus what that is, you generally can't even have a conversation about diet without triggering a flame war.
A complete diet to the best of our knowledge, consists of getting enough macronutrients like protein, lipids, and carbohydrates in addition to an immense number of different micronutrients that while seemingly daunting in size are actually relatively easy to get enough of as long as you eat a diverse mixture of different foods. If that answer doesn't satisfy you, there have been many different studies and current ongoing ones as well to try and pinpoint all the essential trace nutrients the human body needs to survive. From the ones that we've been able to gather over the years, if you were to solely supplement yourself based on those listed, you'd probably be fine. Though it's likely that there would be some things missing.
I run about 7-10 miles a day and mediate, and no I am not talking about me, I am talking about the effects of cortisol and chronic stress generally. And not to take away from the stress you felt in your studies, as I say stress is cortisol and the effects are the same no matter the trigger, but in the scheme of life stress in studies is very low. Consider people who have been through traumatic events war, rape, homelessness, kidnappings, murder of a loved one, the death of a child, etc... ]
>You'll still see benefits as you are incorrect that, there has to be a strict limit of precisely 20 hours to get beneficial effects.
I never said there are no beneficial effects of IF, caloric restriction is good for most people and IF helps that. However, I think you should read the actual Nobel Prize winner's papers and research before you say I am incorrect, or consider you are saying the Nobel Prize winner is incorrect, because I was quoting him.
>It's just that the longer you fast, the more your body gets tilted towards consuming/recycling until of course you end up in starvation.
No autophagy has a peak and it is far short of dying of starvation. Again read the work.
For example, looking at some of the most common "life-extending / anti-aging" supplements people use which might hold promise of clinical efficacy:
[melatonin] -> proper sleep (usually there's an underlying issue of anxiety, stress, bad posture, sleep apnea, etc. that's being supplemented here)
[an innumerable count of different micronutrients] -> complete diet (those that see the most benefits are people that have deficiencies in those areas whether due to poor diet or genetic mutations from birth that lower efficiency of production but perhaps aren't so noticeable that they result in life threatening effects)
[metformin] -> intermittent fasting (which really ends up being the process of autophagy that you want to occur)
Personally, I think a vegetarian diet strikes a better balance that's also more sustainable in the long term, assuming that you also do care about maximizing life span as well.
That, however, doesn't preclude meat being beneficial as well. It's not an analog one is better than the other, and it doesn't mean you can't build a complete diet being vegan either. It's possible, in fact, to build a complete diet eating meat only as well if you really wanted to. Generally though, it's far more difficult, and you have to be pretty meticulous about what you eat in addition to probably having to supplement additional micronutrients into your diet to do so.
B12 you can get from a pill. The same stuff they inject into beef. 
So if you skip eating red meat, you can avoid the toxins from cooking, such as HCA and PAH , the exogenous cholesterol, atherosclerotic carnitine , hormones, etc. I think that's a better way to get B12.
If you feed cows corn all day every day, yes they need B12 injections. I buy beef from a local butcher and the beef comes from our local farm of pasture-raised cows. It's more expensive but because of this it limits my beef intake to a few times a month.
Everything is toxic in inappropriate doses.
Also, given enough time, I ought to be able to amass a self-sustaining pile of wealth and then I can retire :)
I think withdrawing 3% a year would have lasted you the entire time since the 1880s (last 140 years of the stock market)
Would be nice to be able to select only those drugs seeking broad spectrum approval based on specific aging biomarkers.
> Thus any approvals would require having a particular condition to get a prescription (or an unethical doctor), and this aren't immediately useful.
So if I sell a drug approved for blood pressure, I can never say it may improve longevity. If there are papers out there claiming good effects on longevity I as a vendor have to be very careful to never make a public claim about that.
However, if you as a physician have read the papers you can prescribe the drug for other uses based on your personal expertise. This is known as off-label (i.e. for a use not covered by the indications for use), and is very common. There are limits of course, but at the end of the day the limits are based on professional conduct/ malpractice - not the FDA. The FDA explicitly does not regulate the practice of medicine.
Note that this doesn't just apply to somewhat speculative uses. For example a significant amount of pediatric care is done off-label, because setting up the clinical trials for pediatric indications is a pain. This may only be a dose change, for example, but is very common.
That's the whole issue with this list: none of these trials are testing the anti-aging hypothesis - it's just mentioning particular pathways -like Wnt (a core development program and implicated in many, many aspects of human health) and saying that the drug would be anti-aging.
As for "unethical" - well, yes, the person would be unethical since they would likely being prescribing a drug for no reason, with no basis, based solely on misguided patient belief. This is more likely to endanger the patient than it is to help. Thus, unethical.
Of course not, but I didn't suggest that at all. In clinical practice they do this quite routinely if there is scientific evidence of efficacy; i.e. there are a number of papers and talks discussing why and how it works. There is a spectrum of course, from "huh, that's an interesting idea" to "came up in training as part of maintaining my board certification". I'm guessing most non-research clinicial staff will be well towards the later category before starting to use something off label. Many probably wait until they know other clinicians are using it - they also talk to each other a lot (hence KOL impact can be huge, here).
How do these papers come to exist? Not through FDA trials. The scientists involved aren't going to jump into a human trial based on nothing but a hunch, but if there is a reasonable hypothesis about it someone will try preclinical work etc. And if all of that looks good eventually someone will report results in humans used off label.
The point is this is a completely different pathway than an FDA clinical trial. I agree with you completely that premature clinical use of a drug would be unethical . However, it is just wrong to suggest that the typical or only ethical path for this goes through an FDA PMA.
You seem to be objecting to something that is a very common part of the development of modern medicine, as if it is obviously wrong. It certainly has interesting questions around it, but seems to be a reasonable compromise between stifling innovation/development and enhanced risk to public/patients.
I'll note I don't have an opinion on whether or not any of this has been done for longevity applications to the point that a clinician could reasonably use it off label; I don't know enough about it. But it is certainly plausible that they could reach that standard at some point, without any of the vendors having it as an indication (at least initially, if it worked they would almost certainly pursue the indication in this particular case, unlike some).
 this use tends to be very much scaled to impact and prognosis anyway - so the longevity stuff specifically, would have a pretty high bar to meet.
Re-use of existing drugs is one of the most parsimonious methods.
Wrong on both counts.
Let me introduce you to indian online pharmacies, where you can get mostly anything already. I get my eyedrops from less than the US deductible, delivered at my door. I have a prescription, but they didn't even check.
Even better: some molecules are on any restricted list, and thus legal to buy. IIRC, mk667 is very popular for weightlifters.
So I think everybody will be able to get their hands on these as soon as their efficiency is proved.
summary: there are extralegal, cheap, and convenient methods of collecting supplements/drugs that will be available to everyone with a credit card and the right risk tolerance, regardless of e.g. FDA approval.