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Progress of anti-aging therapies by clinical trial stage (lifespan.io)
262 points by apsec112 82 days ago | hide | past | web | favorite | 146 comments



Quick summary of the meaning of Phases in medical trials:

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.


More like:

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.


This is a super pessimistic and misleading description of phase 2 & 3 trials; actual efficacious drugs do come out of the FDA review process. Many phase 3 trials are against standard of care rather than placebo and many are longer than a few weeks, particularly for treatments where efficacy is hard to prove.


> Many phase 3 trials are against standard of care rather than placebo and many are longer than a few weeks

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.


Or take a long time to prove such as against cancer.


Just to be clear, which of these phases is the "clinical trials" stage? Are all of them clinical trails and we're starting at zero now? (Not that Roman numerals have zero, by the way :).) The dictionary says clinical trials are about "safety and effectiveness" so I guess that is indeed early phases?


NIH Definition of a Clinical Trial:

"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.


I may be wrong, but I think they are all different forms of clinical trials.


Phase I is more “what is the highest dose that can be given safely?”


I think also w/ increasing phase, the n sample size of the trial increases so the fisherian statistic has more "power" and more practitioners trust the study results...


There is a real possibility that in the next few decades some of these therapies might work.

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.

https://www.amazon.com/Lifespan-Why-Age_and-Dont-Have/dp/150...


There's a real possibility that some of those therapies might work in the next 6.5 years, as per Greg Bailey @ Juvenescence.

https://www.forbes.com/sites/robinseatonjefferson/2019/08/26...



So when it happens, will we stop having kids? Because our current population and lifestyle do not seem sustainable. I only see population increasing and lifestyle being more burdensome on environment.


Ironically, if people that care about the planet don’t have kids to save the planet, you will be left with more people that don’t care about the planet down the road


I don't know about you, but some of my teachers and favorite musicians had far more of an impact on my attitudes toward the environment and having children than my parents ever did.

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 don't have interest in having kids. But I guess that if I was facing immortality or the prospect of reaching twice my age I would be even less interested on having kids.

I imagine people with access to anti aging therapies would postpone having children further and further.


Just let immortal people have no more than one kid. That way the population (of immortals) can double at most.


Then non-immortals can have as many immortal kids as they want, so immortals can still increase without bound.


maybe immortal people care even more about the longterm well being of climate / ecosystem?


I already did!


population will plateau


One can only hope that it wont be yet another hyper inflated bubble like ai is now.


Ai is hardly hyper inflated. Everything from your phone to cars to planes use ai and machine learning one way or the other.


But it's not actually AI, it's just programmable probability.


Which is what modern AI is - neat linear algebra that can perform certain tasks that are commonly associated with human cognition.


How and when did this become the definition of AI? I feel like we techies lost an important distinction by simply accepting the marketing appropriation of the term. What do we now call real AI?


It was that way from very beginning. It's Artificial _Intelligence_ , not an Artificial Human.


So is your brain. But it's not even yet programmable.


The brain is not programmable?


It really depends on your definition of programmable, I can see how it could be argued both ways.


It's only programmable in the Matrix movie.

Today's real world requires you to practice before saying "I know kung fu".


This is a simplistic, incorrect view of biology.


Well, we happen to call that AI nowadays.


While I'm taking NMN, as it's proven to be safe, I know that HGH + DHEA is the only drug from the list that has already proven to make healthy people younger.

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.


> I know that HGH + DHEA is the only drug from the list that has already proven to make healthy people younger.

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.


My guess is he is referring to this paper, which made headlines a few months ago:

https://onlinelibrary.wiley.com/doi/full/10.1111/acel.13028


...tested on 7 people.


Is HGH + DHEA available to buy like a supplement? I would have presumed something containing hormones would be more regulated?


Not only is HGH regulated, it even is specifically addressed under law (in the US) that lead some to believe that even prescribing it off-label it is illegal. See:

https://en.wikipedia.org/wiki/HGH_controversies#Law


No, as it requires strong medical supervision. Greg Fahy’s company is running experiments on humans approved by the FDA in his company in Los Angeles.


Not in the U.S.


Maybe you know this, but: Interpreting DNA methylation isn't straightforward. Since it's involved in gene regulation and cell differentiation, it's variable across cells. Due to regulatory networks, whether any particular methylated region is responsible for some outcome may also be unclear.

That being said, if you have reason to believe that the knowledge will help, or are just curious, feel free


sure, I understand that, but from what I saw the data isn’t that hard to process either, there are multiple R libraries actually that help, I’m currently also learning Genomics Analysis Harvard course at edx.org.

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).


I’m going to give the strong recommendation of NOT supplementing HGH ever unless your physician advises it. HGH is a potential trigger for cancer, onto of how it is a potent anabolic hormone that will enlarge all your organs. Unless you have certain medical conditions, there is very little reason for one needing HGH.


What makes you think NMN has been "proven to be safe?" That's a pretty strong standard to conform to. There's virtually no clinical work that's been done at all, for starters.

A lot of genuine promising research in animals, but you also have this animal cancer model that suggests at least a little caution... https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6448588/


NMN is a B-vitamin derivative.


HGH being Human Growth Hormone? I've taken that during puberty, as a medium to get to "normal size"

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.

Be careful.


chances are you had your dna genotyped, not sequenced, if it was cheap. measuring your methylation patterns is not going to be cheap as you need to sequence your dna twice to see what has actually been methylated. i'm not sure if any companies are offering a consumer targeted panel approach.

https://en.wikipedia.org/wiki/Bisulfite_sequencing


I’m planning to do 450k or EPIC BEADS chip, not whole epigenom sequencing, as most researchers used 450k chip for finding the interesting methylation differences for people affected by high air pollution. I saw about $500/sample, but if it’s significantly more, it’s not a problem for me, my chronic disease isn’t going away anyways.


> 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.

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.


Methylation is changes slowly throughout the life, the strongest predictor of age inside the body (that's why it's used as an aging clock).

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.

https://en.wikipedia.org/wiki/Epigenetic_clock#Properties_of...

There are other hallmarks of aging though:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3836174/


What's the difference between NMN vs NR? I take NR and they're chemically similar and I thought both are sold as anti-aging?


They are similar, David Sinclair prefers NMN, but he doesn't have that strong preference.


It's been claimed by some that NR is less stable in the bloodstream and doesn't boost NAD+ levels as much as NMN.


How does one go about measuring their methylation?


See also: AgingBiotech.info Specifically AgingBiotech.info/companies (esp. the clinical stage & clinical trials columns).


Looks interesting, but how could I ever afford to buy ~12 designer drugs which I figure likely cost at least $1-2/day if they are effective? Cost per year is $4K- $8K?

I'm guessing I'll wait 20 years until they are off patent?


Living longer with good health means significantly extending the most lucrative years of your life. Although it sounds trite, the cost should correctly be thought of as an investment.

(Assuming they actually work. I'm skeptical.)


Maybe it's that I'm mid-career and burnt out, but the idea of getting to be a draft animal for an extra decade is utterly unappealing.


Agreed, but keep in mind rejuvenation means it'd be a lot harder to get burnt out and easier to recover.


Feeling better about it does not change the fact that you're a draft animal.

(Not doing what you actually want to.)


Not all of these are new drugs. NMN, for example, is a supplement that you can buy now. It's a bit expensive but the price is dropping as it becomes more popular.

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.


I am not saying there isn't a use case for HGH, but you can increase your own natural HGH production through intermittent fasting, l-glutamine, and cycling up/down a few other molecules. I learned this by mistake, from trying to repair damage to my gut. The weird side effect was quite a bit of muscle development and I don't even work out. On top of that, I dampen mtorc1 with Berberine, Sulforaphane, Myrosinase, TransResveratrol, DIM+Quercertin and that should slow HGH production, but has the opposite effect and increases it.

And I second the NMN being expensive. I use about 800mg a day and it is by far the most expensive thing I take.


It would be great if someone out there could build a simple site to track cheap quality sources of NMN and the progress of price decline over time!


Just saw this after googling NMN supplement. https://www.scientificamerican.com/article/cancer-research-p...


I could really use that weird side effect. What other molecules did you cycle up/down?


I owe HN community a blog update on this process and I promise I will do that in the coming couple weeks. I've been a bit busy as of late. When I do, I will add it to my profile. It's not quite as simple as what to take, but also when to take, in what combinations and why. And it probably isn't the most scientific process, so I'm sure I will catch some flak for it.


It might be worth posting to reddit.com/r/longevity as well. I'm looking forward to it.


HGH is a wonder drug, but it's tricky. Not only for the expense factor, but like everything else, when you add exogenous hormones, your body stops producing them.

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.


Probably worth cycling it then but no one is sure of optimal schedules even for fasting, let alone this...


Yes the tumors part was always what scared me about it and why i would not do it again. Its the first time i hear about hgh being able to stop your own production its not something ive found researching the downsides. Its Well know for steroids though.


I don't care how young HGH will make me feel if I'm sacrificing longevity because of increased cancer risk. Cancer is the #1 enemy of longevity.


Hgh works wonders used it for about 3 months and got sixpack doing hardly any workout. Lost all excess fat. Got a better sleeping pattern. Its easy to get your hands on online. Problem is that its mad expensive even more so with a prescription as the stuff without you might get was stolen or a cheaper brand.


That sounds cheap compared to the cost of old-age healthcare. For comparison, Alzheimer’s care homes cost ~£1000/week in the UK.


A lot of preventative care just delays old-age care rather than avoiding it entirely.

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.


dying early while straining the system tasked with treating your lung cancer and emphysema might not actually save more money


Most people don't die from old age and nothing else, though. If someone doesn't die from lung cancer, they're most likely going to die from some other kind of cancer, heart disease, Alzheimer's, diabetes, or some kind of organ failure, none of which are exactly inexpensive to die from (barring very sudden death from a heart attack or stroke).


This is my main concern too. That I'll fund the research and then not be able to afford the treatment.

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."


Medical tourism.


Maybe take once a week, then you will need to wait only 20 * (365 - 52) / 365 years?


You will get old. You will die. Just face reality. This trying to always put off aging is hopeless. Utterly futile. Enjoy every day, don't waste a second.

You will die. And you ain't ready for it. But Mother nature is.


You have misunderstood what this is about. Yes we all know that we will die. And yes we still think that if you can add 1 or 10 or 50 or whatever healthy years by using some simple to use technology - then that is very valuable to a lot of people, and is a very worthwhile scientific pursuit.

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?


this is a pretty naive approach to aging.

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.


The common cold use to kill us. Science helped a lot of people overcome the common cold. One day we will look at aging like the common cold.


By the same mindset, you oughtn't eat healthy or exercise.

Remember, it's not only about lengthening the lifespan, but healthspan.


These guys do some neat things like this roadmap and their main news site is really quite interesting too over at :https://www.leafscience.org/


Proper sleep, a complete diet, minimizing stress (I'm personally biased towards meditation), intermittent fasting, and vigorous cardiovascular exercise complemented by strength training will by far have the most impact in maximizing your natural lifespan.

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.


This post is poorly researched or misguided relative to the topic at hand.

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.


I'm sorry to disappoint you, drugs (defined by the simple macromolecules we know them to be today) can supplement your body in doing only what it is already capable of.

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.


> drugs (defined by the simple macromolecules we know them to be today) can supplement your body in doing only what it is already capable of.

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 tend to think of aging as an overall degradation of the system. For instance, there’s loss of hair cells in the ear that reduces hearing higher frequencies. There’s clouding of the eye lens as the proteins there aggregate. Long lived cells like neurons accumulate oxidation and probably die at some slow rate.

I can’t quite see how drugs which modulate existing biochemical pathways can stop, let alone reverse the processes I’ve named.


> 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:

https://onlinelibrary.wiley.com/doi/full/10.1111/acel.13028

https://www.sciencedirect.com/science/article/pii/S009286741...


The body forms structures over the course of development. But I don’t think it can replay those actions again. In places like the knee and eye lens, the cells that formed those structures did their job and dissolved their nuclei. I’m more familiar with the eye lens example so let’s go with that. The cells there are just bags of proteins and antioxidants. No nuclei, no mitochondria, no activity. Oxidation from the environment gradually damages those proteins and lead to cataracts. Everyone would eventually get cataracts if they could live forever.

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.


Eye damage repair: https://www.biorxiv.org/content/10.1101/710210v1

Also, the cornea does heal from some damage, so clearly it's not just passive tissue.


That’s a very good summarization of the problems we face in dealing with aging. No drug can fix the damage that is caused by it. We have very early therapies that try to jumpstart or uplift existing biological machinery like the various immunotherapies currently being targeted towards cancers, but that’s still just taking advantage of what is inherent to our bodies. Over time these processes inevitably begin to fail.

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.


> I tend to think of aging as an overall degradation of the system

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.


Put it simply, there is reversible damage and irreversible damage. Oxidized protein aggregates that the cell can’t degrade are an example of irreversible aggregates. Amyloid protein fibrils, although no longer implicated in disease, are another example of a stable, irreversible state. The process of repair slows down not due to programming but because the cells of the body get progressively worse at identifying and repairing damage, because the very machinery that carries out these processes, proteins, get damaged.


I guess you haven't heard of steroids. Taking 10x your natural level can increase your muscle strength above physiological limits. So there, you have the ability to reverse the degradation of muscle with aging.

Similarly, you can reverse other negative effects with other drugs. One thing at a time.


> 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'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.


> can supplement your body in doing only what it is already capable of

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


>Proper sleep, a complete diet, minimizing stress (I'm personally biased towards meditation), intermittent fasting, and vigorous cardiovascular exercise complemented by strength training

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.


Agreed as to your finale, most people have a pop culture understanding of physiology, but remain vehemently opposed to certain ideas largely accepted by alternative health communities. (And the functions, for those of you still unclear, are many including balancing the blood pH and removing actual toxins from the body.) However, regarding fasting, one of the most recent studies (<1month, dec19) around is pretty compelling.(0) Though the breakdown is 6/18 vice 8/16 and it seems they do advocate for a weekly fast of 5/2 days (eat/fast). How's that for a weekend?

0. https://www.nejm.org/doi/full/10.1056/NEJMra1905136


"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)."

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.


>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:


>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).

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.


How would you go about reducing chronic stress? Or are the causes of chronic stress so differentiated that there isn't a prescription you can make?

Also, how did you go about detoxing, in your case?


> most people who are chronically stressed will generally never be able to obtain relief

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.


>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

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.


What makes sense to do personally is very different from what makes sense to research as a medical device or drug candidate. If a therapy has a 10% chance of extending lifespan by ten years, it's marginal for any particular person (given the current evidence), but a great candidate for a clinical trial.


Oh, I don't disagree. There's the entire burgeoning field of nootropics from which you can pick and choose as many supplements / drugs as you could want to test. An interesting point you might find, is that the nootropics which often have the greatest effect are the ones that help to deal with one or more of the items listed above.

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)


Agreed. If you want to add to it, there's evidence that sauna and donating blood have benefits as well.

https://www.ncbi.nlm.nih.gov/pubmed/25705824

https://www.ncbi.nlm.nih.gov/pubmed/26098293


bunch of research into metformin for anti-aging, which is very cheap


How do you get a prescription for it if you don't have diabetes?


you can't really, unless you have a doctor who is willing to. otherwise only illegally.


A vegan/plant-based diet and now we're talking! I like this list a lot!


There's very little evidence that completely abstaining from meat (animal based protein) brings any meaningful advantages from the perspective of life span. In fact in general, it's far more difficult to build a complete diet eating vegan only. I of course do think there's a moral argument to a vegan lifestyle, and am a definitely a strong proponent on that end.

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.


I think you've got some homework to do :-)

https://nutritionfacts.org/topics/lifespan/


Your link has some great information. Plants are highly nutritious, and people who don't get enough of them are probably unlikely to be as healthy as they could be.

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.


I abstain from red meat, but I eat plenty of chicken and fish...


red meat is a good source of heme iron and vitamin b12. I agree with my coworker, a little steak a few days every month is good for you.


Heme iron is toxic. [0]

B12 you can get from a pill. The same stuff they inject into beef. [1]

So if you skip eating red meat, you can avoid the toxins from cooking, such as HCA and PAH [2], the exogenous cholesterol, atherosclerotic carnitine [3], hormones, etc. I think that's a better way to get B12.

[0] https://www.sciencedirect.com/science/article/abs/pii/S03784...

[1] http://eerainuh.com/supplementation-of-vitamin-b12-in-cattle...

[2] https://www.cancer.gov/about-cancer/causes-prevention/risk/d...

[3] https://www.prevention.com/food-nutrition/healthy-eating/a20...


Heme is also what makes a burger taste like a burger. https://impossiblefoods.com/heme/

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.


> Heme iron is toxic. [0]

Everything is toxic in inappropriate doses.


liver == steak * 1000 Only problem is being able to stomach liver a few days every month. I know it's a super food but I'll be damned if I can eat it more than once every few months.


Agree that eating meat at every meal is a dumb idea but is there much difference between a plant based diet and a mediterranean one in this regard ?


I guess not


They need to hurry up with this, I'm not getting any younger and I haven't saved enough for retirement :O


Many studies suggest it's easier to prevent ageing from the beginning rather than de-ageing old people :(


Where can I find more about this?


Aging is basically cumulative damage to your body and its' ability to repair itself, especially mitochondrial DNA


Yeah but if they extend your life won't you need even more for retirement?


If I'm healthy enough to keep working, retirement isn't really necessary.

Also, given enough time, I ought to be able to amass a self-sustaining pile of wealth and then I can retire :)


If everyone does that, nobody is making the things you want to buy with that wealth pile. Not until we also get enough automation to also have UBI.


I don't think that's a problem in their scenario, since the situation is leveraging life extension to work past retirement age. Working until age 80 and living out retirement until 120 would mean a vastly expanded labor pool, unless you're assuming everyone stops having kids.


This is technically true, but once you plan for a 60 year retirement, going out 90 or 100 years is not as difficult as lasting the first 30 years.

I think withdrawing 3% a year would have lasted you the entire time since the 1880s (last 140 years of the stock market)


I personally believe that it's not aging and death that are the disease, but our powerful fear and abuse of them.


Interesting but a bit confusing since most of these drugs are for other conditions, and are not seeking approval based on ability to slow/stop /reverse aging. Thus any approvals would require having a particular condition to get a prescription (or an unethical doctor), and this aren't immediately useful.

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.
That's not how any of this works (US specific to follow). FDA approval to market is a constraint on how the vendor markets a drug or device, not how a physician uses it. This is known as indications for use.

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.


Aware of what off label is, thank you, but I think you grossly misunderstand modern medicine if you think a doctor is going to prescribe a drug originally approved to treat cancer because you _hypothesize_ it might have some anti-aging properties.

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.


> if you think a doctor is going to prescribe a drug originally approved to treat cancer because you _hypothesize_ it might have some anti-aging properties.

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 [1]. 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).

[1] 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.


Doctors are allowed to do off-label prescriptions and it's not considered unethical.

Re-use of existing drugs is one of the most parsimonious methods.


I mean, this seems to be the biological parallel of everything related to AI: there are massive discrepancies between the general public's perception of and expectations from the technology (a general-purpose AI), vs. what the technology actually does (very specific applications of statistical modeling using lots of data).


> any approvals would require having a particular condition to get a prescription (or an unethical doctor)

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.


Other than the condescending tone, this comment is probably worth keeping.

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.


Great, so the advice is, "Take a drug, compounded in a foreign country with different/more lax regulations, for some hypothesized, 100% unproved reason, without a doctor monitoring it."

Good luck.




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