Review of Anti-Aging Drugs | Hacker News Reader

Review of Anti-Aging Drugs

scienceblog.com

179 pointsXzetaU8170 comments

There's a fascinating tension with anti-aging drugs, which is that your preference would obviously be to take them as early as possible, so you spend more time at a younger age as opposed to just prolonging the last years of your life, where you'll be stuck in a nursing home anyway.

But taking experimental drugs while you're young is also much higher risk, and you might see people sacrificing their 20s for the sake of their 70s in a way they end up regretting, even if there aren't any side effects.

If we really manage to crack the code on aging, How certain are we that it's merely something to be delayed? Apparent age is at least somewhat reversible via lifestyle factors e.g. diet/exercise/sobriety.

In fact that's Aubrey de Grey's approach: rather than trying to figure out all the complicated processes involved in causing the damage in the first place, so you can slow them down, just directly fix the damage afterwards. There's been quite a bit of research on this.

de Grey is not using sobriety as a lifestyle factor to reverse anything I'm pretty sure.

A question - why hasn't Aubrey de Grey been more successful in getting some tech billionaire to fund his research agenda? He seems charismatic and smart, and had some promising ideas.

I presume, death by accident becomes a statistical certainty rather quickly.

Taurine and Vitamin E are readily available and seem prudent.

For melatonin, tryptophan plus niacin would maximize the serotonin pathway (note this is dangerous when used with SSRIs).

How many of these are easily available? I had no idea that royal jelly is sold as a supplement.

Don’t listen to this stuff, he sounds so confident but it’s like he’s stapled together info nuggets. This isn’t like a thing people know with certainty.

Of the prescription options, estradiol is probably the most common and easily available, between hormonal birth control and HRT.

It is also likely the most easy to study, as we have 60-70 years of usage that is not correlated with prevalence of other diseases that might skew life expectancy (like metformin etc.), and quite high-quality medical records by virtue of it being vended on a prescription basis.

Despite this, there is not really any clear evidence that it increases life expectancy.

Estradiol should not be supplemented for men.

Helps this masculine man. Low E2 is one of the most awful experiences.

Estradiol isn’t very well studied. It may be used for a few years in menopause, only in rare cases off-label, otherwise. Scientific and commercial interest seems pretty non existent. Probably because patentable synthetic derivatives historically fared worse risk-wise, than bioidentical estrogens, and the market outside of menopause issues is too small. Research on trans people, who would make interesting study subjects for hormonal matters, just got outlawed in the US.

Hormonal contraceptives typically do not contain estradiol, but ethinylestradiol and/or progestins.

I was going to note that a relatively large sample group has been taking estradiol en masse for many years, but you rightly called out that studying trans folks is now forbidden in the US. A shame, we could have offered up quite a bit of knowledge on it.

Estradiol is _extremely_ well studied, including non-HRT in AFAB/AMAB cisgender eugonadal populations

Birth control uses Ethinyl Estradiol which, despite the name, is not actually Estradiol and so does not undergo the same metabolic pathways and metabolites production

I know this because I recently had to source exogenous Estradiol for my wife after making this same mistaken assumption and being surprised at bloodwork and lack of improvement

> I had no idea that royal jelly is sold as a supplement.

Given that actual honey on the shelf is often mere sugar water, and people buy chakra-alignment crystals online, what about the idea surprises you?

Especially selegiline, MAOIs are dicey business.

There's also a fascinating tension with physical exercise, which is that your preference would obviously be do it as early as possible, so you spend more time at a younger age as opposed to just prolonging the last years of your life, where you'll be stuck in a nursing home anyway.

But doing exercise while you're young is also much higher risk, and you might see people sacrificing their 20s for the sake of their 70s in a way they end up regretting, even if there aren't any injuries.

That said, even with risk of injuries it feels like a no brainer to be active and to be active from an early age.

Also I don’t think people should wait until their late 50ies to make sure they get enough vitamin c to “avoid sacrificing their 20ies”

> Fast for short intervals regularly, and longer fasts as they feel good to you.

You can effectively do this every day if you just eat once per day. When I was properly obese, this technique resulted in rapid weight loss. Zero exercise was required to see results, which was good at the time because the not eating part was about all I could handle.

Being in a fasted state is as close as you can get to actually reversing aging. Your body engages in a process called autophagy when nutrient-sensing pathways are down-regulated. When you are stuffing your face constantly (i.e., every ~8 hours), there is less opportunity for this mechanism to do its job.

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

Do you get acid reflux?

Simple solution: take an antacid, like Tums.

Which happily, is totally devoid of side effects.

While autophagy does correlate with fasting and some studies link it to health markers, it should be noted that it usually takes at least 18 hours of continued fasting to even start and only goes into full swing after 48 to 72 hours. It is also an extreme cell response that is associated with high levels of cellular stress, which might have understudied long term detrimental effects. A simple calorie reduction either by eating fewer highly processed meals or regular intense exercise is much more universally accepted as longevity boosting, because it combats overweight, which is by far the most common disease that shortens general lifespan in the western world. There's really no good reason to force your body through these extreme diets. Don't be overweight, don't smoke, don't drink alcohol, maybe go easy on junk food and maybe do some exercise. And get your regular medical check-ups. Then you're already at the pinnacle of clinical longevity science. There is no actual anti aging drug yet that has a proven effect on humans. Best we have are some moderately promising monkey and small mammal studies, but they generally don't translate well.

Is exercise really a maybe?

Even stuff like "don't be overweight" is a maybe. This meta-analysis famously found that being overweight actually has a moderate protective effect: https://pmc.ncbi.nlm.nih.gov/articles/PMC4855514/

I feel like at the very least being overweight is harder on joints.

Also overweight is not obese.

This is a BMI-only study and should be treated carefully. They also found a protective effect for one of the obese categories, which seems extremely weird (unless you consider bodybuilders or strength athletes, in which case it would be reasonable). If you replace "don't be overweight/obese" with "don't have excess amounts of fat" (in particular vascular fat) it is certainly not a maybe.

Autophagy research is all over the place and its hard to understand this stuff or make blanket statements, instead we just have to be flexible with it. Autophagy is always working and the ramp up happens pretty quickly for a lot of people. I think aiming for the 48-72 hour peak isn't helpful. Most people cant or wont fast that long. A lot of people on 16-18 hour daily fasts see benefits that suggest autophagy working well.

Also biology isnt computers, its not exact and all our bodies are very different. For example, say your standing autophagy rate is 3. 16-18 hours fasting its 7 out of 10. But at 48 hours its 10. The difference between 7 and 10 might not even be very meaningful on a practical health level. The difference between never getting to 7 because of "it takes 48 hours" thinking and never trying is then huge. Just a couple hours a day at level 7 autophagy or whatever could be life changing. I do about 14-16 hours a day and am happy I made that decision for myself. I do see benefits that are real seeming to me.

From what I've seen there's no real downside to 14-18 hour daily fasting and in theory incredible benefits. Its also worth mentioning for a lot of people just sleeping with an empty belly means a higher quality of sleep, so there's secondary benefits as well. Your gut 'taking a break' during those hours may also be another benefit in terms of gut health as well, but I'm more skeptical of that claim.

I have personally reduced my a1c from 6.2 to 5.3, mostly by fasting for 36 hours per week.

I already cut refined sugar out of my diet several years ago.

> reduced my a1c

And therefore ?

Prediabetes is 5.7 to 6.4- this is a significant improvement.

All cause mortality or gtfo.

hopefully the OP is still alive, so we'll need to get back to you on that one.

Personally I'd add 'consume and make tons of fermented food' to that list and also eat lots of prebiotics. Gut health is key to so many aspects of a healthy life - I have to imagine it helps with longevity (and lower stress). Nobody likes having stomach pain!

People love their probiotic pills but I'm not convinced - the amount of beneficial microbes is measured at bottling or production and who knows how many survive by the time they get to you. Not to mention how many survive into your gut once consumed.

Homemade sauerkraut or natto though? Pretty much guaranteed to be teeming with the stuff. And your grandparents and their parents were probably eating it their whole lives. It's a whole forgotten art / science that is thankfully making a comeback.

Anecdotally (obviously sample size of 1 so big grain of salt here) every person in my personal life who I saw live to a super long age and also maintain good mental fitness followed what you are saying above plus made their own fermented food into their elderly years.

At the worst it does nothing for longevity and you end up with more unique tasty food for yourself and your friends :-D

Probiotics fall into the same category as all other supplements: i.e. they can have some short term effects if your diet is really bad or you are recovering from GI disease, but there is not much evidence regarding general health improvement. And you also have the same issues as with all food supplements in that they are not FDA regulated or approved. So even if you think you actually need a particular dosage, you can't rely on what is written on the packaging. A balanced diet is a much better and healthier approach without any downsides.

> autophagy [...] usually takes at least 18 hours of continued fasting to even start

False. That would mean cellular debris would pile up unconstrained for pretty much everybody, which is clearly absurd.

> It is also an extreme cell response that is associated with high levels of cellular stress

Also false. It is a very essential cellular process. Read up on it, please.

You should read up on the literature. There isn't much, but this part is pretty well established.

Latest research (as in only ~2m old) dispels that narrative a bit but not entirely. Looks like spermidine is the autophagy signal but they’re not sure fasting does t always increase spermidine

Also…lifting light weights for like 10 minutes a day at home is a lifechanger in the early days

What do you mean by 'the early days' ? And how is it a life changer?

Early days as in the first ~4 months of the journey (which is lifelong…a formerly obese person will always be highly likely to regain the weight)

It’s a life changer because when you’re at a significant caloric deficit, your body sheds both fat and muscle. When you lose muscle, your metabolic rate drops, also lowering your rate of fat loss

If you lift even a little, your body will hang on to muscle more effectively, making it easier to lose and maintain weight over a longer period

Fasting without any exercise has a hidden downside: you’re not just burning fat, you’re also burning muscle. Less muscle → lower glucose disposal capacity → systemic insulin resistance. The problem is that insulin resistance doesn’t stop in muscle — the brain is highly insulin-sensitive, and once central insulin signaling gets disrupted you start seeing network-level dysfunction and cognitive impairment (there’s a reason Alzheimer’s is sometimes called “type 3 diabetes”).

So yeah, autophagy is real, but pairing fasting with at least some resistance work is critical if you don’t want the “anti-aging hack” to backfire by accelerating muscle loss and brain decline.

See https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5462531/ for brain insulin effect

This. Burning muscle also means losing tendon strength, which has downstream effects on your joints.

Associating weight loss with the healthiness of oneself is a mistake.

One can subsist on Oreos at a "healthy" weight if they consume <2,000 calories worth of cookies per day. They will not be a healthy person.

You can't meet your daily protein / caloric requirements in one meal. Also many vitamins / minerals compete for absorption so you don't want to consume all of them at the same meal either.

Autophagy sounds like a great idea... if you completely ignore the Hayflick limit - non-cancerous human cells don't divine indefinitely!

> "human cells don't divine indefinitely!"

I apologize about the typo, but it's true that cells don't divine without a (Hayflick) limit due to telomere shortening. Excessive autophagy is detrimental. The best strategy is to prevent cells from becoming senescent.

No worries!

Not all cells divide (neurons and some muscle cells don't divide); some cells divide very slowly. And in some cases telomeres may be repaired but this increases the risk of cancer [0]

https://biologyinsights.com/what-is-telomere-repair-and-is-i...

I'm fully aware of cancer risks with substances such as astalagus extract, but maybe telomerase activators can be combined with anti-cancer strategies such as fasting, etc.

What I mean is that the Hayflick limit is a concept from the laboratory; it applies to cells that divide quickly, like skin cells, but it has limited practical use for strategies aimed at extending an animal's lifespan, because as the animal or human ages, it will lose neurons and muscle strength (including heart muscle).

In other words, 100% of humans relying only or mainly on telomere repair will be faced with Alzheimer’s, Parkinson’s, and/or ALS, as well as cardiovascular diseases, before they reach 100 years old.

I thought we're past the times when we thought cartilage, neurons, and other tissues cannot regenerate. Didn't we, for example, find that BDNF activators can trigger neurogenesis?

How do you create a well-connected motor neuron with a 3-foot or one-meter-long axon? Or brain neurons that are highly connected to other areas?

I would appreciate any pointers to a scientific article that describes this.

Peripheral neurons can regenerate [0]. Heart muscle also can repair through other factors [1].

[0]: https://pmc.ncbi.nlm.nih.gov/articles/PMC6336700/

[1]: https://www.sciencealert.com/new-study-reveals-more-about-ho...

You are overstating the benefits of fasting. While it can be an effective weight loss strategy for some people, for those of us at a healthy weight there is no reliable evidence that it will improve lifespan compared to eating the same nutrients spread out across multiple meals.

I'm a large man and fairly active so I have to consume ~3000 kcal/day to maintain weight. If I try to eat that much in one meal it will make me physically sick. My digestive system just can't handle that much in one bolus.

What's striking about "anti-ageing" research is how it keeps circling back to the same boring truths: don’t smoke, keep your weight down, move often, sleep properly, keep blood pressure and cholesterol in check, and go easy on the booze.

If something makes an overweight, sedentary smoker hit 100, then it’s a miracle drug. Please let me know if/when you've seen that drug...

GLP-1s are the first hint of that.

You’re right. I can’t think of anything else with that level of impact. Maybe we're all just taking things like statins or blood pressure drugs for granted, but I don’t think those have much effect on people who are already healthy...

> don’t smoke, keep your weight down, move often, sleep properly, keep blood pressure and cholesterol in check, and go easy on the booze.

And UVs, don't forget UVs.

As in UV light?

Maybe it’s the clockwork orange protocol: lots of milk and Ultra Violence.

This is just another way of saying there have been no big advances in clinical anti-ageing. And that's probably because little serious effort is going into it, compared with say, military spending.

It's easy to poke at the military budget as wasteful, but human history has shown that military expenditure is at a minimum, necessary. The same cannot be said of most preferred spending avenues for the cause of the day.

I'm reading that the US spends about $893 billion[1] on national defence and about $5.3 trillion on health care in 2024, with spending on track for roughly $5.6 trillion in 2025 [2][3]. These figures don't match my intuition...

---

[1] https://www.congress.gov/crs_external_products/IN/PDF/IN1242...

[2] https://www.healthaffairs.org/doi/pdf/10.1377/hlthaff.2025.0...

[3] https://www.healthsystemtracker.org/chart-collection/how-muc...

Are you comparing total health care spending to direct government spending on the military?

In the absence of actually lengthening the telomeres, everything falls short in the anti-aging department.

Most lifestyle habits contribute to shorting the telomeres as little as possible, which guarantees good health no matter the age, but still aging, albeit slower.

Given the current technology trajectory, many people including me, think that we are very close to totally stopping aging, and even reversing it.

one of the compounds mentioned in the article appears to promote telomere elongation

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

You missed the most important one, strong social connections. Maybe smoking might beat it out, but otherwise make sure you have a strong social network if you want to live longer (and with better quality of life).

Be careful when reading such blogs:

> Note that the dosage in the mouse experiments is quite high — 0.1% of the body weight every day, meaning about 2 ounces a day for me (70 kg).

Mouse and human metabolism are very different. A better starting estimate would be 5g/day, not 57g/day. I hope people dont accidentally overdose themselves because of lack of a pharmacology background.

Lack of pharmacology background doesn't seem like the biggest issue when extrapolating from mouse to human.

I just learned this the other day, but its called allometric scaling. Definitely far off linear.

lol, that one was really a howler.

You're spot on. But for the rest of the forum:

The most commonly accepted mouse-to-human conversion is: (D)*(3/37) = H

Where D = the mouse dose in mg/kg. H = human dose in mg/kg.

So if a 25g mouse eats 0.1% of its bodyweight in taurine, that comes out to 1000mg/kg. It translates to 81mg/kg for a human. If you weigh 100kg, an equivalent daily dose for you is 8.1 grams/day.

The rat equation is similar, but 6/37 rather than 3/37.

In plain English: scale by body weight then divide by 12.

Scaling mouse doses to human by body weight is a common rookie mistake.

A better estimate for dose scaling uses body surface area. Even with that, inter-species differences don’t allow prevent extrapolation.

Scaling by body weight leads to the common mistake of dismissing mouse studies because the casual observer does the match (by weight) and thinks the dose used was excessive.

It’s such a basic topic in medicine and scientific research that I don’t trust anyone who scales by body weight.

> Be careful when reading such blogs

I followed a link to another blog post of theirs in which they go on a rant claiming there was a conspiracy to suppress chloroquine and ivermectin as COVID treatments. I dont think anyone should be taking health advice from this person

Amusingly, this was a very common if not the most common stance on this very website some time ago. Surely, don't look for assistance on the internet regarding memory issues.

Ascorbic is not a correct name of a compound. Should be 'ascorbic acid' or Vitamin C. Such sloppiness cast doubt on accuracy of the whole review.

I mean this guy is not a scientist. He's an enthusiasts aping scientific process. Look at how he talks about the "10-20% flexibility". Hypothesis assumed true, no supporting evidence. Same with his idea of being young longer. No evidence supports this, yet his comments proceed as if it's a gospel truth

Agreed, I would have appreciated this more as a peer-reviewed meta-analysis than a blog post.

First time I hear about him, but it looks like he is a scientist:

https://www.researchgate.net/profile/Josh-Mitteldorf

> Look at how he talks about the "10-20% flexibility". Hypothesis assumed true, no supporting evidence.

He started that part with "Here’s my perspective:", so for me it sounded more like his personal opinion/hypothesis, not a scientific consensus (and that hypothesis wasn't the topic of the article, so it's not strange for me that he gave no evidence for it there).

That makes this even worse, he should know better. I took a look at his publications and they're nuts. He's actually published claiming that covid vaccinations increase the spread of covid.

Read a little further... it's specifically called ascorbic acid and vitamin C.

He probably just wanted to save space within the table.

In the table there is also 'Skulachev quinone (SKQ)', so it doesn't look like he ran out of space for writing out the whole name.

It kind of gross to call ascorbic acid like that, as someone who studied chemistry I'm revolted.

This, and the fact that Ascorbic acid leads to hardening of the arteries also makes it suspect.

Many of the studies he refers to are old. There was a widely held belief in the early 1980's promoted by Linus Pauling that Vit C cured cancer.

> This, and the fact that Ascorbic acid leads to hardening of the arteries also makes it suspect.

Source?

These articles really need a lot of context to parse as they paint some of the compounds as having potential upside without downsides.

Metformin is amazing in people with diabetes, but among non-diabetics taking it for vague life extension claims it’s often discontinued due to side effects.

Rapamycin has fallen out of favor among many in this space because they felt it was producing net negative effects as well as causing very annoying side effects like blisters in the mouth.

I’ve followed supplement and fitness forums for years. It’s amazing how frequently a prescription medication will be held up as a wonder drug, but then people who try it discover it isn’t helping them or is even causing other problems they didn’t think about.

EDIT: There are some serious scientific errors in this blog (dose conversions from mice studies). After clicking around the author appears to be into some quackery and conspiracy theory stuff as well. I flagged this submission because it’s not as scientific of a source as it claims.

I'm surprised at the lack of intersectional shitposting when it comes to this subject, something along the lines of "FAANG intern tech bros making $1.5m TC are microdosing on ivermectin for health benefits." Get Wired or some other shit rag (the Altnatic?) to run with it complete with fancy full-viewport animations and gushing narrative intro over how it all started when someone's pitbull decided to take a shit in jeff bezos office.

Underappreciated comment.

What side effects cause people taking Metformin to discontinue it? I'm taking, but haven't noticed any, but... you don't notice your baseline, I suppose!

Metabolic acidosis. Not trivial at all.

For diabetics, Metformin is usually a net win. Having controlled diabetes is better all around than uncontrolled.

For non-diabetics hoping Metformin will bring health benefits, the subtle side effects like reducing adaptive responses to exercise ( https://pmc.ncbi.nlm.nih.gov/articles/PMC6351883/ ) and other small negatives aren’t usually advertised by the anti-aging influencers who only talk about the lifespan studies (in mice)

Nausea

Shitty shits. Literally. As for metabolic acidoses, rates are extremely low (<10 cases per 100,000 patient-years, per https://pubmed.ncbi.nlm.nih.gov/26773926/), so it's almost a non-concern.

~1/10.000 patient-years is a non-concern ?! I hope you're not an epidemiologist.

I think this depends on the context. For your epidemiologist perspective, or looking at populations, that's a big rate! (Given how much metformin is taken) Would be easy to find people who suffer from it.

From the perspective of "Should I be worried about side effects from taking this drug / should I not take this because it might give me this effect", I think this falls under "be aware of symptoms and stop or weigh the costs if you get it, but you're probably fine".

“ Josh Mitteldorf studies evolutionary theory of aging using computer simulations.”

> This is exactly why one must read the author before going into their content. What does this even mean?

From the conclusion paragraph:

> Your primary life extension program is diet and exercise. Choose a diet that works for you. Stay slim.

Considering heart disease is the #1 killer, doing whatever you can to not die from heart disease is the best place for most people to start.

Even in 2025, diet and exercise are still king.

Also this:

> The best reason to take multiple life extension supplements is to hedge our bets, because we really don’t know which of them are effective in humans.

And earlier:

> Personally, I take large doses of rapamycin 2 days a week, 8 weeks per year. For personalized recommendations, you can consult your favorite life extension doc.

Rapamycin modulates the immune system. I get that he's probably consulting a doctor but can you imagine taking this risk during a pandemic or even in older age? It makes me uncomfortable to play around with these very powerful drugs.

These roads people go down always arrive at eating collidal silver...

Get with the times, methylene blue is the new it girl.

As a party trick, it'll make people pee blue. But don't do this, it isn't safe. Especially without consent

The dosage for longevity is supposed to be low enough that this risk is minimized. Lots of things you do modulate your immune system (including e.g. exercise). It's a risk/reward thing, every time you get into your car you're also taking a longevity risk.

I think there are some proper human trials happening but the jury is still out.

> I think there are some proper human trials happening but the jury is still out.

That's exactly my point. No one really knows the risk that they are taking.

Surprisingly, many people seem to think that pushing a few random pills into a machine optimized over some million years of evolution will tune it so it works better. Go figure...

It works for the majority of modern medicine, so it's not all that black and white.

Yes, although even for modern medicine curative and preventative strategies are very distinct. Sure, they'll give you pills to compensate for a problem you already have. But there are few meds that protect you against stuff you'll maybe catch in the future. Vaccines and antibiotics are obvious examples, but I'm not aware of many others. The rest of preventative strategies overwhelmingly consists in correcting deficits or excesses (calories, vitamins, sleep, exercise etc.)

People are still getting nerve damage from too much vitamin B6 in energy drinks and vitamin supplements, and that's a well known and widely taken vitamin. The idea that you can take experimental drugs your entire life at little risk is optimistic.

I had no idea. At points in my life I consumed a lot of nutritional yeast.

How to hedge a bet 101:

1.you bet on risky stuff using something of value (money, health,...)

2.since you're unsure whether your bet will pay off, you bet some more on some other risky stuff, just to be sure.

BTW if you were wondering, of course all those proposed weird life-prolonging treatments are totally devoid of side-effects.

Oh there's plenty of people selling "side effect free" life extension supplements. But there's another name for side effect free medication: effect free.

Never put 100% of your savings into a single slot machine. Take 10% of your savings to 10 different casinos and distribute them to 10 slot machines in each, in order to hedge.

I recently saw a patient with overwhelming MRSA sepsis with multiple foci of infection including epidural abscess (around the spinal cord), and meningitis. This person was taking rapamycin presumably for "life extension" purposes. Almost certainly the immunosuppression from the rapamycin made the infection much worse.

I'd be very wary of taking an immunosuppressive drug as an otherwise healthy person for theoretical life extension properties.

Don't come and spoil our nice individualism with populational effects, you filthy rationalist !

What was the dose and frequency? I bet it was rather high. Or do you really think that 1 mg once per week will suppress the immune system?

And if diet alone isn't getting you to a healthy weight, the GLP-1 drugs are miraculously effective and don't have a lot of downsides aside from cost.

Is way too early to know about any downsides of these drugs. I’m afraid too many people are gonna find out the downsides when it’s too late.

These drugs have been around since 2005. Exenatide was approved by the FDA for use in 2005.

We've had plenty of time. Only their approval for weight loss is new

Exenatide was a very small population base. The approval for weight loss means this drug is being taken by millions of more people which leads to a larger sample size. The larger the sample size the more negative effects will be revealed. I’ll just leave this here for the future m. I have no evidence other than common sense that it is ridiculous to think that injecting a hormone randomly in your body does not lead to side effects.

Besides, who is going to be the one that links thyroid cancers and pancreatic cancers to these drugs? My father died of pancreatic cancer, no one really thought to ask why.

The majority is gaining literal years of healthy lifespan. It would take a lot of damage to even approach this gain for the average person. Like we used to do very invasive and impactful gastric surgery to try and get weight loss and nobody batted an eye, no?

> The majority is gaining literal years of healthy lifespan

You’re saying this like it’s true already. Let’s give it 10 years.

> You’re saying this like it’s true already

Because it is true already? You take an obese person who has a lower quality of life because of their obesity and give them a drug that helps them lose that weight and keep it if, they're literally gaining function and a higher quality of life from it. Today.

Phen-fen helped people lose weight.

Yeah, and? Fen-phen was a drug controversially approved in April 1996 and withdrew from market September 1997.

GLP-1s aren't remotely similar. Their approval was 20 years ago and have been in used by diabetics since.

I think for myself, regardless of what the downsides are - the likely alternative was death, which is still an option.

Your overall mortality is actually best when you are overweight but not obese.

Life expectancy at overweight bmi > standard bmi > obese bmi > underweight bmi.

A few extra pounds when you are older helps you survive illness.

The data is really really clear and replicated on this.

This only really holds for older people, who have basically no ability to recover lost muscle mass after a serious illness which makes it difficult them to continue to exercise.

The correlation is unambigous. The causation is a different story, e.g. illnesses often cause weight loss.

Which segments of these populations have high BMI because of muscle mass instead of excess body fat? Which segments have low BMI due to childhood malnourishment or current or chronic illness? These are just some of the very obvious questions that have already been used to relegate your conveniently concise "fact" to "interesting, but not instructive".

> A few extra pounds when you are older helps you survive illness.

This doesn’t mean being slightly overweight from age 20 through 60 is an advantage.

And sleep

I am very certain that framing ageing as a disease that can be treated with a drug is a false oversimplication that can not yield meaningfull results. Personaly I love complexity and trying to parse all of the moving peices in a problem, but ageing involves an unknown total number of peieces, and what we do know is daunting, many of the biological processes operate within tollerances of parts per billion, and the large number of processes effect each other. The worst part of "anti ageing" is that it completly ignores the reality of lifestyle inputs demonstrably having accelerated ageing effects. cart, horse

I thought this was an informative post, but for many of these compounds the simple "life extension" metric is the one that is least interesting to me.

I have no problem dying in my 80s or 90s, but I just want to ensure that as much as possible that I have a solid mind and body right up until I die. For example, my father has been taking metformin for nearly 30 years after surviving a heart attack in his 50s (he has type 2 diabetes). He's now in his mid 80s and has basically no significant cognitive decline, despite that his father and both of his brothers had severe dementia when they died. Obviously this is just one anecdote and I'm not arguing anything about the specifics of metformin, I'm just saying that the fact he is able to enjoy such an active life in his 80s is the biggest gift - if he died tomorrow I think he and all of his family would just be so grateful at the vibrant life he had.

Heck, for me I'd be fine with a drug that slightly reduced my lifespan if it gave me better quality of life up until the end.

Diet and exercise are well know for the effect you're looking for. Its just not easy

This is useless. It takes zero account of genetic variability. I can tell you several of those things on that list that will decrease my lifespan.

If you care about your personal lifespan, you should care about your personal genetics and your personal heritage.

This was the same stupidity we saw with the blue zones. They didn’t think for a minute that these people lived for a long time because they were eating the foods they grew up on for generations.

Actually, those people lived for a long time largely because they had poor or compromised records of birth and death dates.

No such discussion is complete without mention of SENS[0] i.e. the rejuvenation approach.

Not about delaying the inevitable, but about undoing the accumulated damage of aging.

0. https://en.wikipedia.org/wiki/SENS_Research_Foundation

How many people can really even afford life extension? As in living all the way into 90s or 100? Your retirement savings have to be pretty solid to enjoy those extra years. It’s not like before, the game has changed.

If 100 year olds were truly healthy, then I strongly suspect we'd see a shift in societal structure and expectations for retirement. Societies tolerances for a permanent upper class of retirees and a permanent lower class of workers would likely not last - worker's would likely be unwilling to do the same job for a century.

If people started to live longer, they would (hopefully) be in better health longer, and retire at a later age.

A better question might be can we afford NOT to have life extension? Advanced economies all over the world are filling up with sick, elderly people who form a massive drain on the economy, and it's going to get much worse. Developing medical technologies that can keep them healthier and productive for longer is the one thing that can save us here.

Winner, "Ascorbic". Do they mean Vitamin C?

The text says yes. Also the text says other studies supposedly shown decrease in lifespan in humans: "but the conclusion of this study was that supplementation with vitamin C depressed lifespan, probably by inhibiting production of the body’s native antioxidants, including glutathione and SOD=superoxide dismutase."

My physician has just advised that I eat a piece of fruit every day, and I try to do so.

I think that is a safe way to ensure this bioavailability.

I have tested low on vitamin D and my physician advised supplements. I see that vitamin E is also on the list.

What natural foods provide those?

Would any of the OTC stuff even be effective? Melatonin, NAC, and Berberine.

A good place to read more about these: https://examine.com/supplements/n-acetylcysteine/?show_condi...

Melatonin is just for jetlag/otherwise shifted sleeping schedule, are people using it as an anti aging drug?

Melatonin is always made from serotonin.

Serotonin is made from tryptophan, which can also be made into niacin.

Taking tryptophan and niacin as a supplement will boost both serotonin and melatonin naturally, assuming these pathways are working properly.

However, this can be dangerous in the presence of an SSRI.

Truth be told, none of either prescription or OTC stuff has any solid research backing it. Some people, especially on HN are obsessed with living long and are always prompt to try the weirdest experimental stuff. Reasonable people should remember what the COVID period was on this website, and act accordingly...

If you want to live long, be bipolar and take lithium.

https://pmc.ncbi.nlm.nih.gov/articles/PMC7553080

(no don't, it's hell on earth)

A lot of people in the comments are talking about the "problem" of death and approaches to take, but really, the only thing you can do is philosophically make your peace. Anything else at this point is yelling into infinity.

Realistically you can maybe get another couple year from what I can tell. Is it worth it?

I'd focus more on qulalitiy of your life. not everyone will die of something all these can help with, the obese person I used to know enjoyed eating - and we can now say in hindsight that diet changes would not have helped him live longer.

leading a healthy active lifestyle DOES improve the quality of your life.

Getting diabetes and injecting yourself daily with insulin is not a quality life.

Having trouble walking or playing with your grandkids because one is too fat and has ruined their joints is also not quality.

Having a miserable last 10-20 years of life due to a stroke is also not quality.

These things don’t mysteriously happen. :) Being able to take care of yourself into old age is the biggest gift you can give yourself. Why? It reduces your suffering as much as possible. But nothing is guaranteed of course.

Personal story time…growing up my parents barely valued their health. Mom and dad were fat for years. My dad had a stroke at 65 and he’s struggling with symptoms 10 years later. My mom got seriously ill at 60 from years of mismanaged diabetes, and was in and out of the hospital for 3 years before dying of a heart attack. She ate a lot of cookies though - quality life achieved?

In contrast my in laws walk 10k+ steps daily, eat healthy, and exercise. They’ve been doing it for years. They are almost 70, travel all the time, and keep up with their grand kids no problem! They themselves are doing better than their parents, who suffered from early onset dementia and high blood pressure.

Just my opinions as someone that’s seen 2 very different approaches to “living”. I try not to obsess over it, but i certainly make sure my BMI is low and make sure my blood sugar is excellent. I’ll do anything to avoid going through what my parents did. I plan to enjoy my 60s and 70s!

Sorry, I didn't mean to imply do nothing. I meant to caution that your best efforts may be meaningless. I have know several people doing thing right who yet got dieabietes, had strokes, or died young. good diet and exercise is important but it isn't everything

agreed. I can get hit by a bus tomorrow crossing the street, or get a stroke despite my efforts. nothing is guaranteed. Should cherish every day!

I don't want to be pedantic but these things do, in fact, 'mysteriously' happen to completely 'healthy' people.

I do agree that the _causes_ for these things happen mysteriously to some people. Or sometimes it’s just part of your family history and you’re predisposed genetically.

But if i have routine labs done and find out i’m prediabetic, i have 2 choices. I could continue eating cookies every day like my mom did and not exercise, or i could make lifestyle changes and take metformin proactively.

Similarly with high blood pressure, and more. That alone addresses like 80% of modern ailments. Things get more tricky when we consider complex conditions like migraines, etc, which you have much less agency over as a person.

There is a difference between dying at 40 and dying at 80. Also, I see no reason why people couldn't live for, say, 200 years or even indefinitely. I think it is an engineering problem that can be solved and I wish we as humanity allocated more attention and resources into solving this particular problem. Especially as it concerns all of us. Solving suffering and then solving mortality sounds like a good project to me.

Philosophically there is no difference. The gun to your head is infinity, 40 years has no meaning.

If life's a game where you try to get the best score you can, more years gives you more chances to rack up points. Philosophically* there's nothing more important, and therefore nothing has more meaning than this.

* different people can have different philosophies on life

It is spreading FUD wrt quercetin. It states there is just applicable one mammalian study which it doesn't even cite. In reality there have been multiple studies in humans showing no harm from a reasonable dose.

Richard Miller's Intervention Testing Program should really be your go-to for this: https://www.nia.nih.gov/research/dab/interventions-testing-p...

He has no conflicts of interests, works for the NIA, and he's quite open to trying other compounds, having put out the call for suggestions.

i haven't read it but i know the tl;dr. none of that shit works.

This is a great discussion on longevity, though the main article focuses heavily on mouse studies. To add to that, I've been thinking about a framework that prioritizes the existing human evidence.

My take, which I wrote about in the linked post, is to use a tiered approach:

1. Top Priority (Human RCTs): Start with what we know works in human randomized trials. This is our most solid ground and includes sustained weight loss, lowering LDL (especially with statins), intensive blood-pressure control, "polypill" strategies, and appropriate TRT for men with a confirmed deficiency. Also in this tier are things with more modest but proven benefits, like flu shots, multivitamins, and specific fish oils.

2. Second Priority (Strong Correlation): Look at interventions with strong positive associations in human studies and/or robust lifespan benefits in mice. This is where things like exercise, Mediterranean diets, social well being, coffee, green tea, fiber, and garlic fit in.

3. Third Priority (Emerging Science): Finally, consider the more experimental options that have shown promise in mice but only have early human signals. This is a long list, including rapamycin, calorie restriction, glycine+NAC, taurine, acarbose, metformin, and NAD+ boosters.

Throughout this process, the goal should be to treat existing medical issues, track what works for you personally (N=1), and always consult with your doctor. Things that are still purely theoretical should wait for better data.

Here's the full post with more detail:

http://mylongevityjourney.blogspot.com/2022/08/a-short-summa...

> appropriate TRT for men with low T

You lost me here since this doesn’t appear in the linked article at all. You seem to be speaking about your own link, not the linked article on Hacker News.

Be especially careful with TRT advice on the internet or from local clinics that push TRT treatments. The definition of “low testosterone” used in the longevity studies is very different than the definition used by TRT clinics looking to grow their customer base.

There was an alarming study recently that showed a high percentage of men on TRT didn’t even have baseline testosterone bloodwork showing a deficiency. The clinics “diagnosed” them based on vague symptoms or questions, which is how they get around the fact that most men seeking TRT are not clinically deficient these days. Taking TRT will suppress natural production of testosterone and can lead to a lifetime need for TRT. Inappropriate dosing (which is common at the TRT clinics who want their customers to feel something early on) can also be net harmful and lead to cardiac complications or even psychiatric side effects like anxiety.

TRT should be a last resort for people with true clinical deficiencies after eliminating the typical contributing factors (alcohol, sleep, obesity, etc). It’s not appropriate to mix into a list of supplements to take because it’s on the short list of medicines that can make you permanently dependent by causing testicular atrophy. This isn’t a concern in patients who already have testicular damage leading to hypogonadism, but it should be a huge concern for the average guy walking into a TRT clinic because they heard it was going to give them an edge or help in the gym.

> You seem to be speaking about your own link, not the linked article on Hacker News.

Correct. The hacker-news linked article talks about drugs that made mice live longer, my article talks about drugs that made humans live longer with some supporting evidence from mice studies.

> Be especially careful with TRT advice on the internet or from local clinics that push TRT treatments.

Correct. If you read my article, it repeatedly talks about working with a Dr on this. Ideally an endocrinologist (in USA), or potentially a urologist.

Healthy doses of TRT, where studies found benefits are with hypogonadal men whose low T is verified via two separate tests (<200 or <250 total T). The dosages used (~100 mg / week or less) are nowhere near gym bro doses (~200, 300, 400 mg/week etc).

An endo will ask you to make lifestyle changes first, and resort to supplemental testosterone as a last resort.

> it’s on the short list of medicines that can make you permanently dependent by causing testicular atrophy.

I believe you're factually wrong on this. I know a lot of people personally who stopped TRT successfully, some after being a decade on it.

> It’s not appropriate to mix into a list of supplements to take

This is a non-sensical idea, because supplements are much like drugs except they don't go through the FDA approval proceess. They're simply unregulated drugs with potentially significant sides. You shouldn't take a light view of them.

Actually, if I were to choose between a drug and a supplement for the same problem (such as living longer), I think people should prioritize drugs first as they go through rigorous clinical trials, their side effect profile is well known, there's post-approval drug monitoring.

Taking TRT or not is a personal choice.

TRT is longevity to me. Feeling younger for as long as possible.

An "alarming study". You just have a puritanical mindset and can't stand someone else doesn't share your shitty sex life.

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