[safety1st]

So in the science of fitness, there's a lot of woo, but there are a few really clear wins. One such example in weight lifting is supplementing creatine. It's well researched, fairly inexpensive, the performance improvements are significant and well documented, and it's very safe with side effects being mild and rare. Once you're actually doing the exercise and nutrition part more or less right, it's hard to argue against supplementing creatine. It's used by the vast majority of professional bodybuilders and most experienced weight lifters.

Is there anything similar in the science of anti-aging? Where (A) The body of research is large, well established, and mostly uncontroversial; (B) The benefits and safety profile are good; (C) The majority of people who are serious about this stuff use it/take it/do it.

[irthomasthomas]

Metformin.

Research in humans suggests that metformin can impact mortality. A meta-analysis published in 2017 that included 53 different studies concluded that metformin reduces all-cause mortality and diseases of aging, independent of its effect on diabetes.

Also, combinations of Metformin, rapamycin and resveratrol, and NMNs.

Davis Sinclaire is probably the leading expert on those, now. He is professor of genetics at Harvard.

https://youtube.com/watch?v=bRWT7hVgwuM

[loeg]

Worth pointing out that Metformin has a host of unpleasant and common side effects. E.g., here's 40% of type 2 diabetics not adhering to the prescribed dosing protocol: https://joppp.biomedcentral.com/articles/10.1186/s40545-022-...

> A number of studies assessing adherence to diabetes medications in patients with type 2 diabetes have reported that metformin has the lowest adherence rates when compared with other OAAs.

[pazimzadeh]

Is it known what the mechanism is for metformin's effect on longevity?

If it's due to its ability to reduce blood glucose levels, then berberine may be another way to get a similar effect.

Berberine stimulates glucose transport through a mechanism distinct from insulin

https://www.sciencedirect.com/science/article/pii/S002604950...

Efficacy of Berberine in Patients with Type 2 Diabetes

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2410097/

It also lowers cholesterol

Berberine is a novel cholesterol-lowering drug working through a unique mechanism distinct from statins

https://www.nature.com/articles/nm1135

But pure berberine is not absorbed very well in the intestines, so you need to buy a good formation for it.

Enhancement of sodium caprate on intestine absorption and antidiabetic action of berberine

https://www.ncbi.nlm.nih.gov/pubmed/20237966/

Amorphous solid dispersion of berberine with absorption enhancer demonstrates a remarkable hypoglycemic effect via improving its bioavailability

https://pubmed.ncbi.nlm.nih.gov/24607213/

The best thing might be to cook with barberries:

https://thecaspianchef.com/2020/01/18/zereshk-polo-saffron-b...

[safety1st]

This one is really interesting, thanks. I think it's the closest any mentioned substance comes to passing the "creatine test" (for whatever that test is worth; I just made it up).

(A) The body of research is, in general, large and uncontroversial.

(B) The safety profile is good. The benefits for diabetics are certainly large. Probably no drug has been studied for anti-aging effects as extensively as creatine has been for fitness applications, so I'm not sure anything can fulfill that criteria. But it seems like the present research on metformin supports a variety of positive effects for non-diabetics with more on the way.

(C) I wouldn't know whether the majority of people who are serious about anti-aging use it but it does get mentioned a lot.

Pretty positive endorsement overall!

[tysam_and]

It looks really promising. However, there are some growing concerns I believe that link it with mitochondrial dysfunction as well, if I recall correctly. Hopefully that's not the case, but it's a developing story. (It does reduce exercise output as well if someone is an athlete and cares about hat, but since it does mimic exercise in a way on a cellular level, that's to be expected I guess). :'(

[irthomasthomas]

There's always exceptions in popular medicine. No doubt a small minority of people get no benefit, or may even be mildly harmed by the medicine. But Metformin, in particular, is one of the most popular drugs in the world, and it's strong safety profile is well established. "All-cause mortality is lower in people on Metformin". So, I don't think there will be any big surprises found in its safety, but maybe we'll find that a certain minority of the population aren't suited for it.

[phkahler]

Mitochondria need proper care too. I take iodine and magnesium for asthma (which is cured) and I hear iodine is also go for mitochondria, which might explain why it's good for so many things.

[xiphias2]

By far the most important thing in anti aging that checks all boxes is excercise and getting nutrition right (no excess fat).

Most of the interesting stuff happens when you focus on just A part: Yamanaka factors are both super powerful, established as reversing the probably most important hallmark of aging and super dangerous (causes cancer) at the same time.

What's promising is the pace of research: in 20 years there's a good chance to have real safe anti-aging available, but we still need to survive until then.

[timmg]

> By far the most important thing in anti aging that checks all boxes is excercise and getting nutrition right (no excess fat).

Do you mean "don't eat excess fat" or "don't have excess fat on your body"? It's not clear to me from the context.

[inciampati]

Second probably.

[xiphias2]

Definately. The optimal body fat percantage is at about 12% for men and 15% for women, but I can't find a study that really tries to find that optimum.

There have been already studies showing that body fat percentage is a better predictor of mortality than BMI, but most studies focused on BMI in the past, as it's easier to measure.

[tysam_and]

I really appreciate this comment a lot. Feels like it hits the nail on the head.

I've seen some of the discussion about/around the Yamanaka factors and it feels like an anime plot point, honestly. I need to look more into them and understand them a bit better. They're the ones implicated in stem cells returning back to pluripotency, right (and then the long deep dive about DNA damage/repair/what the heck is happening in the disparity between repairing damage for reproduction vs the everyday repair, etc...)?

[xiphias2]

You're half right, they are only resetting epigenetics (for example DNA methylation that is important in cell specialization), not DNA.

Altos Labs being funded is both a blessing and a curse, because it funded the best researchers in this area with hundreds of millions of dollars (5-10x their salary in what they were making as university professors), but since it was founded, there are much less publications available.

[ben7799]

I think the important thing is to concentrate on the diet and exercise and not sit around living an unhealthy lifestyle and hoping to get on one of these drugs that is possibly not that great anyway or has some serious side effects you could end up with.

It's pretty obvious older people who have kept their fitness (cardio & strength, not just one of the two) up and their weight down their entire lives have profoundly higher quality of life.

That requires a totally different lifestyle from the standard "geek lifestyle" though.

[tysam_and]

Very much so, I think it's about healthspan rather than lifespan for many people.

Hopefully we can improve that. Many people would be much more okay with feeling great up until an old age, have a few weeks of infirmity, and then pass away rather than the multiple decades of gradual decay that we have now.

Not that that's necessarily entirely realistic or possible, but it would be nice, if it is a possible thing indeedy.

[ubercow13]

What's wrong with excess fat as opposed to excess calories in the form of other macronutrients?

[andrekandre]

its a little ambiguous but they might have meant body fat, not intake....

[outworlder]

> By far the most important thing in anti aging that checks all boxes is excercise and getting nutrition right (no excess fat).

Nutrition is difficult to get right because of the contradictory and plain harmful information that we have been receiving for so long.

For example: is fruit juice "healthy"? Not really, when you consider that you are far more likely to consume way more fruit that you otherwise would, and a lot of fiber content is removed. We are unlikely to eat 10 oranges in a row, but that's easy in juice form. That's without extra sugar - if sugar is added, then it's just a soda with added nutrients. And the problem with that is that fructose is only metabolized by the liver (turning into triglycerides), with a mechanism that's comparable to the one used to metabolize alcohol.

We have been told that fat is bad. Due to consumer demand, the industry start removing fat content. But then things taste horrible, so the solution was to add sugar.

So now we are worse off: not only we are consuming a lot of sugar (75% of all products in the supermarket have sugar, including 'salty' ones), but we haven't even attacked the problem that prompted fat removal (increase in heart conditions) in the first place. Fructose in particular turns into triglycerides, and gets stored as fat(with uric acid as byproduct, with way more free radical formation than glucose, and it even uses up ATP). It didn't address the heart issue, and actually made it worse. People have become far more obese than when they ate fats, as fats (plus fiber) make you feel full for longer. It also screws up hunger hormones and sugar is addictive by itself.

Or let's take bread. White bread is starting to get considered harmful, but then the alternative that's pushed is whole bread. It matters very little. If that's all we ate, we could have some bread, as our ancestors did. But in combination with all other crap, it's way too much sugar.

If you eat cereal for breakfast, some rice and beans for lunch with a glass of orange juice you have already exceeded dietary sugar limits by a lot. And that's a far, far healthier diet than what's done in the average household.

Whereas if you had an avocado for breakfast, meat and vegetables for lunch you would be in a far better shape (literally and figuratively) even if the second diet had more calories. Calories are not all the same, and calories contained in food are not the same as calories absorbed (or stored). We accept that, when we fuel our car, a bunch of energy in the fuel will be wasted. Somehow, when we count calories, we assume we'll absorb them all.

The end result is that we are prematurely aging (due to all the oxidative stress), getting diabetes, non alcoholic fatty liver disease, high blood pressure, gout, cardiac problems. Possibly even Alzheimers (research ongoing, but there's growing evidence) and a few types of cancers. Also oral health in general. Basically, most of the mortality these days is directly or indirectly linked to sugar and insulin resistance in general. 88% of Americans have some form of metabolic dysfunction.

> no excess fat

Too much fat is usually the symptom of a disease (generally metabolic illness). Just fat, by itself, can be ok(also depending on where it is) – there are fat people who are otherwise healthy (a tiny minority, but they exist). And there are people that are thin but otherwise unhealthy (TOFI, Thin on the Outside, Fat Inside). What commonly happens is that we get sick first (insulin resistance) and then we get fat. For most people, being obese is the symptom, not the cause.

Diabetes does not strike out of the blue, although if you ask most people, they got "surprise" diagnoses. You check your glucose levels, and they are normal. You keep checking them for a few years, they are normal. Then "out of the blue" they are outside limits, and you get a diagnosis of pre-diabetes (or full blown diabetes). What was missed all these years was that your body was fiercely fighting against the glucose increase by raising the amount of insulin produced. But there's only so much the body can make (and also the cells will be resisting that), at some point, the combination of not being able to increase production plus resistance will be too much to overcome. Insulin measurements are not part of standard bloodwork yet, but at least they are now including A1C.

Completely drop added sugar. Reduce sugar in all forms, added, "natural", it doesn't matter. A sane amount of fruits is ok for their other benefits. Increase the amount of fat and fiber. Hydrate. And then drop processed foods in general. That's how we survive until 'anti-aging' is available.

[andrekandre]

  > Completely drop added sugar. Reduce sugar in all forms, added, "natural", it doesn't matter.

i think i would also say the same about sodium as well... many foods already have natural levels of sodium already (and can be tasted/enjoyed just fine if one gets used to it)

[jaredhallen]

From my experience, it's the sodium that's in things more than on them. When you look at the sodium content of a lot of processed food, the amount you might sprinkle on at serving time is pretty insignificant.

[scythe]

>Is there anything similar in the science of anti-aging? Where (A) The body of research is large, well established, and mostly uncontroversial; (B) The benefits and safety profile are good; (C) The majority of people who are serious about this stuff use it/take it/do it.

The sodium/potassium ratio, and particularly keeping it smaller. The top answer right now is "nutrition", but that's a hairball, and the Na/K is a bright spot that gets left out of the discussion precisely because it is much less controversial than the endless debate over macronutrients and staples. The sodium/potassium ratio has effects on:

hypertension: https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1440-1681....

stroke/CVD: https://bmjopen.bmj.com/content/6/7/e011632.short

bone density: https://academic.oup.com/jcem/article/87/5/2008/2846608

chronic kidney disease: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6047877/

and even such seemingly unrelated conditions as depression: https://physoc.onlinelibrary.wiley.com/doi/full/10.14814/phy...

and age-related cognitive decline: https://www.sciencedirect.com/science/article/pii/S258979182...

[Woberto]

But where can we get potassium from?? I feel like when I've looked, it's harder to come by than other vitamins/minerals

[scythe]

In general, potassium is found in fruits and vegetables. It has to be spread throughout the day, because high quantities of potassium at once have a laxative effect. The highest concentrations are found in some vegetable concentrates — the densest source in your cabinet is probably tomato sauce. It is present in milk and yogurt but not in cheese.

Potatoes and other starchy vegetables like squash and plantains have significantly more potassium than grains, but it's not necessary to completely give up grains. I usually put a 50/50 potassium/sodium ("Lite") salt on the oatmeal or grits I make for lunch (work requires speed), but I don't bother with it otherwise.

[tysam_and]

Creatine for brain health is unbelievably good too IIRC (don't quote me on it though, please! ;P)

One of the hard parts of aging stuff is how nonlinear it is. A lot of the good drug treatments seem to be short term/cyclical, along with significant lifestyle modifications.

In addition to what the other commenter said, I've heard of OMAD and having a strong community/having a purpose or something to do as another strong factor in longevity, in the 90-100+ year olds in Japanese community for example. I can't remember if OMAD was correlated to that community or a different study, however.

[GordonS]

Can you say some more about brain health, like how much creatine to take, what the expected benefits are, please?

[tysam_and]

Here is a good article, I think my favorite part is the paragraph containing reference #146: https://www.mdpi.com/2072-6643/14/5/921

[Parmenidea]

Do you give any credence to the reports that creatine can cause hair loss? It seems like one study found a link, but nobody has tried to directly replicate it since. Anecdotally, Reddit is filled with stories of people claiming it caused hair loss, though I’m sure there are a ton of confounding variables.

[yeeeloit]

Seems to be one of those topics... but anyway this study from 2009 found that creatine did in fact increased DHT.

https://pubmed.ncbi.nlm.nih.gov/19741313/

To be clear, no one is arguing that Creatine causes hairloss, simply that it exacerbates hairloss in people with so called androgenetic alopecia.

I recall a study that was set to try and replicate these results, but I worry that it was impacted by COVID. If anyone else can find it, I'd be very interested to see it.

[chpatrick]

I think people will always seek dubious explanations for why they're balding apart from "bad luck" and "you're old".

[sn9]

https://examine.com/supplements/creatine/faq/ZJ73RJV-does-cr...

[tysam_and]

Well, people who use creatine also have a greater chance of having dihydrotestosterone, if I recall correctly....

Honestly hard to say, because that doesn't immediately "disprove" it either....

[m463]

Eating a calorie-restricted diet (fasting must be part of this).

[snvzz]

Intermittent fasting and eating keto rather than carbs.

Health aside, it is hard to stress how much better I feel on ketones, relative to carbs.

[shagymoe]

Anecdotally, creatine makes me angry and a little unhinged. I've found evidence of other people complaining about this but it's not considered a known side effect. YMMV

[ekanes]

Yes, creatine is everything you say, but it also seems to cause hair loss in males with male pattern baldness. If you look at youtube videos (for example) they often dismiss that, and then you see comment after comment of people who started losing hair. I'd use it in a heartbeat, but when I did my hair came out in the shower undeniably more. Boo. :(

[oarfish]

The study I'm aware of documents a links between biomarkers associated with hair loss and creatine supplementation. Not between supplementation and hair loss. Without clinical data actually demonstrating this, its FUD.

[ekanes]

Just because something isn't studied doesn't mean it should be dismissed as FUD. It's just unstudied.

[ekanes]

I have a hunch that lifting weights would qualify. Not a pill, but huge research behind its effectiveness at a host of things, including improved/maintained balance (when older, falling and breaking a hip is often the start of a downward spiral..)

[haskellandchill]

What about nootropics? What is the creatine of the mind enhancing drugs?

[tysam_and]

Weight lifting, ironically.

(see the rating + probability of positive effect charts here. [Warning, this is another insane rabbit hole of research to fall into!]): https://troof.blog/posts/nootropics/

[tonymillion]

Modafinil