Some concerns around caloric restriction longevity studies in mice

#1

So, I think we’re all familiar with the longevity studies that show caloric restriction extends lifespan in mice. Many drugs and longevity ideas for humans are also based on the idea that some part of the chain of caloric restriction’s biological interactions is good for lifespan (e.g. fasting, ozempic, etc, are based on “body consume less = good”).

However I’m concerned about some things here and would like some input from other people who may know the subject well:

  1. Are these mice being fed healthy diets? Or are we just seeing positive effects from generally putting less bad things in their bodies? AI tells me they were eating casein, corn starch & sucrose, and soybean oil. I’m not sure those are good choices if we’re interested mainly in the effect of caloric restriction. They may be particular stressors of some other thing causing early death.

  2. These mice appear to be dying primarily from cancer. The ones who are on CR just die from cancer later. Isn’t CR basically targeted to prevent cancer growth, or at least over a lifetime would cause cancer onset to happen later in life and thus extend the lifespan? i.e. if mice are particularly prone to die from cancer, then CR is just a good life extension strategy specifically for mice.
    In humans, cardiovascular disease is the leading cause of death, and I don’t see that CR is a good treatment for cardiovascular disease. In particular, cardiovascular disease seems to be mainly caused by diet and habits, not by number of calories consumed. If that is the case, it may not make sense to extrapolate: CR extends mice (who are prone to cancer death) lifespan to CR extends human (who are prone to cardiovascular disease death) lifespan.

Thoughts?
Are there good responses to these concerns?
Is CR well established enough, controlling across a plethora of animal species and across a plethora of diet compositions that we can safely extrapolate it to a large set of animals and diets?

#2

This is expected for the types of mice they use in those studies. They will all die of cancer.

#3

Sure, but my main idea there is that the best strategies for prolonging life in organisms that primarily die of cancer may be different from the best strategies for organisms that primarily die of cardiovascular disease. i.e. we should not try to extrapolate these results to humans.

#4

Your question contains the answer. The number of CR studies since the 1930’s has been practically countless, not just in mice and rats of various strains, but other species too, including dogs and even cows. Recently there were results in mice where CR was instituted in two cohorts with the difference that one had access to their isocaloric allotment spread across the 24 hr time span, and the other got it all at once resulting in the mice being fasted the rest of the time. It was the fasted mice that got the benefit - and since the calories were the same, clearly it’s not a “less bad diet” effect.

Anyhow, as you can imagine your questions are some of the ones that come to mind most readily. Since these CR experiments were conducted by a variety of scientists over decades, it’s safe to assume that these very obvious questions occurred to at least some of them also, them being specialists in the field where they spent years thinking about such issues, and they’d have taken steps to account for that. This line of thought would prompt me to immediately search the literature for answers to such questions. This, btw. is the rule of thumb I use in general - if confronted with extensive literature in a field I’m not super familiar with, I assume that questions that occur to me (a layman) must have occurred to the specialists in the field, and then I start looking for answers. You asked good questions, and they have good answers and that is as it should be​:v::grinning:.

“In humans, cardiovascular disease is the leading cause of death, and I don’t see that CR is a good treatment for cardiovascular disease.”

And why would you say that? If you are not really familiar with CR research - and based on your questions and speculations, clearly you are not - then why would you make assertions about what CR can and can not affect either in humans or animals?

Caloric restriction alone and with exercise improves CVD risk in healthy non-obese individuals

Long-Term Caloric Restriction Improves Cardiac Function, Remodeling, Adrenergic Responsiveness, and Sympathetic Innervation in a Model of Postischemic Heart Failure

“Caloric restriction (CR) has been described to have cardioprotective effects and improve functional outcomes in animal models and humans.”

If you are interested in some results of a CR intervention in humans, you can also look at the CALERIE study:

2 years of calorie restriction and cardiometabolic risk (CALERIE): exploratory outcomes of a multicentre, phase 2, randomised controlled trial

Anyhow, you, like anyone, certainly have a lot of questions about CR and PubMed searches can be very helpful here. Once you become familiar with the literature, you will likely still have very complex questions, at which point you can always post them here for answers from those who have devoted a lot of time to the field. It’s good to be curious!

#5

Recently there were results in mice where CR was instituted in two cohorts with the difference that one had access to their isocaloric allotment spread across the 24 hr time span, and the other got it all at once resulting in the mice being fasted the rest of the time. It was the fasted mice that got the benefit - and since the calories were the same, clearly it’s not a “less bad diet” effect.

If the allotments are isocaloric, then isn’t it also not a CR effect? I’m not seeing the relevance. This seems orthogonal to the CR question, and is a new claim that fasting is beneficial for longevity.

And why would you say that? If you are not really familiar with CR research - and based on your questions and speculations, clearly you are not - then why would you make assertions about what CR can and can not affect either in humans or animals?

My statement is that I do not see that it’s true, not that it is not true.

It’s good to see that there are some rudimentary studies that show some positive effect wrt CVD from CR, but these studies linked don’t actually state what the participants were eating, so again we don’t know if they should attribute the results to the CR or to simply eating less bad things.

And finally I’ll say that your statement that we should assume that scientists and specialists are doing a good job at answering very obvious questions is very dangerous and I will never adopt that mindset. Maybe I’m bad at finding answers or my standards are too high but I’m basically finding that most if not all studies (increasingly with their similarity to humans) are not using optimal food for their CR studies.

#6

Come again? The idea here is that CR has benefits when two conditions are met: number of calories are cut, and that fasting is instituted. Fasting by itself doesn’t result in life extension without cutting calories - if you eat ad lib and then fast, you don’t benefit. If you do CR, but also fast, you get all those additional benefits. Now being isocaloric is precisely what demolishes the “bad diet” argument. Because you have a “bad diet” in both cases - in both cases on CR you eat less, but if you also fast, you get benefits in life extension. If the “bad diet” was key, then it should have been equally bad for both cohorts since they ate the same amount (isocaloric). Crude example, if we are testing to see if there is arsenic (bad diet) in a food, then an equal dose (isocaloric) should kill both. Not that one is spared. Both took the exact same (CR’d) dose. That tells me that the diet doesn’t have arsenic since one survived even though both took exactly the same dose (isocaloric). So it’s not the diet quality being poisonous.

As to diet quality and CR studies. There have been literally thousands upon thousands of studies in a variety of species all showing the same effect. For diet quality to be the deciding factor, you’d have to have had a bad diet in literally all those thousands of studies - and the diets varied enormously. That would be quite the coincidence if each and every diet was “bad”. Like lottery odds. It’s starting to sound like a “no true Scotsman” problem. You can claim that every time the ad lib didn’t beat out CR for LE, it’s because the ad lib diet just wasn’t “good enough”. Here, we can extend this argument to gunshots to the head. Someone says “gunshots to the head are strongly against life extension” - and someone else can say “but that’s only because they have a bad diet”, on a good diet, their heads would grow bone to withstand a gunshot. And no matter that we have thousands upon thousnds of gunshot studies with a tremendous variety of diets, they’re never theoretically “good enough” to grow that bone. It’s a bonehead argument.

But OK, I’ll prove it to you and demolish your argument. One factor in longevity of animals is the very obvious one - husbandry. Poorly kept and cared for animals (mice, rats, whatnot), lead shorter lives. That is also well known in all studies. The husbandry factor. So how have scientists gotten around that factor? You are skeptical that they can look adequately at such basic objections - but here they have. Namely, that mice and rats (and all animals) have maximum lifespans. Poorly kept animals - which includes poor diet as that’s obviously a big factor in husbandry :roll_eyes: - lead shorter lives, period. So you account for all that by having your controls live close to maximum lifespans. If well kept mice of a good strain live around 900 days, then if your controls live for 900 days, obviously their diet is good enough to allow the natural maximum lifespan of their species. Again - the species, because there are no recorded examples of naturally longer lived ones in that species (whatever it may be). That’s the maximum. Period. Now, you do your intervention - in this case CR. If your CR suddenly takes the mice to 1200 days, you’ve just beat the lifespan records by a country mile. Sorry, but that’s not due to diet or any other aspect of husbandry - that’s the freakin’ intervention (in this case CR). That’s the whole point of the so called 900 day rule by Matt Kaeberlein. His point is that if your controls (for any intervention) don’t live for 900 days, you are likely dealing with poorly kept or screwed up mice, and your intervention (drug, CR, whatnot) cannot be legit claimed to be extending maximum lifespan, only possibly fixing what’s wrong to begin with in your husbandry (say, diet quality - as in your exact example!), and therefore your result has little value. Meanwhile, if you pass the 900 day test, it’s like a stamp of good husbandry (which prominently includes diet), and the rest is the intervention effect, particularly - as is the case with CR - when the effect is HUGE. That’s not compensating for a bad diet. No amount of fancy diet composition takes a mouse cohort outside it’s alloted 900 days give or take a few weeks. And then WHAMMO, you get a 40%, 50%, 60% life extension, dear Virginia, that’s not diet related at all.

It’s good to be skeptical - as you are. It’s even better to be skeptical of your own ideas, by questioning them. If you are tempted to say - as you do - that the thousands of scientists who devoted their lives to these studies just missed the obvious you came up by your lonesome self in a few minutes, then hold on to that temptation and ask yourself: how likely is that, what are the odds of that being the case, and what evidence can I dig up to prove or disprove my case, before asserting that all those rubes in lab coats are confused doofuses. I leave you with this Feynman quote:

The first principle is that you must not fool yourself and you are the easiest person to fool. - Richard P. Feynman

Before I’m tempted to drink my own bathwater, I do a sanity check, figuring that maybe, just maybe I have not thought up an extremely basic objection that just didn’t occur to all those geeks in lab coats. Stay alert, but stay humble! And at least not outside of sanity defying odds…