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Calorie Restriction, Exercise, And Longevity: Luigi Fontana, MD PhD

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Hi Mike!

Thanks for posting this -- it was a pleasure to hear from Luigi again.

I also learned something new -- something that had been troubling me, and many (most?) other practicing CRONies -- why our IGF1 is not different from AdLibbers; while animals on CR had reduced IGF1.  Luigi pointed out that e.g. rats on CR, are fed once daily -- that's equivalent to a human fasting for several days.  Apparently, IGF1 drops, if one is fasting for long periods; that's appears to be why the animals on CR show reduced IGF1, but not humans.

Thanks again,

  --  Saul

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Thanks @Mike Lustgarten - great interview!

At 16:30 Luigi says he will soon publish a paper showing that CRONies in his cross-sectional study (that Saul and I participated in) who had a BMI less than around 19.6 were aging FASTER than normal according to the biological clock they looked at. That's disconcerting. I'm looking forward to seeing that paper. 

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1 hour ago, Dean Pomerleau said:

BMI less than around 19.6 were aging FASTER than normal according to the biological clock they looked at. That's disconcerting.

After that he blasts the notion of exercise being the most powerful anti-aging intervention.  I half expected he would next slam excessive cold exposure and excessive plant consumption but fortunately some sacred cows were spared.

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Thanks, Mike, a great interview.

Notable swipes at (Attia's?) claims that "diet doesn't matter" ironically combined with his "high-quality" (animal) protein push, and at the "exercise is the most important" for longevity.

I am curious if some extreme CR practitioners were significantly malnourished, which may explain the faster aging to an extent.

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I should listen again to the part on exercise . In his book 'The path to longevity Fontana stresses the importance of exercise and also proposes a weightlifting routine which to all effects is a routine for hypertrophy. So, he is convinced that exercise constitutes a primary intervention for longevity.

In Mike's podcast, he says that it is not proven that exercise is the best intervention for longevity, but he goes on to say that exercise has a positive effect on longer healthspan if I remember well.

On the other side, Attia provides often evidence that VO2 max is positively associated with lesser mortality, with very high HRs. Also, the literature is replete with studies outlining grip strength (a proxy for muscular strength) and its positive correlation with diminished mortality. The same cannot be told of dietary regimens, probably, that is, there are not so strong associations, with multiple times the HR. So, I think, Attia by logic deducts that exercise is the most important intervention.

I also add that there might be some pitfall in Attia's reasonings, like, elite endurance athletes (all with very high VO2 max) should have much lesser mortality than control, Is that proven?

AFAI remember, Fontana was specifically speaking about some studies on lab rats and exercise. So, it is not proven that exercise in rodents (mainly lab rodents?) is the most significant factor in longevity. Probably he meant that it has been disproven. But what about human beings, dividend into ages, dietary regimens, lifestyle and so on?

My point is that the issue, as usual, is far more complex that it may seem and that, even if exercise is not the most important factor for longevity, it is, as Fontana himself implies as well, one of the most important factors. Attia may say it is THE most important factor. What does it change? It may even be that the factor that governs longevity is different for every individual, for what we know.

My thought is that the effects are synergistic, so the factors are not independent of each other and the argument is moot.

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I'm 100% pro-exercise, as it is a part of the approach to improve healthspan and average lifespan, but where are the 115yr old fitness enthusiasts?

In terms of lifespan, exercise training is simultaneously good (increased average) and bad (not reaching the maximal).

Can we be more specific with regular training, to get closer to, or beyond the maximum? I say yes, and it involves daily monitoring of overtraining via HRV and RHR, which are great indices for that.

Peter's advice is basically the LaLanne approach, i.e. eat real food and exercise. I think there's a higher level compared to that.

Edited by Mike Lustgarten
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mccoy, you must remember that Fontana comes from the perspective of CR both in animals and in humans (since he was involved in the human studies).

One can speculate whether CR works at all in any animal or in primates or humans, but without opening that can of worms, classical CR studies have traditionally had a pretty clear position on exercise and longevity. So that's what  we'd posit from a perspective that "CR works":

Exercise does NOT extend maximum lifespan. Period. In contrast, CR DOES extend maximum lifespan (at least according to classical CR studies). That right there tells you everything - if you say "exercise is the most important factor in longevity" then that is clearly wrong, because restricting energy as a component of diet would show that it is DIET that is the most important factor in longevity, because it does extend maximum lifespan and exercise does not. 

In fact, at least in classical animal CR studies, you can comfortably achieve maximum lifespan in individuals that are CR'd and that do NOT exercise at all. So, sedentary but CR'd will let you live maximum lifespan, in other words, you can skip exercise altogether and live a maximum lifespan as long as you are CR'd. That not only makes exercise *not* the most important factor in longevity but a completely irrelevant factor in longevity. Now, there are various wrinkles here, insofar as there are studies that show that you can do a certain amount of exercise which would result in a slightly elevated energy consumption than max CR and also extend maximum lifespan similar to CR without exercise, but you cannot achieve maximum lifespan just with exercise (while you can with just CR). Then there are the rats with cold feet experiments and the whole cold exposure/heat shock proteins angle, but again, exercise is not the "most important" factor in longevity.

To put it bluntly, Peter Attia is clearly *wrong* in saying that exercise is the most important factor in longevity - it is not, diet is (treating energy intake as part of the diet).

So where does the all cause mortality benefit of exercise come in? It comes in for subjects that are AD LIBITUM in energy intake. What happens is that exercise attenuates rates of *premature* death. It still does not extend maximum lifespan, even in ad libitum subjects, but it certainly does lower *premature* all cause mortality. It "squares the curve" - instead of the curve of survivors gently going down with age - i.e. there are fewer and fewer individuals the longer the years lived axis in a cohort of non-exercisers, in exercisers the number reaching old age will be much greater. Here's how to think of it: exercise can help you reach your full potential ad libitum lifespan, compared to if you don't exercise, but it won't push you beyond that - meanwhile, you can skip exercise altogether and as long as you CR, you can push beyond what an optimally exercised ad libitum individual would achieve. Again, diet trumps exercise - Peter Attia is dead wrong (pun!).

Now, ignoring the whole CR angle, sure moderate exercise can help with healthspan, but you can't ignore diet quality either (apart from energy). That was Fontana's point - he claimed that exercise will not rescue you from a bad diet. 

But the real controversy is about quantifying the amount of exercise. Peter Attia claims that diet composition (let us assume energy intake is not a factor, apart from sticking to "don't overeat") is not very important - as long as your diet reaches a minimum treshold of "healthy", any longevity benefit from "excellent" diet is miniscule, whereas exercise will disproportionately influence longevity.

This is where the dispute enters. Just as Attia claims that minimum "healthy" diet is enough and "extremely healthy diet" gives almost no benefit, others would claim exactly the same about exercise - moderate exercise (a certain treshold of minimum) will give you almost all the benefits of longevity and doing more exrecise will also bring about minimal gains, if any at all. You gain the vast majority of longevity benefit and more exercise approaches the line of further benefits asymptotically - another 300% might give you only 1% longevity benefits. In fact one might posit the opposite from Attia: there is no treshold of healthy and "healthier" and "healthier yet" diet where a *more* healthy diet tips into "unhealthy" at some point along that continuum (again, apart from energy, because Fontana would maintain that too extreme an CR accellerates aging). Meanwhile, if you keep adding exercise, you might experience a decline in longevity. So that's an assymetry in favor of diet.

A larger point is that there are no studies conclusively proving that there is a longevity benefit to exercise beyond a moderate level. Obviously there may be performance or even perhaps quality of life benefits, but not raw longevity. It looks like moderate exercise will give you all the health benefits you can get and doing more will not make you live longer or even healthier necessarily with a caveat to performace - sure, you may be able to, say, lift 300lbs instead of 200lbs with more than moderate exercise, but who cares, as long as your activities of daily living (ADL) are not affected. If you enjoy exercise, go ahead, but if you don't (as I don't), then I'd rather do the minimum and save the time for more rewarding activities, since I will not experience health or lifespan benefits from more exercise and I don't care about sports achievements outside of ADL.

Meanwhile the issue of a U curve in exercise vs longevity is not settled. There are studies on both sides. There certainly are studies that suggest that beyond a certain level you not only don't get more health benefits of more exercise, but you actually start getting worse, and worse than if you were completely sedentary.

Either way, it seems pretty clear that Peter Attia does not have indisputable arguments proving that exercise is the most important factor in longevity (and all that without even getting into pharmacological interventions such as rapamycin, which looks like it might work better than exercise too!). 


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TomB, I don't believe that you are doing only moderate exercise, I remember you running regularly and doing hundreds of squats. Maybe that's your idea of 'moderate',. LOL.

Re. Luigi Fontana vs. Peter Attia. it all comes down to degrees of belief, to me. Nothing is really proven as you say, not even that CR in humans increases longevity. In lab rats, yes, but only in a few strains. Not in all lab rats though. It remains a very interesting hypothesis, yet far from being proven in human beings (and most mammals). This as far as I understood (I may have gotten it wrong).

For example: Luigi Fontana is a supporter of CR for longevity. Valter Longo says the opposite (CR is advised against). Both are eminent longevity researchers. Both have much in common. Yet they differ in this basic hypothesis (or better, belief). A lot in longevity is informed belief, very little is indisputable evidence.

The best I can do is to listen to the opinion of every credible expert and analyze them through the lens of my discrimination. Discussing opinions in this forum as well, the brainstorming sure helps.

After this stage, I'll pick single suggestions from everyone, what my reason and logic tell is valuable and applicable to my individual case.



Edited by mccoy
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You are right, mccoy. For cardio, I still jog four times a week 50 minutes each session, so 200 minutes per week, with a Swedish fartlek slash HIIT protocol each session I do four 30 second max speed sprints. 

Anaerobic these days I've cut back, two sessions a week of 30 minutes each continous squats with only 40lbs weight bar Hackenschmidt style (i.e. bar held behind your back). And two 30 minute sessions a week focused on the upper body. 

Is that moderate? Yes in my book, since it's only 200 minutes of not super intense (except the HIIT portion) jogging, and 120 minutes of not heavy weights per week, not much above official CDC recommendations.

You are right wrt. CR, it's just a hypothesis, I was simply saying that Fontana's views are informed by a CR perspective (whether CR is valid or not, is a separate issue).


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CR fits very good into https://en.wikipedia.org/wiki/Mitochondrial_theory_of_ageing

and all the strategies based on consume more energy to do more work are contradicting it. There is a small "zone of overlapping" of these "consume less" and "consume more" where probabilistically assessed chances of an individual organism are maximized but just plain body of evidence of what happens with bodies that consume more (not only those breaking the energy regulation machinery but also just those producing more raw physical work and getting bigger stronger bodies) suggests that this overlap is not wide.

IMHO off course



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4 hours ago, TomBAvoider said:

Is that moderate? Yes in my book, since it's only 200 minutes of not super intense (except the HIIT portion) jogging, and 120 minutes of not heavy weights per week, not much above official CDC recommendations.

Tomb, to me it sounds like an appropriate routine for healthspan, suited to your personal requirements, which may be different from others. My weekly routine is shorter for example, so far 90 minutes cardio zone 2, mainly, and 120 minutes weights although the latter includes pauses within sets which can be sometimes lengthy.

According to an article recently posted in these fora, our routines would be excessive and would imply an RR for all cause mortality higher than unity, the optimum being 40 minutes per week. Less than 6 minutes per day! I really wish it! That study seems to be excessively biased toward shorter times of exercise.


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mccoy, I'm aware of those studies, but I don't have enough information about some aspects. For one, does the time include rest time between sets or not? I assume not - and in any case, I personally don't use much rest between sets, practically none, as in close to circuit training.

The latter point is also of interest in this context. How *exactly* do they define this type of exercise? After all, even cardio uses muscle, and the exact dividing line is tricky. I say this, because my exercise is very specific and carefully designed.

How do you classify circuit training? Cardio *and* weight - if so, does circuit training fall under the graphs in these studies? I suppose you could say it depends on the proportions of weight vs cardio. Example: very light weight vest while jogging - still cardio? Heavier weight vest just walking - cardio? 

Squats, even air (bodyweight) squats are often classified as weight training (hello leg day!). But why? Because they are not cardio - i.e. do not involve much sustained cardio-pulmonary exertion. However that is only true if you do a limited number of squats. What if you do my style of squats: 30 minutes of nonstop squats with only 40lbs weight (btw. full squats, so called ATG - a$$ to grass)? I can promise you it fully involves sustained cardio-pulmonary exertion - you are breathing hard and sweating heavily. If you want to still call it "weight training", you can probably duplicate the same effect by running up a steep mountain or long stairs - people would call it "cardio", even though it stresses the leg muscles like my squats do.

When I do my upper body workouts, I do them pretty much without pauses between sets, circuit training style, though using very light weights (10-40lbs). Example: 12 reps bicep curls - 12 pushups - 12 reps bicep curls - 12 reps pushups and so on for a few minutes, then immediately 12 reps Arnold flies - 12 reps back rows - 12 Arnold - 12 rows etc. for another few minutes, various core exercises and so on for a total of 30 minutes. Is this cardio or weights as far as those studies are concerned?

Also, even though it's high reps light weights, my style involves more than endurance slow twitch fibers, because of how I execute the movements. I try to do *very* explosive concentric movements, to train for *power* - for example I explode up from my squats, almost jumping with the 40lbs, meanwhile I do very slow eccentric movement with a isometric pause included because that maximizes muscle volume. So a squat: 3 second descent plus a 3 second isometric hold slightly below parallel, plus 2 second further descent until my buttocks touch my heels (I do all my squats on my toes) then explode up *less* than 1 second and so on nonstop for 30 minutes. The same protocol for my upper body exercises - explosive concentric, slow eccentric, incorporating isometric holds. This involves fast twitch and slow twitch fibers, endurance, power, and muscle volume, so cardio and weight bearing  IN THE SAME EXERCISE. How much time would be counted in those studies for those graphs with this protocol? 

Here is the kicker: if a very overweight person jogs, or even only walks, they are doing what is classically called cardio, yet they are carrying a huge weight stress on bone and muscle - in fact, overweight people have some of the benefits of weight bearing exercise in stronger bones. But if I put on a weight vest of the same weight or do my squats for equally long heavy breathing sweating exercise I'm suddenly not doing cardio? 

I suspect my exercise style is quite atypical and not what those studies classified when they examined typical weight training. So how relevant are those studies to my exercise?

Therefore when you bring up those studies and say my 120 minutes of weight training is "too much" according to them, I say I don't know, because I don't know how my exercise protocols fit into their study parameters.




Edited by TomBAvoider
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On 9/19/2023 at 6:42 PM, TomBAvoider said:

So a squat: 3 second descent plus a 3 second isometric hold slightly below parallel, plus 2 second further descent until my buttocks touch my heels (I do all my squats on my toes) then explode up *less* than 1 second and so on nonstop for 30 minutes.

The above would probably constitute more of and endurance duty, probably zone 2 due to lactate development but not very high, congratulations because it's pretty tough, I already told you you are a missed navy seal!

Re. the article, if I remember right it also considered endurance exercises, so we would all derive increased mortality for our efforts.

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