CR and Exercise

[Michael R]

I wrote this survey of the literature in the early 200s; there have been a few studies examining the intersection of CR and exercise since then, but none to my knowledge have been lifespan studies, and therefore don't ultimately resolve anything.

The findings from existing studies are that:

1. Exercise-induced Caloric deficit (ECD) ALONE does not extend maximum lifespan (LS) (1-10). The majority (1,3-6) of studies find that it increases average LS, but a substantial minority (2,8,9,10) haven't even found this. It improves health, but it does not slow aging.

2. CR alone increases max and average LS (2,5-10). It slows aging, and thus improves health.

2a. CR alone causes a greater increase in average LS than does an equal degree of CD from exercise alone (2,5,6); likewise, albeit less powerfully (because less rigorously), 40% CR ALONE causes a greater increase in average LS than does the large ECD (alone) typical of the AL, voluntary-exercising rat (2). Likewise for alternate-day fasting (EOD] vs voluntary exercise (7,10). The health results of slowing aging (thru' doing CR) are greater than those from exercising.

3. Within the confines of what Steve Austad once called "full-blown, weep-on-your-knees CR" (≥40% CR [the most commonly used in studies on "the effect of CR on parameter X,"]) none of the studies (2,7-10) examining the effect of adding extra CD via ECD at a given absolute caloric intake in CR found further increases max LS. (9), in fact (which was on forced exercise, unlike the voluntary exercise in the other studies), found a decrease in max LS.

The above points clearly show that ECD is NOT equivalent to CD from CR.

5. CR + ECD at a given absolute caloric intake yields inconsistent results on average LS relative to that level of CR alone: 2 studies found a benefit ([2,9] — NB this latter still found a shorter max!), another reported a detriment (5), as apparently did (7); (8) found no effect.

Now things get tricky!

6. What happens when you put an animal on full-blown CR, and compare it to an animal on LESS CR, but with the difference in CD "topped up" with ECD, such that the total CD is equal to "full-blown, weep-on your knees CR"? This is what (3) tested in comparing groups C and D (both at 44% CD). And, the "responsible" reading is that the two are equivalent. That is, there ARE nominal differences between the two — the CR-only group DID have longer average AND max LS than the combined-CD group — but the differences were statistically insignificant.

Likewise with Holloszy's earlier work (5): when a group given full-blown CR (group E, 40% CR) is compared w/a group on mild CR (24%CR) + ECD to bring the total CD down to the same level (as assessed by BW: group D), there there are no statistically significant differences in max or average LS; yet the nominal data favor the CR-only group on both points.

The most scientifically respectable conclusion to draw from this (these are AFAIK the only data on this key point) would be that "two nonsignificant differences do not create a significant one." But to see the same patter repeated twice is, to me, "suspicious" -- esp in light of all the other data clearly showing the greater LS results from CR vs ECD. The cohorts having been so small (n=30 (D) & 44 (E) in (5), & 31 © & 65 (D) in (3)), it's easy to see a significant difference being masked by sheer lack of statistical power.

This, unfortunately, is the one piece of data MOST relevant to the human CR practitioner. We don't have the answer. But clearly, ECD is not fully equivalent to CR, even when the 2 are combined, under any other circumstances; my guess is that the same holds here.

Implications for Human Practice
I simply don't believe that anyone is doing the human equivalent of genuine "weep-on-your-knees" CR on a voluntary basis: few of us are doing CR at all, as vs. healthy weight maintenance, so my point (3) above simply falls out of it. The key findings are therefore those discussed in my points (5) and (6) above.

There's obviously a bit of a tension between these 2 sets of findings, in terms of how one should govern oneself and extrapolate from current practice, unfortunately, but Holloszy's key study (1) below, and the centerpiece of my point (6) is a better-quality study, and probably should be given more weight. Thus, it does appear that, once you pass a certain minimum threshold (significantly more than healthy weight maintenance), Calories burned thru' exercise probably does add to Calories not consumed in the first place — just not as fully, and with some manner of ceiling or asymptote.

At the end of the day, clearly, a person should do as intense a level of CR as s/he finds tolerable, subjectively and on a risk-management basis; any additional benefits to Calories burned to exercise (as opposed to the direct benefits of cardiovascular fitness, bone health, strength, etc) are gravy — but should not be assumed to be fully equivalent to Calories not consumed in making tradeoff decisions.

Also, Holloszy's studies in particular are consistent on every point except one: does combining exercose with a given level of CR increase early mortality? (5) found yes; (3) found no. The data on the same point published by other labs are likewise inconsistent. We ought to suspend judgement on this point, IMHO.

Another interesting point: (7) reports that CR animals overall ran less for the first ~3.5 mo of CR than ALers, & cites previous work (8,9) as reporting the same thing. 3.5 mo ~11.6 human years. Not too damned many of us fall into that length of CR!
 
Semi-Digression on Mitochondria
Another interesting tie-in is with de Grey's hypothesis on why CR reduces mtDNA damage and, thus, ultimately, aging.((15), and see (14) for background) It involves shuttling more NADH away from the mt to a surface membrane electron acceptor — the PMRS. de Grey's theory predicted this phenomenon, and subsequent experiments (16,17) confirmed it. Fewer electrons into the electron transport chain, fewer fumbled, less mitochondrial inner membrane damage, less passed along to mtDNA. But ALSO, less energy being produced per electron run thru' the system at peak output. Perhaps the subjective feeling of a paradoxical inability to run harder, despite the fact that one is not really breathing hard yet, is the subjective correlate of this experience?

One last point. There may be another reason exercise might help slow aging, under the right circumstances — again, tying in with MiFRA. One intuitively expects that MiFRA ought to mean that exercising should speed aging due to more ROS being produced. Yet it doesn't. The reason, as de Grey points out, is that exercise doesn't actually increase the number of e- being rushed thru' each mt, because the number of mt are increased. Thus, the danger of ROS damage to mtDNA remains the SAME for each mt.

And yet, this isn't quite the whole story, because an equal chance of an accident happening per car still leads to more accidents total when there are more cars on the road. De Grey agrees that this thus predicts some pro-aging effects of exercise, but that they would be minor. I've never found this to be fully convincing.

Well, exercise has a mitigating effect.

Apparently, "physical exercise .. modifie the fatty acid profile of the mitochondrial membranes. Total monounsaturated fatty acids decrease [and] Total polyunsaturated fatty acids in mitochondrial membranes of LIVER increase (P < 0.005) after exercise but [PUFA] in mitochondrial membranes of skeletal muscle decrease (P < 0.05)." (13) As those familiar with MiFRA will know, the former "don't count," but the latter are central, to the hypothesis. A decrease in mt membrane PUFA (which, NB, by the structure of phospholipids entails of necessity a concomitant increase in MUFA) would decrease the desaturation index of individual mt, increase their resistance to oxidation, & thus actually reduce the odds of each mt going evil on us.

 

References
1: Holloszy JO. Longevity of exercising male rats: effect of an antioxidant supplemented diet. Mech Ageing Dev. 1998 Feb 16;100(3):211-9. PMID: 9578110 [PubMed - indexed for MEDLINE]

2: McCarter RJ, Shimokawa I, Ikeno Y, Higami Y, Hubbard GB, Yu BP, McMahan CA. Physical activity as a factor in the action of dietary restriction on aging: effects in Fischer 344 rats. Aging (Milano). 1997 Feb-Apr;9(1-2):73-9. PMID: 9177588 [PubMed - indexed for MEDLINE]

3: Holloszy JO. Mortality rate and longevity of food-restricted exercising male rats: a reevaluation. J Appl Physiol. 1997 Feb;82(2):399-403. PMID: 9049716 [PubMed - indexed for MEDLINE]

4: Holloszy JO. Exercise increases average longevity of female rats despite increased food intake and no growth retardation. J Gerontol. 1993 May;48(3):B97-100. PMID: 8482812 [PubMed - indexed for MEDLINE]

5: Holloszy JO, Schechtman KB. Interaction between exercise and food restriction: effects on longevity of male rats. J Appl Physiol. 1991 Apr;70(4):1529-35. PMID: 2055832 [PubMed - indexed for MEDLINE]

6: Holloszy JO, Smith EK, Vining M, Adams S. Effect of voluntary exercise on longevity of rats. J Appl Physiol. 1985 Sep;59(3):826-31. PMID: 4055572 [PubMed - indexed for MEDLINE]

7. Goodrick CL, Ingram DK, Reynolds MA, Freeman JR, Cider NL. Effects of intermittent feeding upon growth, activity, and lifespan in rats allowed voluntary exercise. Exp Aging Res. 1983 Fall;9(3):203-9. PMID: 6641783; UI: 84057947
"There is also an indication that [EOD CR] was somewhat less effective in enhancing [LS] in the exercised rats, when compared to the survival of groups fed EOD in conventional cages. The mean [ls] of 124 weeks in the exercised EOD group is nearly 14 weeks shorter than that of a caged EOD group prevously observed in our laboratory. Of course, [comparing data from seperate studies is problematic]."

8. Goodrick CL, Ingram DK, Reynolds MA, Freeman JR, Cider NL. Differential effects of intermittent feeding and voluntary exercise on body weight and lifespan in adult rats. J Gerontol. 1983 Jan;38(1):36-45. PMID: 6848584 [PubMed - indexed for MEDLINE]

Max LS data cribbed from (11): 158 vs. 145 weeks, sedentary vs. exercising CRONies. Max LS in ALers: 88 vs. 115 weeks -- ie neither AL group broke SPECIES max LS.

9. McCay CM, Maynard LA, Sperling G, and Osgood H. Nutritional requirement during the latter half of life. J Nutr. 1941;21:45-60.
(Yes, THAT McCay!) result cribbed from (11).

10. Beauchenne RE, , DellwoM, Darabian P, Haley-Ziltin V, Wright DL. Biological aging and longevity in diet-restricted and exercised rats. Abstracts of Biological Effects of Dietary Restriction, an international Conference. Washington, DC:1990. Results cribbed from (11).

11. McCarter RJ. Effects of exercise and dietary restriction on energy metabolism and longevity. In Yu BP (ed). Modulation of aging processes by dietary restriction. Boca Raton, FL: CRC Press, 1994.

12. Austad, Steven. Why We Age: What Science Is Discovering About The Body's Journey Through Life. Paperback, 256 pages . April 1999: John Wiley & Sons, Inc. ISBN: 0471296465

13. Quiles JL, Huertas JR, Manas M, Battino M, Mataix J. Physical exercise affects the lipid profile of mitochondrial membranes in rats fed with virgin olive oil or sunflower oil. Br J Nutr 1999 Jan 81:1 21-4

14. The Mitochondrial Free Radical Theory of Aging Aubrey D.N.J. de Grey Landes Bioscience, 810 South Church Street Georgetown, TX, USA tel: +1 512 863 7762, fax: +1 512 863 0081 ISBN: 1-57059-564-X

15: de Grey AD. A proposed mechanism for the lowering of mitochondrial electron leak by caloric restriction. Mitochondrion. 2001 Aug;1(2):129-39. PubMed PMID: 16120273.
 
16: Hyun DH, Emerson SS, Jo DG, Mattson MP, de Cabo R. Calorie restriction up-regulates the plasma membrane redox system in brain cells and suppresses oxidative stress during aging. Proc Natl Acad Sci U S A. 2006 Dec 26;103(52):19908-12. Epub 2006 Dec 13. PubMed PMID: 17167053; PubMed Central PMCID: PMC1750890.
 
17: López-Lluch G, Rios M, Lane MA, Navas P, de Cabo R. Mouse liver plasma membrane redox system activity is altered by aging and modulated by calorie restriction. Age (Dordr). 2005 Jun;27(2):153-60. doi: 10.1007/s11357-005-2726-3. Epub 2005 Dec 10. PubMed PMID: 23598622; PubMed Central PMCID: PMC3458500.

[mikeccolella]

well I think the problem is that studies do not measure 24 hour energy expenditure. The exercising twins might be lounging around more than their so called non exercising twins for all we know. A person takes a walk and then feels like they can take off the rest of the time. We have seen research that suggests exercise couped with a sedentary lifestyle is not very effective for overall health. But The evidence for being active vs sedentary is compelling for a whole host of reasons, but I agree marathoning etc. is probable a negative. My hunch is that simple purposeful activity is a survival advantage.

[Saul]

Hi Gordo!

 

I'll respond to your query:

 

I started practicing CR since 04/1996 -- so for a little over 21 years.  I've also been a fairly vigorous exerciser since age 21. For the last decade or so, I work out 6 days a week in my gym, on the latest model Precor elliptical cross trainer with arm motion, at the maximal resistance for an hour -- covering a little over five miles distance.  This provides high quality aerobic exercise -- and, because it is preformed at the maximal resistance of the machine, has some muscle strengthening effect as well. 

 

I will be 78 later this month.  I feel great.  I don't feel problems with sarcopenia.  I'm a Full Professor of Mathematics at the University of Rochester, with a full time teaching load.   And I published a mathematics research book with World Scientific last summer.

 

I find that exercise works well synchronously with CR.  Last term (Spring, 2017), my teaching schedule forced me to reduce my exercise time to 30 minutes instead of an hour.   It left my skeletal muscles feeling a bit weaker.  I  was happy to return to a full hour on the elliptical at the end of the term, and I feel great again.

 

So:  I am a long term CR practitioner (over 21 years); and I feel great, and I continue to be quiet active.  And, at least in my case, I find it virtually necessary to exercise, fairly vigorously, for a full hour, with an aerobic exercise that also has some strengthening effects, almost daily (in my case, 6 days a week).

 

  --  Saul

[Mechanism]

Edited

[Sibiriak]

Michael R:  Also, Holloszy's studies in particular are consistent on every point except one: does combining CR with a given level of CR increase early mortality? (5) found yes; (3) found no.  [blue color added]

 

Should that read "combining exercise with a given level of CR"?

 

I'm going to suggest a new thread, "Gaining Healthspan without Lifespan" or somesuch, ito which I'll move your posts.

 

I'm looking forward to that thread...

[Gordo]

Thanks for sharing Saul.  Interestingly, my Dad is the same age as you (to the year) - he doesn't practice CR, but isn't overweight, does a lot of gardening and walking, and eats a lot of superfoods and especially nuts.  I'm eager to learn what I can from his (and your) experiences.

Gordon in the Biblical Garden

 

Regarding "Gaining Healthspan without Lifespan" -- who believes that extreme calorie cutting alone can increase lifespan?  I believe there are multiple ways to fundamentally slow the aging process (and ward off the leading causes of death).   

[Michael R]

Bringing back in some material germane to the thread that was moved elsewhere:
 

Nice overview, MR! With time, I've grown ever more skeptical about extrapolating almost anything from rodents to humans. It's gotten so bad, that when I see a paper that says "in mice" or rats, I don't even bother to read it. To me, studies done in mice or rats apply to mice or rats, and that's that - and only to a given strain of rodent.

The squaring of the curve question wrt. exercise therefore is another way of addressing the question of how close the relationship between lifespan and healthspan is.

Thank you Michael for that very helpful and lucid synopsis. Indeed you make a strong argument that "Calories burned thru' exercise probably does add to Calories not consumed in the first place — just not as fully, and with some manner of ceiling or asymptote." The semi-digression was also interesting and worthwhile keeping with this post.

[mccoy]

Deleted because related to the moved post

[Michael R]

(AIL's and others' discussion of "CR weight" is now in the thread "How to determine my goal weight?".