16 replies to this topic

[leha]

I'm not talking about intermittent fasting, here, but rather, what happens if you (or another species) are on CR for several months, then go ad libitum, then back on CR for several more months, then back off for another period, then back on.

I can't imagine it's a very healthy thing to do, but I just wonder if it's been studied. There are the questions of the possible cumulative effects of CR, as well as possible metabolic issues from going back and forth, and maybe even just issues from stopping CR at all.

There might be studies I haven't come across, or people that went on CR for a time and then stopped, and I'd like to hear from those.

Anyone have any info on this?

Edited by leha, 15 September 2010 - 09:54 PM.

[Sillewater]

A women could practice CR and then at 50 decide to have children because during that time CR has slowed down aging (possibly I'm not sure if it has had an effect on the age of the oocytes that have been frozen in prophase), a better example would be a man who will maintain fertility into much older ages. But I do not know how long it takes for CR to take effect so that the long-term benefits could be realized.

[e Volution]

Probably posting above my knowledge quota here, but don't we now know that aging is a multifaceted affair with numerous processes constantly taking place that contribute to the whole. I would think then that the benefits of CR are almost certainly cumulative, upregulating repair mechanisms, lowering the buildup of junk, preserving telomers, lowering the loss of cells, etc?

[leha]

That's what I'm hoping, e.

I just wish there were some studies or stories or something to confirm it.

[JLL]

The time you're not on CR is time you're aging at normal speed. At least, that's the case in rodents.

The problem is that CR should be induced slowly in order to get the benefits. Slowly as in the course of months or years. That doesn't go well with the idea of intermittent CR.

[leha]

Thank you. That makes sense.

[Guest]

Well, IMO the issue with switching between CR/ad lib is probably the weight loss/gain involved. My oppinion: when you are on CR and go back to ad lib for 6 month you more or less rapidly will regain you ad lib weight. Switching back to CRON for 6 month would mean

a) you have to start slowly again, to limit the weight loss to a certain rate, thus you will on average have only a low level of CR before you start ad lib again 6 month later

or

b) you will jump from e.g. 2500 kcal to 1750 kcal at once, resulting in rapid and unhealthy weight loss (and this every year you do the cycle)


but if you manage to limit your weight gain during ad lib periods, I could imagine that switching could be done without much harm

[leha]

That's an interesting theory, but I never meant to imply six-month on and off periods. When I said "several months" I was thinking more like 2-3 years. Still, the notion that maybe the amount of time and the length of transition can influence the result is intriguing.

In my case, I was doing mild CR for about six years, then fell into a 4yr relationship that involved a more ad lib style of eating. Eventually that broke off and I went back to my old habits (CR) for about another 2-3 years, then got in another relationship that initially involved a lot of restaurant eating (for the first couple of years), then got seriously ill for 6-7 months, then I very gradually (over 2 years) returned to good nutrition, and finally, in the last few months, to CR again.

Only in this last round did I even know about CR for longevity. I was previously just obsessed with healthy eating and staying thin. Plus I have always been into growing or foraging my own food (the latter being more of a hobby than a true means of sustenance). So overall, it was CR, but I didn't know it--until having gotten so sick left me weak as a kitten and then I started studying what I could do to get my strength back. While I was doing that, I stumbled on CR, because there is so much research on the subject it's hard to avoid. I realized that the reason I was always so much stronger and healthier was the CR, so I decided I had to return to that way of living.

It is definitely making me strong again, but I wonder how much time/health I lost going back and forth like that.

The sickness I had is classified as an autoimmune disease, but in my case it was a reaction to antibiotics. I'm pretty sure whatever cumulative strength I'd gained during CR periods helped me through that a *lot*, but I wonder, too, if I might have avoided that strong reaction if I'd just stayed on CR in the first place... It's a long shot, but maybe?

[Matt]

I had a huge reaction from antibiotics too while i was already on, so maybe not ;-) I had a reaction to ciprofloxacin invloving lots of tendon damage, nerve damage, chronic insomnia... many of other things too... (3 doses). It took around 2 years to fully heal CR doesn't protect you from everything haha

Edited by Matt, 20 September 2010 - 03:53 AM.

[leha]

Oh, man--that hurts. Yeah, but I'll bet the CR made you heal faster or kept it from killing you. Drug reactions are the worst!

[Michael]

I'm not talking about intermittent fasting, here, but rather, what happens if you (or another species) are on CR for several months, then go ad libitum, then back on CR for several more months, then back off for another period, then back on.

I can't imagine it's a very healthy thing to do, but I just wonder if it's been studied.

I would agree in general with previous comments about the importance of gradual weight loss, which somewhat renders the question moot, and of the cumulative effects of CR. There are no strong, direct studies of this matter. On the one hand, there are several studies on short-term (a few days to a couple of weeks) "cycling" on and off of CR for a week or so in rodents administered nasty toxins or very high-saturated-fat diets (which do incrase cancer in many rodent models, thoh' it's clearly irrelevant in humans), which find that either has no beneficial effect upon (1-4), or actually INCREASES (5-15), such carcinogenesis. Models using leptin knockout animals with a viral oncogene show a protective effect,((16), and others by this group) but that's an even less relevant model.

Also not quite what you're looking for, but more informative, are (17-19), which are for single periods at different point in the lifespan, not a series of such cycles:

Male Wistar rats were maintained on four dietary regimens: fed ad libitum throughout life (A); fed intermittently either during the first year of life and ad libitum thereafter (RA) or vice versa (AR); and fed intermittently throughout life ®.[Yes, actual Caloric intake was reduced in this study -MR] Low body weights, low amounts of body components (protein, fat, moisture, and ash), and long life spans were observed in R. AR and RA lost or gained body weight, respectively, after dietary transfer and lived longer than A. Maximum body weight and the age at which it was attained were correlated positively with life span in A. Predicted mature body weight was correlated negatively with life span in R. RA and AR differed in growth and body composition, but their life spans were similar and intermediate to those of A and R. Increases in life span were obtained by intermittent feeding during all or part of the life span, but growth and body composition data did not consistently explain the mechanism of this effect.(17)

Here are the exact LS numbers (Table 5):

Group||Mean LS(wk)|| Maximum LS* (wk)
--------------------------------------
AL || 133.1 +/- 4.1 ||169.4 +/- 1.9
CR || 163.4 +/- 3.9 || 200.1 +/- 3.1
AL-->CR || 150.0 +/- 4.6 || 178.6 +/- 1.5
CR-->AL || 149.2 +/- 3.6 || 182.6 +/- 2.1
*Mean survival time for the longest lived 10% of each population.

Back-of-the-envelope calculations suggest the AL/R and R/AL mice had similar lifetime energy intakes.

Then there's (18) (check out rows 1-3 adn 5-8):



... and (19) (diets eaten from 6 weeks (weaning) to 6 months are given first, followed by that eaten from 6 mo until death):

Group||Mean LS(d)|| Maximum LS* (d)
-----------------------------------
AL/AL|||| 701 |||| 822
CR/CR|||| 1057 ||| 1226
CR/AL|||| 808 |||| 918
AL/CR|||| 941 |||| 1177
*Again, mean LS for the longest-lived decile.

... and, of course, there's the adult- and early-seniority only work by (respectively) Walford and Weindruch, and by Spindler, further documenting the cumulative-period-on-CR phenomenon. Looking at the data, it does look as if this is more consistent in mice than in rats, who also often show different effeccts on mortality-rate doubling time on CR (dominated by later onset of exponential decline, vs. expansion of the doubling time itself).

-Michael

1: Harris SR, Brix AE, Broderson JR, Bunce OR. Chronic energy restriction versus
energy cycling and mammary tumor promotion. Proc Soc Exp Biol Med. 1995
Jul;209(3):231-6. PubMed PMID: 7777584.

2. Tagliaferro AR, Ronan AM, Meeker LD, Thompson HJ, Scott AL, Sinha D. Cyclic food restriction alters substrate utilization and abolishes protection from mammary carcinogenesis female rats. J Nutr. 1996 May;126(5):1398-405. PMID: 8618136

3. Mehta RS, Harris SR, Gunnett CA, Bunce OR, Hartle DK.
The effects of patterned calorie-restricted diets on mammary tumor incidence and plasma endothelin levels in DMBA-treated rats. Carcinogenesis. 1993 Aug;14(8):1693-6.
PMID: 8353853

4. Buison AM, Pellizzon MA, Brogan KE, Barnes MJ, Jen CK-L. Weight cycling did not increase tumor incidence in high fat-fed rats treated with a low-dose, 7,12-dimethylbenzyl(1)anthracene. Nutr Res. 2005 Dec; 25(12):1097–1108.

5. Hikita H, Nuwaysir EF, Vaughan J, Babcock K, Haas MJ, Dragan YP, Pitot HC. The effect of short-term fasting, phenobarbital and refeeding on apoptotic loss, cell replication and gene expression in rat liver during the promotion stage. Carcinogenesis. 1998 Aug;19(8):1417-25.
PMID: 9744538

6. Hikita H, Vaughan J, Pitot HC.
The effect of two periods of short-term fasting during the promotion stage of hepatocarcinogenesis in rats: the role of apoptosis and cell proliferation. Carcinogenesis. 1997 Jan;18(1):159-66.
PMID: 9054602

7: Caderni G, Perrelli MG, Cecchini F, Tessitore L. Enhanced growth of colorectal
aberrant crypt foci in fasted/refed rats involves changes in TGFbeta1 and p21CIP
expressions. Carcinogenesis. 2002 Feb;23(2):323-7. PubMed PMID: 11872640.

8: Tessitore L, Tomasi C, Greco M, Sesca E, Laconi E, Maccioni O, Ramo R, Pani P.
A subnecrogenic dose of diethylnitrosamine is able to initiate
hepatocarcinogenesis in the rat when coupled with fasting/refeeding.
Carcinogenesis. 1996 Feb;17(2):289-92. PubMed PMID: 8625452.

9. Tessitore L. Hepatocellular carcinoma is induced by a subnecrogenic dose of
diethylnitrosamine in previously fasted-refed rats. Nutr Cancer.
1998;32(1):49-54. PubMed PMID: 9824857.

10. Tomasi C, Laconi E, Laconi S, Greco M, Sarma DS, Pani P. Effect of
fasting/refeeding on the incidence of chemically induced hepatocellular carcinoma
in the rat. Carcinogenesis. 1999 Oct;20(10):1979-83. PubMed PMID: 10506114.

11: Tessitore L, Chiara M, Sesca E, Premoselli F, Binasco V, Dianzani MU. Fasting
during promotion, but not during initiation, enhances the growth of
methylnitrosourea-induced mammary tumours. Carcinogenesis. 1997
Aug;18(8):1679-81. PubMed PMID: 9276649.

12: Chiara M, Sesca E, Binasco V, Tessitore L. Fasting/refeeding enhances the
development of mammary tumors induced by methylnitrosourea in the rat. Boll Soc
Ital Biol Sper. 1996 Jul-Aug;72(7-8):211-6. PubMed PMID: 9009060.

13: Premoselli F, Sesca E, Chiara M, Binasco V, Tessitore L. Fasting/refeeding
enhances the crypt multiplicity in rat colon carcinogenesis induced by
azoxymethane. Boll Soc Ital Biol Sper. 1996 Sep-Oct;72(9-10):239-45. PubMed PMID:
9425720.

14: Caderni G, Bollito E, Tessitore L. Colon cancer is induced by a single low
dose of azoxymethane in fasted-refed rats. Nutr Cancer. 1999;35(2):137-42. PubMed
PMID: 10693167.

15: Laconi E, Tessitore L, Milia G, Yusuf A, Sarma DS, Todde P, Pani P. The
enhancing effect of fasting/refeeding on the growth of nodules selectable by the
resistant hepatocyte model in rat liver. Carcinogenesis. 1995 Aug;16(8):1865-9.
PubMed PMID: 7634416.

16. Cleary MP, Jacobson MK, Phillips FC, Getzin SC, Grande JP, Maihle NJ.
Weight-cycling decreases incidence and increases latency of mammary tumors to a
greater extent than does chronic caloric restriction in mouse mammary tumor
virus-transforming growth factor-alpha female mice. Cancer Epidemiol Biomarkers
Prev. 2002 Sep;11(9):836-43. PubMed PMID: 12223427.

17. Beauchene RE, Bales CW, Bragg CS, Hawkins ST, Mason RL
Effect of age of initiation of feed restriction on growth, body composition, and longevity of rats. J Gerontol 1986 Jan;41(1):13-9.
PMID: 3941250

18: Merry BJ, Kirk AJ, Goyns MH. Dietary lipoic acid supplementation can mimic or block the effect of dietary restriction on life span. Mech Ageing Dev. 2008 Jun;129(6):341-8. Epub 2008 Apr 22. PubMed PMID: 18486188.

19. Yu BP, Masoro EJ, McMahan CA.
Nutritional influences on aging of Fischer 344 rats: I. Physical, metabolic, and longevity characteristics. J Gerontol. 1985 Nov;40(6):657-70.
PMID: 4056321

[leha]

Thank you, Michael. I appreciate your taking time to look into this. Since my last posting I also found this article:

Rapid and reversible induction of the longevity, anticancer and genomic effects of caloric restriction.

The abstract states that 8 weeks is all it takes to reverse the effects of CR, but to know more about their parameters I would have to have access to the full text (which I don't). Since they also state that their evidence implies rapid onset of CR (also within 8 wks), the whole thing should probably be viewed in context, as I have seen other papers/reports suggesting it takes much longer than that to really see longevity benefits. They are presumably talking about some subset of benefits.

Still, it seems the safest plan is a more consistent approach, although the time onset aspect is interesting, and to that, there is also this article adding an interesting twist, and tying in with the protein/amino acid discussion:

Life-Span Extension in Mice by Preweaning Food Restriction and by Methionine Restriction in Middle Age

[Forever21]

The abstract states that 8 weeks is all it takes to reverse the effects of CR, but to know more about their parameters I would have to have access to the full text (which I don't). Since they also state that their evidence implies rapid onset of CR (also within 8 wks), the whole thing should probably be viewed in context, as I have seen other papers/reports[citation needed] suggesting it takes much longer than that to really see longevity benefits. They are presumably talking about some subset of benefits.

[leha]

Sorry, Forever, but I don't have a citation for that. It was a casual observation based on memories that go too far back, so you will have to just write it off or take it in that context. Most of what I seem to remember was either posted in this Forum or on one of the other CR websites, and was summarization of presumably 1st- or 2nd-hand research, if that's any help.

[Forever21]

Thanks.

http://www.imminst.o...post__p__432778

[Michael]

Thank you, Michael. I appreciate your taking time to look into this. Since my last posting I also found this article:

Rapid and reversible induction of the longevity, anticancer and genomic effects of caloric restriction.

The abstract states that 8 weeks is all it takes to reverse the effects of CR, but to know more about their parameters I would have to have access to the full text (which I don't).

This is largely a review of this study. Saying that this is all it takes to "reverse the effects of CR" is a bit ambiguous: it's enough to reverse the gene expression profile induced by CR. It doesn't undo the damage that the prior CR pattern has already averted: if it did, of course, you wouldn't live any longer if you ever went off CR, and as the studies I already cited clearly document, it ain't so.

Since they also state that their evidence implies rapid onset of CR (also within 8 wks), the whole thing should probably be viewed in context, as I have seen other papers/reports suggesting it takes much longer than that to really see longevity benefits.

Again, he's just talking about entering into the CR metabolic state, as reflected by the underlying shift in gene expression: after 8 weeks, the animals have apparently fully entered a stable CR state, but obviously slowing aging for just 8 weeks wouldn't add much to lifespan, because (again) the anti-aging effect -- the reduced rate of accumulation of cellular and molecular aging damage -- is a cumulative process. The two survival curves are just beginning to separate at that point: you have to keep it up to keep seeing the m continue to separate further:


(CR was initiated at 19 mo).

[leha]

Okay, that makes a lot more sense (and makes me feel better!)--thanks again for your voice of clarity whilst wading through the sea of studies...