64 replies to this topic

[xEva]

8 hrs fast in mice corresponds to a 2-day fast in humans.

The Circulating Metabolic Regulator FGF21 Is Induced by Prolonged Fasting and PPARalpha Activation in Man (2008) http://www.sciencedi...550413108002076

The metabolic rate is about 10-fold higher in mice than in humans, and energy stores are thus rapidly depleted in mice upon food deprivation. Interestingly, fasting of mice for 8 h did not increase plasma FGF21 (Badman et al., 2007). This time period may correspond to the present 2 day fast where we saw no FGF21 increases in man. A 24 hr fast in mice should correspond to about a week of fasting in humans

[xEva]

Michael, I have just carefully read the paper and I do not see the food reduction. I see an increase in food consumption in (grams of food) per (grams of body mass) in FGF21-tg mice compared to the wild type mice. So, where does this 30% CR that you claim come from?

Both groups of mice ate ad libitum except before the tests that required fasting.

The transgenic mice grew small due to the low levels of IGF-1, an effect similar to the long-lived Ecuadorians with Laron-type dwarfism reported by Longo.

The logic used in your deduction is twisted. It's like saying that a chihuahua is food restricted, because it eats less than a poodle. Again, gram per gram, FGF21 transgenic mice ate a little more food than wild type. Where is the restriction you talk about?

FGF-21 (Fibroblast Growth Factor 21), a hormone shown to extend lifespan in mice by 30% without food reduction

Despite what both the popular press and even the abstract of the paper has said, the FGF21-Tg mice did, in fact, reduce their food intake: food intake is reported in g food/g mouse/3days, and is unchanged or even slightly increased in Tg vs WT mice -- but body weight was reduced by ~1/3 in males and by even more in females, so actual food intake was also cut by >30%. (Despite the widespread misunderstanding, long-term CR does not reduce food intake per unit of metabolic mass). And lifespan was increased by ~30%.

Edited by xEva, 29 October 2012 - 12:42 AM.

[Michael]

After putting this aside and then forgetting about it:
 

Michael, I have just carefully read the paper and I do not see the food reduction. I see an increase in food consumption in (grams of food) per (grams of body mass) in FGF21-tg mice compared to the wild type mice. So, where does this 30% CR that you claim come from?

It comes from the data I cited from the paper (1):
 

Despite what both the popular press and even the abstract of the paper has said, the FGF21-Tg mice did, in fact, reduce their food intake: food intake is reported in g food/g mouse/3days, and is unchanged or even slightly increased in Tg vs WT mice -- but body weight was reduced by ~1/3 in males and by even more in females, so actual food intake was also cut by >30%. (Despite the widespread misunderstanding, long-term CR does not reduce food intake per unit of metabolic mass). And lifespan was increased by ~30%.

The finding that "body weight was reduced by ~1/3 in males and by even more in females" is reported in their Figure 1 (E); the fact that "food intake is reported in g food/g mouse/3days, and is unchanged or even slightly increased in Tg vs WT mice" is reported in their Figure 1 (A). Again, if you cut body weight by a third, and the mice eat the same number of grams of food per gram of their body weight averaged over 3 days, you're talking about a reduction of food intake by about 30% -- which corresponds with the extension of LS, consistent with crypto-CR.
 
Also, we kind of got off on the wrong assumption with this entire thread: you (xEva) quoted an Interview with Dr. Thomas N. Seyfried in which he said
 

It must be recognized that caloric restriction in mice is not the same as caloric restriction in humans. Basal metabolic rate is about 7-8 times greater in mice than in humans. A 24-hour fast in mice is comparable to a 6-7-day fast in humans. We recently published a paper showing that a 40 % CR in mice mimics a full therapeutic fast in humans. Thus, the health benefits attributed to CR in mice can be realized in humans who engage in water only therapeutic fasting for at least three to four days.

Now, this  seemed to imply, and much of the ensuing discussion also revolved around, the idea that to get the metabolic effects of CR required long-term therapeutic fasting in humans. Now in addition to the contrary data cited by me, Kismet, and TFC, I notice that the actual scientific paper doesn't make this rather strong claim:

 

The physiological relationship between CR in mice and humans is unclear. ... [P]lasma biomarker changes we observed in B6 mice [looking at plasma glucose and β-hydroxybutyrate levels and on neutral and acidic lipids, for none of which is there any actual evidence of involvement in the anti-aging effects of CR -MR] which received approximately 60% of the food given to the UR mice on a daily basis [ie, 40% CR -MR], are generally similar to those observed previously in humans during very low calorie diets or during "water only" therapeutic fasting. .... Our findings indicate that moderate CR in B6 mice [40% CR is not moderate CR!! -MR] mimics very low calorie diets or therapeutic fasting in humans. Hence, the numerous health benefits documented in mice following CR may be experienced in humans on very low calorie diets or therapeutic fasting.(2)

You (xEva) even quoted the abstract in your originating post, and we all managed to miss it .

 

References
1: Zhang Y, Xie Y, Berglund ED, Coate KC, He TT, Katafuchi T, Xiao G, Potthoff
MJ, Wei W, Wan Y, Yu RT, Evans RM, Kliewer SA, Mangelsdorf DJ. The starvation hormone, fibroblast growth factor-21, extends lifespan in mice. elife.
2012;1:e00065. doi: 10.7554/eLife.00065. Epub 2012 Oct 15. PubMed PMID: 23066506;
PubMed Central PMCID: PMC3466591.

 

2: Mahoney LB, Denny CA, Seyfried TN. Caloric restriction in C57BL/6J mice mimics therapeutic fasting in humans. Lipids Health Dis. 2006 May 18;5:13. PubMed PMID: 16709251; PubMed Central PMCID: PMC1513228.

[xEva]

After putting this aside and then forgetting about it:
 

Michael, I have just carefully read the paper and I do not see the food reduction. I see an increase in food consumption in (grams of food) per (grams of body mass) in FGF21-tg mice compared to the wild type mice. So, where does this 30% CR that you claim come from?

It comes from the data I cited from the paper (1):
 

Despite what both the popular press and even the abstract of the paper has said, the FGF21-Tg mice did, in fact, reduce their food intake: food intake is reported in g food/g mouse/3days, and is unchanged or even slightly increased in Tg vs WT mice -- but body weight was reduced by ~1/3 in males and by even more in females, so actual food intake was also cut by >30%. (Despite the widespread misunderstanding, long-term CR does not reduce food intake per unit of metabolic mass). And lifespan was increased by ~30%.

The finding that "body weight was reduced by ~1/3 in males and by even more in females" is reported in their Figure 1 (E); the fact that "food intake is reported in g food/g mouse/3days, and is unchanged or even slightly increased in Tg vs WT mice" is reported in their Figure 1 (A). Again, if you cut body weight by a third, and the mice eat the same number of grams of food per gram of their body weight averaged over 3 days, you're talking about a reduction of food intake by about 30% -- which corresponds with the extension of LS, consistent with crypto-CR.

-?? You focus on the graph that shows weights of both groups of mice, one normal and one transgenic, and totally disregard the fact that the transgenic group is of 'dwarf' phenotype.

Did you miss that? Surely you're aware of the fact that smaller animals require less food than larger animals -? Or are you saying that, if only those mice did not engage in their subversive 'crypto-CR', they would be of normal size?

Here is the human equivalent of what those transgenic mice were supposed to emulate.

Ecuadorians with Laron-type dwarfism

 

Also, we kind of got off on the wrong assumption with this entire thread: you (xEva) quoted an Interview with Dr. Thomas N. Seyfried in which he said
 

It must be recognized that caloric restriction in mice is not the same as caloric restriction in humans. Basal metabolic rate is about 7-8 times greater in mice than in humans. A 24-hour fast in mice is comparable to a 6-7-day fast in humans. We recently published a paper showing that a 40 % CR in mice mimics a full therapeutic fast in humans. Thus, the health benefits attributed to CR in mice can be realized in humans who engage in water only therapeutic fasting for at least three to four days.

Now, this  seemed to imply, and much of the ensuing discussion also revolved around, the idea that to get the metabolic effects of CR required long-term therapeutic fasting in humans. Now in addition to the contrary data cited by me, Kismet, and TFC, I notice that the actual scientific paper doesn't make this rather strong claim:
 

The physiological relationship between CR in mice and humans is unclear. ... [P]lasma biomarker changes we observed in B6 mice [looking at plasma glucose and β-hydroxybutyrate levels and on neutral and acidic lipids, for none of which is there any actual evidence of involvement in the anti-aging effects of CR -MR] which received approximately 60% of the food given to the UR mice on a daily basis [ie, 40% CR -MR], are generally similar to those observed previously in humans during very low calorie diets or during "water only" therapeutic fasting. .... Our findings indicate that moderate CR in B6 mice [40% CR is not moderate CR!! -MR] mimics very low calorie diets or therapeutic fasting in humans. Hence, the numerous health benefits documented in mice following CR may be experienced in humans on very low calorie diets or therapeutic fasting.(2)

The other point you missed is that mice on 40%CR, due to their super-fast metabolism, go into ketosis soon after they digest their once- or twice-a-day meals. And, as you rightly point out, this is not the case with humans on CR, who never quite deplete their liver glycogen between meals and so don't go into ketosis. In 4 years that passed, this was already discussed in other threads on the similar topic, namely: mice on CR are engaged in periodic fasting (to which their dips into ketosis amply testify). And so it follows that the life-extension seen in CR mice --but not in CR primates!-- may be due exactly to the fact that they fast proper.

Unfortunately, there was no study that would compare 2 groups of CR mice, both fed the same amount of food, one group fed once a day and the other 6-8 times a day. That frequently fed group would be a close match of a human on CR.

Edited by xEva, 14 March 2015 - 06:58 PM.

[xEva]

Unfortunately, there was no study that would compare 2 groups of CR mice, both fed the same amount of food, one group fed once a day and the other 6-8 times a day. That frequently fed group would be a close match of a human on CR.

But there was! Here it is: Meal-timing, circadian rhythms and life span of mice. 1986 http://www.ncbi.nlm..../pubmed/3794831
PMID: 3794831

The scoop: Out of 3 groups of 25% CR mice, 2 were fed once a day (resulting in daily 20h+ fast) and one fed 6 times, every 2 hours (resulting in one daily 12h fast, which was close to the feeding pattern of AL group). Results: no difference in life extension in all 3 CR groups compared to the AL group. So, the timing of meals did not matter!

But I found this study by following a ref in this study: Calorie restriction increases fatty acid synthesis and whole body fat oxidation rates [in mice!] http://ajpendo.physi...298/1/E108.long
This 2009 study found that 30% CR mice, fed once daily, showed intermittent fasting pattern of metabolism. If you look at the graphs, the mice began fasting at 6h+ post their only meal, which, for most humans, starts at 36-48h after their last meal.


PS
Something is terribly wrong with the linking popup. Hope it's temporary -?

Edited by xEva, 11 April 2015 - 02:25 AM.