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Michael R

Human CR Greatly Suppresses Senescent Cell Accumulation in Colon

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Aging Cell. 2018 Mar 25:e12746. doi: 10.1111/acel.12746. [Epub ahead of print]
The effects of graded caloric restriction: XII. Comparison of mouse to human impact on cellular senescence in the colon.
Fontana L1,2, Mitchell SE3, Wang B4, Tosti V1, van Vliet T4, Veronese N1, Bertozzi B1, Early DS1, Maissan P4, Speakman JR3,5, Demaria M

... Here, we show that a number of classical transcriptomic markers of senescent cells are reduced in adult but relatively young mice under CR. [FULL: "mice were aged 20 weeks when they entered four levels of CR for 12 weeks: 10%, 20%, 30%, and 40% restriction from baseline food intake"]. Moreover, we demonstrate that such senescence markers are not induced in the colon of middle-age human volunteers under CR in comparison with age-matched volunteers consuming normal Western diets.

[specifically: "we recruited and studied 12 middle‐aged (61.7 ± 8.4 years), weight‐stable very lean (BMI = 19.1 ± 1.3 kg/m2) members of the Calorie Restriction Society who have been practicing ~30% CR with adequate nutrition (at least 100% of RDI for each nutrient) for an average of 10.1 years ... and a control group of 12 nonobese (BMI = 27.4 ± 2.5 kg/m2) age‐matched sedentary controls eating a typical Western diet (WD‐o; Figure 2a) ... [whom] we compared ... with younger (24.3 ± 2.0 years, range 21–27 years) nonobese (BMI = 25.7 ± 0.9 kg/m2) humans (WD‐y). All the genes measured were expressed at higher level in WD‐o than in WD‐y volunteers."

"Levels of p16 were significantly lower in the CR compared to WD‐o volunteers (Figure 2b). Levels of p21 followed the trend observed in p16, but did not reach statistical significance (Figure 2c). In accordance with a previous study, we observed significantly lower level of the pro‐inflammatory cytokine IL‐6 in the CR colon mucosa (Figure 2d; You, Sonntag, Leng & Carter, 2007). The other SASP factors analyzed Cxcl1, Il8, Il1a, and Mmp9 followed similar trends, but only the latter two reached statistical significance (Figure 2e)." [i can't post the Figure here due to Forum software rules, but see

 

https://wol-prod-cdn.literatumonline.com/cms/attachment/ea5d511e-f43a-42f1-9361-9284e344a7fa/acel12746-fig-0002-m.jpg

[MR: the gist of it, tho' the numbers are not all statistically significant, is pretty clearly that 61-y.o. CR practitioners' senescent cell burden is clearly much closer to that of 24-y.o. AL than to age-matched AL controls, with p16, IL-6, and IL-1α (which last enforces the SASP through a positive feedback loop) being the most dramatic.]

PMID: 29575469

https://onlinelibrary.wiley.com/doi/full/10.1111/acel.12746

 

Diet quality may play into this, and the fact that the 27.4 ± 2.5 kg/m2 average BMI in the controls includes some significantly overweight people. And it's n-12, and only in the colon, where narrow diet effects might be most strongly observed (note that dietary influences on colorectal and GI cancers are more consistent than other tissues). But it seems pretty good evidence that human CR suppresses SC accumulation rather strongly, consistent with CR's tranlatability.

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Interesting study Michael, promising but also agree with the limitations you mentioned. Thank you for posting it.

 

Additionally, exercise does the same thing: http://diabetes.diabetesjournals.org/content/65/6/1606.full-text.pdf

 

This poses a couple of closely related questions:

 

1) Could this have been achieved with exercise as an alternative to CR ( with a low normal range BMI)

Well, the paper you link clearly rather strongly suggests that it can't. Note that the human CR paper looked at people aged on av'g 61 at time of sampling, who had been on CR an average of 10 years — but they had senescent cell burdens similar to those of lean controls who were 37 years younger. By contrast, in the paper you link, there were no significant differences in SC burden between lean, Normal Diet-fed sedentary mice and even leaner Normal Diet-fed exercised mice, despite the latter having less visceral fat— and if anything, in the visceral fat tissue of greatest interest (as well as in pancreas), it looked as if these animals had more senescent cells:

 

F3.medium.gif

Exercise-induced weight loss blunted the excess accumulation of senescent cells inflicted on animals by a high-fat, high-HFCS, obesogenic diet, but it did nothing for the "normal" age-related burden of SC.

 

2) Since the CR group is self-selected, how much of the difference observed in the CR group was mediated by potential differences in exercise itself? — CR tends to attract the health-conscious to orthorexic crowd and while some sedentary CR individuals were no doubt included in the CR group, these can easily be outnumbered by higher intensity exercise within the CR group even if the younger control group was not sedentary per se. Is it unreasonsble to entertain that confounding may mediate anywhere from some to all of the purported effects of CR in this study?

I have no idea what you're talking about here.

 

Excercise and CR are of course not mutually exclusive and it is possible they have synergistic effect.... but It may be equally conceivable that either is sufficient for full or near-maximal effect.

Again, there is evidently none from exercise in already-lean mice.

 

While hedging bets by doing both is one strategy, if the cost/effort for one is substantially lower/higher than for the other ( eg- exercise over CR), clarity whether exercise alone is adequate is helpful

 

N.b., yes, at least one study I know of suggested for one breed that CR+exercise>CR alone though the outcome variable was not senescence per se and moreover in contrast with this study, it was not in carried out in human subjects which was a key strength of this study. Of course there is a vast CR literature I am not familiar with and I am interested to evaluate any examples and counterpoints.

There is a substantial body of research showing that CR retards aging and exercise doesn't except possibly as an add-on to more moderate CR, most importantly the lifespan studies summarized in a post that is MIA in the Archives, but includes notably PMIDs 9177588 and 9049716.

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Thanks Michael, I appreciate your thoughts on the study-

 

I agree with your statement: “Exercise-induced weight loss blunted the excess accumulation of senescent cells inflicted on animals by a high-fat, high-HFCS, obesogenic diet, but it did nothing for the "normal" age-related burden of SC.”

 

Might the reduced rate of SC accumulation in the context of an obesogenic diet understate the benefits of exercise had the mice been given a normal diet? ie, reducing SC relative to sedentary age-matched controls rather than merely slowing down their accelerated accumulation in the setting of an obesogenic diet. If this is an open question, then confounding by differences in exercise status relative to controls may over longer stretches of time mediate some of the difference in SC burden in the CR group relative to the sedentary controls.

But the point is that we don't have to guess about this: they had both sedentary and exercised Normal-Diet-fed, lean mice, and in these animals, and there was no effect (or, if anything, it made the burden of SC in the visceral fat worse). It didn't slow it down; it didn't reduce it; it did diddley squat. So this strongly suggests that exercise isn't some kind of cryptic confounder in comparing lean and CRed humans, either.

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Please point out if I am mistaken

OK: you're mistaken ;)xyz .

 

The mouse treatment study I cited found, in the words of the author ( p. 1611) "To explore whether exercise mitigates diet-induced cellular senescence, we conducted gene expression profiling on visceral adipose extracts. Similar to the prevention study, exposure to the FFD for 30 weeks resulted in a significant fourfold increase in p16 expression in visceral fat of sedentary mice (Fig. 5E). Despite continued consumption of the FFD, the treatment of obese mice with exercise for 14 weeks reverted this effect, as evidenced by reduced expression of p16 to levels that were not different from ND-fed control mice."

Right. You're looking at the wrong group, Mechanism. Again: yes, the data shows that if you're obese, eating a ridiculously high-fat/high-sugar diabetes-inducing diet (FFD), you'll accumulate supernumerary senescent preadipocytes, and doing exercise (and accompanying weight loss) will bend the curve on its progression to similar to sedentary animals eating a Normal Diet (ND). But the same study also shows that exercise has no effect on those merely eating a Normal Diet, and thus not becoming overweight. There is no excess here to slow.

 

In the mouse study accompanying the human study, even 10 or 20% CR was inadequate to reduce the burden of senescent cells purely attributable to aging (normal but ad libitum diet) (tho' arguably the "10% CR" group here were the real controls); it's at 30 (or maybe we should say 20) or 40% (30%) CR that you see a genuine effect on obligate aging-induced SC.

 

In the human study itself, all the CR subjects are lean and eating healthy diets, whether they exercise or not, and even the young controls are only slightly overweight; an effect against obesity/crap-diet-induced excess just falls out of it.

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