Please point out if I am mistaken, but on my read that does not appear to be quite right:
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."
They went on there fill in some additional nuances on the other biomarkers with some mixed results but on the whole felt and concluded "Cumulatively, these results point to diminution of a diet-induced senescent phenotype in visceral adipose tissue as a means by which exercise provides restorative benefit to abate chronic disease after long term sedentary behavior and nutrient excess."
Now I completely appreciate the distinction you emphasized between
(1) exercise preventing and even reversing [ at least in visceral fat] a senescent phenotype in the setting of an obesogenic sedentary lifestyle ( such as we saw in the mouse study)
versus on the other hand
(2) long term CR practitioners having expression levels of senescence and SASP markers in the colon more closely resembling the youthful controls than those for the age-matched controls.
You emphasize in this distinction that preventing or even reversing diet-induced senescence down to control group levels of senescence is not the same thing as having senescence revert to or more closely match levels found in more youthful individuals than in age-matched controls.
However here lies the problem with the study you cited - Whereas the mouse study controls were similar to the intervention groups ( and had the added benefit of randomization of unknown as well as known potential as it was an experimental design), in contrast, the CR society study you cited has a self-selected intervention group of CR practitioners with middle-aged controls that are not suitable for the inferences drawn.
Not only do we have reason to believe that individuals selecting CR are likely to be more health conscious than average ( lest of all orthorexic), and hence more likely to exercise and consume a less obesogenic diet than average, practices and in all likelihood a variety of other pro-longevity lifestyle practices, but also the authors additionally and explicitly indicated that the age-matched controls were weak indeed ( here we go NIA monkey trial again!) characterizing them as e" a control group of 12 nonobese (BMI = 27.4 ± 2.5 kg/m2) age‐matched sedentary controls eating a typical Western diet"
So these controls (1) had higher BMIs ( BMI of 27.4 is not obese, but a far cry from lowest morbidity end of the BMI curve in the 18-24 range [ I explicitly factor in that they are older with a wider range of BMIs as some data suggests a little extra weight may help] and (2) they had a "typical Western diet" .
A true CR study would compare CR with a healthy if not truly optimal at the very least "Dietary Guidelines for Americans" diet) and (3) they were described by the authors as "sedentary." The CR hypothesis pertains to an impact of calories controlling for other variables and I would be hard pressed to find more impactful potential confounders requiring control that were not accounted for..
The relevance here is that we don't know whether it is CR per se that mediated the observed differences, or whether a better diet, exercise, other healthiful lifestyle factors, or some potentially synergistic combination of health behaviors differentiate the very health-conscience CR practitioner group from a handful of age-matched sedentary ~27 BMI adults consuming the standard American diet. There is no reason to believe it is the CR that made them more like the lean young controls than due to any other health behavior.
Now recall in the mouse study that SC burden was lower in visceral fat -- so we have:
(1) The observations in your study does not exclude that any number of health seeking behavior related variables besides CR ( yet associated with health-conscious individuals who practice CR relative to sedentary individuals on the SAD) is responsible for the reduced colon tissue SC in the human study.
(2) In the CR Society study the only tissue sampled was from the colon, so I see no evidence presented that this population had a global reduction in SC ( outside the GI tract) either ( we saw no reduction in SC in the pancreas, liver, heart in the mouse study). Granted, there is no evidence of an absence of such effect in the CRSociety study since it was examined to my knowledge ( please correct me if I am mistaken), but the burden of proof is to demonstrate an effect in other organ systems rather than for it to the default assumption.
Now playing devil's advocate on my poin (2) above - I do recognize that the mouse study did fail to show reversal of SC in the GI tract which you point out was seen in the CR Society study --- a key observation that deserves explicit mention here. I absolutely agree with you here that this is a "promising" finding and deserves further investigation. However, the fact remains that given the major differences in health behaviors ( not limited to exercise) between CR group and the age-matched controls we have a major attribution problem: We cannot attribute it to CR per se,
This situation is exacerbated by the long-term nature of CR practice: it may be explained in part or whole by the other health behaviors in the CR group over 10+ years ( I include the plus(+) because pro-healthful behaviors often start well before establishing a CR practice, lest such behaviors indeed by confounding the observed differences in colon SC burden). Already simply maintaining a long-term CR practice says something very special about that individual who perhaps represents the top 0.1%-1% of health conscious individuals.
I would suggest that the next study incorporate an age-matched "healthy but not CR diet" and "physically active lifestyle" control, more akin to the exercise ( non-CR) group from Fontana's classic RCT on the effects of long-term calorie restriction and endurance exercise on glucose tolerance, insulin action, and adipokine production Age (Dordr). 2010 Mar;32(1):97-108. doi: 10.1007/s11357-009-9118-z
It did not elude me that Dr Fontana is one of the authors of the very same CR Society study under discussion here. I have much respect for him and his work ( thank you Dr. Fontana!), and he indeed generally produces very high quality work. It is not the quality of the methodology but inferences drawn that I object to. Namely, that is CR that is responsible versus merely that exercise and avoiding the SAD and embracing other prohealth behaviors may be responsible for some to to all of the differences noted.
I am very pleased the research done, but much more work needs to be done to determine whether this effect was from CR or something else, as well as to confirm and quantify the hard health status outcome(s) clinical impact of the finding.
I sincerely hope that some facts have evaded me in this regard and I would be quick to update my position if I missed something. As a student of science and in the spirit of learning and mutual exchange I pose these issues for discussion in my exchange with you Michael on this forum.
Edited by Mechanism, 02 April 2018 - 06:28 AM.