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Michael R

Human CR Has No Obvious Long-Term Effect on Immunological Aging

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All:
 
This is from the CRONA study, centered at UCSF, and involving people largely from the CR Society on rigorous, long-term CR:
 
 

Long-term calorie restriction in humans is not associated with indices of delayed immunologic aging: A descriptive study
Existing evidence for delayed immune system aging [in CR] are predominantly in model organisms with conflicting results [9]. In the mouse model, one study observed that CR enhances adaptive immunity during a viral challenge [10], whereas other studies have found impaired immunity [11, 12]. In non-human primates, studies have found no enhancement of peripheral blood mononuclear cell (PBMC) response to stimulation in CR versus normally-fed controls [13, 14], whereas another study observed an overall markedly delayed T cell senescence [15] [but this was highly dependent on age of initiation -MR]. ...
 
In mice, CR led to fewer senescent intestinal crypt enterocytes and liver hepatocytes and better telomere maintenance in these cells [42]. However, in primates, CR did not lead to changes in telomere length in leukocytes or other tissues. [However, cells go senescent for all kinds of reasons unrelated to CR -MR]
 
We tested whether long-term CR practitioners (average 10.03 years of CR) evidenced decreased expression of T cell immunosenescence markers and longer immune cell telomeres compared to gender-, race/ethnicity-, age-, and education-matched “healthy” Body Mass Index (BMI) and “overweight”/“obese” BMI groups.
 
RESULTS: Long-term human CR practitioners had lower BMI (p <  0.001) and fasting glucose (p <  0.001), as expected. They showed similar frequencies of pre-senescent cells (CD8+CD28 T cells [typical of "anergic" T-cells] and CD57 and PD-1 expressing T cells [PD-1 "guards against autoimmunity through a dual mechanism of promoting apoptosis (programmed cell death) in antigen specific T-cells in lymph nodes while simultaneously reducing apoptosis in regulatory T cells (anti-inflammatory, suppressive T cells)" per wikipedia; inhibiting this pathway revs up the immune system, so drugs that block its receptor are used in cancer immunotherapy -MR]) to the comparison groups.
 
Even after adjusting for covariates, including cytomegalovirus status, we observed shorter peripheral blood mononuclear cell telomeres in the CR group (p = 0.012) and no difference in granulocyte telomeres between groups (p = 0.42). ... T cells make up 60% of the PBMCs [41], and so differences in T cell telomere length could have a large influence on PBMC telomere length. The difference in PBMC telomere length could potentially be due to a skewing in major memory T cell subsets (i.e. effector vs central memory) in the CR group due either to increased subclinical infections in this group or how their immune system maintains latent viral infections such as herpes viruses (e.g. CMV, Epstein Barr Virus). This however would have required more complex phenotyping to detect. ... We do not know why CR was associated with shorter PBMC telomere length, but we can offer speculation. Given the pattern of findings here, one possibility is that the CR diet as practiced left those individuals more vulnerable to infection, despite that CMV seropositive status was no different between the groups. ...
 
Due to their rapid turnover, granulocyte telomere length is thought to more directly represent the common myeloid progenitor stem cell compartment,[38, 39]. Thus, it is possible that the short lived granulocytes may have less variance in turnover, between people, and may be less influenced by environmental exposures, like dietary factors, in the blood. PBMC telomere length may be more influenced by biochemical and lifestyle factors. ...

CONCLUSIONS: We observed no clear evidence that CR as it is currently practiced in humans delays immune aging related to telomere length or T cell immunosenescent markers ...

[No PMID yet].

 
Disappointing, obviously — but in  line with the broad lack of obvious effect on most measures of immunological aging in animal models. See also Fontana's previous study on immune effects of anorexia.

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Disappointing, obviously — but in line

I participated in this study -- seems like a million years ago now -- and at the time I had only three or so years of CR practice, but they let me join anyway. I felt like an outsider's outsider.

 

When the telomere length results came back a few years later, there was nothing special about my telomere number. It was right in the middle of the range for my age group -- neither longer nor shorter -- and when I showed this to my doctor, she said aww that must be disappointing, all that work and effort... but she said she wasn't surprised, either, and said the telomere story was still raw and unfolding and may not even matter much in terms of slowing aging progression...

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Thank you for the update Michael. Can you please put this in perpective with Valter Longo's finding on intermittent fasting with immunologic regeneration re-feeding?

 

http://www.telegraph.co.uk/science/2016/03/12/fasting-for-three-days-can-regenerate-entire-immune-system-study/

 

Recovery from autophagy with regeneration has been touted as one potential ( hypothetical) advantage of fasting cycling over chronic lower caloric intake without recovery windows.

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Disappointing, obviously — but in line

I participated in this study -- seems like a million years ago now -- and at the time I had only three or so years of CR practice, but they let me join anyway. I felt like an outsider's outsider.

 

When the telomere length results came back a few years later, there was nothing special about my telomere number. It was right in the middle of the range for my age group -- neither longer nor shorter -- and when I showed this to my doctor, she said aww that must be disappointing, all that work and effort... but she said she wasn't surprised, either, and said the telomere story was still raw and unfolding and may not even matter much in terms of slowing aging progression...

 

 

I totally agree with you on av'g telomere length in PBMC as a generic indicator of health or aging (which is how it's often (wrongly, in my view) touted). I'm assuming, but don't actually know, that that's the readout that CRONA participants were given. However, it's more plausible that average telomere length in T-cells (which is what they're measuring here) might be more specifically informative about immunosenescence, and they did also test several other markers.

 

Thank you for the update Michael. Can you please put this in perpective with Valter Longo's finding on intermittent fasting with immunologic regeneration re-feeding?

 

http://www.telegraph.co.uk/science/2016/03/12/fasting-for-three-days-can-regenerate-entire-immune-system-study/

 

Recovery from autophagy with regeneration has been touted as one potential ( hypothetical) advantage of fasting cycling over chronic lower caloric intake without recovery windows.

 

They really aren't related: this is about slowing (or not) immunological aging, whereas that is about spurring the death of the existing cells and the generation of "new" ones by division of stem cells from the existing reserve: it doesn't tell you that those cells are any "younger" except in the trivial sense of having been derived from (aging) bone marrow HSC more recently. "Regeneration" in the narrow sense does not mean "rejuvenation," IOW.

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Thank you Michael- I see the difference. Would it be fair to say, however, that even if the replacement cells by some measures may be similarly aged, that their overall patten of differentiation may promote a healthier biologically more youthful phenotype?

 

For example, in FMD, "the number of MSPCs increased 5-fold in the FMD cohort" ( source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4509734/#!po=21.6814) among other changes. The ratio of cells and their functional properties in part govern the efficacy of mounting immune response, which declines ( in part mediated by these changes ) in normal immune aging.

 

Another example may include apoptosis of senescent cells, autophagy of organelles, etc., leading to reduced susceptibility towards neoplasm initiation, promotion, etc in a manner mirroring chronologically healthy younger subjects not in CR.

Edited by Mechanism

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Thank you for the update Michael. Can you please put this in perpective with Valter Longo's finding on intermittent fasting with immunologic regeneration re-feeding?

 

http://www.telegraph.co.uk/science/2016/03/12/fasting-for-three-days-can-regenerate-entire-immune-system-study/

 

Recovery from autophagy with regeneration has been touted as one potential ( hypothetical) advantage of fasting cycling over chronic lower caloric intake without recovery windows.

Yeah, with the same old body producing the same old cells, I can see where fasting isn't aging us backwards. The practice might clear out some deranged stuff we're better off without. Or not. But it's still me and you at whatever stages of degradation aging has gifted us. If fasting followed by refeeding is shrinking organs, then rebuilding organs with new cells is probably healthy. But I think Longo's speeches and interview comments sometimes mislead me regarding "rejuvenation of the aging immune system."

 

My understanding is his lab's work has suggested that fasting stimulates bone marrow, but does his work say much about regenerating the immune system? Increasing bone marrow output is not equivalent to regenerating the immune system. The word "T cell" -- is it mentioned in Longo's studies -- did he measure T cell levels or T cell functions?

 

He does point out that fasting and refeeding is extending what the body is already attempting to do.

 

I wonder if CR or fasting:refeeding stints do anything to help keep the thymus from rotting away to nothing. Whatever happened to Greg Fahy and all that promising thymus regeneration? I read his patent on the process -- https://www.google.com/patents/US6297212 -- looks like arginine and DHEA along with some other trickier stuff.

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I participated in this study

 

You were recently trying to find out your CMV status...  Looks like they tested your sample for this and other things... I wonder if you could get your own results from them?

 

As far as the study goes - I guess it is disappointing for CR but besides doing what you can via diet content to avoid heart disease, stroke and cancer -- emerging tech is the only thing likely to seriously impact life expectancy.

Edited by Gordo

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Thank you Michael- I see the difference. Would it be fair to say, however, that even if the replacement cells by some measures may be similarly aged, that their overall patten of differentiation may promote a healthier biologically more youthful phenotype?

 

For example, in FMD, "the number of MSPCs increased 5-fold in the FMD cohort" ( source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4509734/#!po=21.6814) among other changes. The ratio of cells and their functional properties in part govern the efficacy of mounting immune response, which declines ( in part mediated by these changes ) in normal immune aging.

Careful: you're reading the section on mice ;) . In humans, in the same paper, "Although not significant, the percentage of MSPC in the peripheral blood mono-nucleated cell population showed a trend (p= 0.1) to increase from 0.15 ± 0.1 at baseline to 1.06 ± 0.6 at the end of FMD, with a subsequent return to baseline levels after re-feeding (0.27 ± 0.2). A larger randomized trial will be required to determine whether the number of specific populations of stem cells are in fact elevated by the FMD in humans."

 

So, clear effect, and certainly no durable effect. IAC, showing a changed cell ratio is one thing: showing a changed immunological function is quite another. For a long time, we in the CR community were seduced by studies showing various changes in cell ratios and ex vivo effects; it was only when researchers started doing more serious vaccine and infectious survival studies that we got a clear picture that the effects of CR on your real-world defense against infectious disease are mixed, even in mice.

 

Another example may include apoptosis of senescent cells, autophagy of organelles, etc., leading to reduced susceptibility towards neoplasm initiation, promotion, etc in a manner mirroring chronologically healthy younger subjects not in CR.

 

But we've gone through that before, yes? FMD/EOD/ADF etc affect cancer exactly in proportion to the degree that they affect Calories. This Longo mouse study does suggest a stronger effect, but they also have an somewhat short-lived control group with a lot of early death, and an FMD group with a normal mouse lifespan, which should make one suspicious of any disease outcome.

 

My understanding is his lab's work has suggested that fasting stimulates bone marrow, but does his work say much about regenerating the immune system? Increasing bone marrow output is not equivalent to regenerating the immune system. The word "T cell" -- is it mentioned in Longo's studies -- did he measure T cell levels or T cell functions?

No.

 

He does point out that fasting and refeeding is extending what the body is already attempting to do.

Aren't we all ;) ?

 

I wonder if CR or fasting:refeeding stints do anything to help keep the thymus from rotting away to nothing. Whatever happened to Greg Fahy and all that promising thymus regeneration? I read his patent on the process -- https://www.google.com/patents/US6297212 -- looks like arginine and DHEA along with some other trickier stuff.

Many studies have shown that CR retards thymic involution: the effect on mass is inconsistent, but the effect on cellularity (ie, the retention of functioning thymic tissue, which is normally in part displaced by adipose tissue and fibrosis) is consistent — see eg. PMIDs 9754130,  19648267, 1910449,1513229, 1528436.

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Over in the CR Society FB page, I posted a link to this study.  Paul McGlothin replied with:

 
 
1958506_10202882858020027_233264655_n.jp
Paul Sandford McGlothin Meredith and I put together the cohort for this [study]. It consisted largely of members of livingtheCRWay. A newer study using different methods is due to report. The findings will be very different and quite positive.The first data will be out in May.
Like · Reply · 
394117_1876756495625_1909365895_n.jpg?oh
Gordo Great, I look forward to seeing that! I think there is still quite a bit of confusion among people in this group about the very idea of "CR". For example in your own book as I recall, despite the title, there is little in there about actual calorie restriction per se. It would not surprise me at all if "The CR Way" on the other hand, turned out to be a lot more beneficial than "CR" strictly speaking. If you are practicing best dietary regimen (according to the science), time restricted feeding, good sleep, good gut biome, stress reduction, and great nutrition (low protein at least before age 65), I don't think calories or BMI matters much at all other than the fact that numerous studies have shown being overweight is bad, and underweight also bad. My gut feeling is that a diverse, phenol rich, plant based whole food diet is responsible for most of the observed health and longevity benefits of people doing lifestyle changes toward that end. There is evidence of this in the longest lived cohort studies.

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Thanks again, Mochael.

 

I remember, you were very skeptical that CR would have any effect on telomere length of leukocytes -- you even thought it possible that we'd have shorter leukocyte telomeres, on average, than ad libbers.

 

You were, as usual, correct.

 

(However, I did enjoy CRONA. )

 

Looking for ward to the next meeting of the CR Society -- whether a big one, or a small one.  {It's good getting together with our CR colleagues.)

 

  :)xyz

 

    --  Saul

 

P.S.:  I'm glad that the CRONA people accuately reported their results -- even though those results were not what they'd hoped for.  (Maybe an advantage of having a Nobel Laureate in the team, above the petty need to "publish positive results, or perish"?)

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Thanks Michael, I see... my initial take on the data is that the human study trend, on the other side of the coin, is at least promising, given the trend and that it is underpowered to detect differences. Even on re-feeding the values were roughly twice the baseline ( though notably not at statistical significance).

 

Might the following be entertained: The human data taken alone with the no significant p-values can readily be disregarded as due to chance, but coupled with the mouse data, harder to dismiss. A larger trial with adequate power is needed to resolve, and further, a pure water fast ( vs the FMD) is more likely to have a larger effect size too. Bottom line is that the sample size is too small to tell.

 

I would add that daily 20/4 fasts and/or CR ( agree it is possible that CR is the underlying mechanism in either case) also may prevent reversion or at near partial regression to baseline effect.

 

Controversy and even risk of harm for immune status ( e.g.- worse adaptive immunity with possibly enhanced inate immunity) is not new on the scene though your citation I agree disappointing. I agree that it is functional and "real world" immune status that is key ( vs biomarker surrogates) though data is still very limited here l, with a strong need for larger in vivo human trials on the impact on immune response and susceptibility to and impact of infection. I think we are a long way from settling this.

 

Also, wouldn't you say that data in other systems ( CNS degeneration, metabolic disease, oncology) is more robust so that even possibly neutral effect ( and certainly not established with confidence given the low power and FMD as a CR-light intervention) acceptable in the setting of the other benefits in other systems?

 

For your reference, do you think the extent of CR in the participants were in the optimal range? I ask because perhaps optimal % CR varies by system ( neuro / endo / immune, etc) with no one perfect level for all systems but trade offs at every level and nevertheless with a net postitive impact on health +/- longevity across a broader range of %CR.

Edited by Mechanism

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Body Mass Index 19.07 (1.84) [15.37–22.55]

 

Wide BMI range;  some participants underweight.

 

Right. We're on CR, silly ;) .

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That's a good point,  Michael.

 

The  wide BMI range is of course not unexpected given the very broad definition of "CR":

 

(CR), defined as a reduction in caloric intake without malnutrition

 

 

 

Inclusion criteria and indicators for CR were reporting calorie restriction without malnutrition for a minimum of two years, BMI <24.99, and fasting glucose <80 mg/dL.

 

Edited by Sibiriak

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I could see this study as an indication that 25% CR is not being enough to suppress the immune system.
It would make sense that a suppressed immune system leads to a slow down in immuno-senescence and higher telomere count. We know that anorexic people get randomly sick from time to time and more frenquently than a non-AN. So they do have a compromised immune system.

 

Is there any study showing a greater % of CR and higher telomere count in immune cells?

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