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CR, immunity and under-nutrition, and Rhesus LS


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Because the archs are down, and I can't find any references to my query via std. Google searches, I'll ask here (warning: I'll digress a lot from the main topic, as typical of my style!) ...


OK, so we pretty much know CR improves immune function ... e.g., fewer colds and flus reported by List members, and (I think) as the animal studies also concur.


But why should CR and improved immunity be correlated?


Perhaps because when animals are in a famine situation...

(1)  they are usually consuming more rotten/decaying/infected stuff, so the body preemptively boosts immunity to protect against pathogens.

(2)  foodstuff is often under-nutritious as other starved animals have gotten to the "good stuff" first; this may also undermine immunity unless the body pumps up its defenses


[if anyone knows of studies or List/forum posts relating to (1) or (2), please let us know. Thx]


If (1) and/or (2) are in order, lowered cancer  and other pathologies (and increased LS) in captive (laboratory-phenomenon) CR animals-- where diet/environment is optimal -- may have exaggerated (=beneficial) CR side-effects.  If true, that's  good news for humans following a strict CRON diet. So ... more police and "fire-dept" attention for cancer, etc.; alternately, in a natural famine, the police and fire dept. would've been distracted by the rotting meat you ravenously/hurriedly snarfed.


What brought the above topic to mind was recent disc. of Rhesus monkeys in the NIA and Wisc. studies.

I can't seem to find good/reliable info on how long these guys last in the wild (4 yrs-15yrs) or zoos. I.e., in a non-lab environment. In the lab (includes CR), 25-40 years (thus far!!)

Any info on this is also  appreciated!


Bottom line: I think what is largely missing from CR science is real-life (famine or near-famine) data.

The Oki data is cool!

Also a potentially huge data-mine is Cuba right after the USSR collapsed. [= state-enforced CR of a whole nation!!!]





Refs to Rhesus LS:





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Hi Khurram,


I think I see what you are saying. Living in the "wild" as we humans do (sort of... more on that below), and as animals exposed to true famines do, might result in greater lifespan extension than animals subjected to lab-induced famines (i.e. in CR experiments), because in the lab both the CR and the control animals enjoy (relatively) germ-free conditions, and so the immunity boosting benefits of CR don't get reflected (much) in survival data.


You may be right, but I'll play devil's advocate, just for fun.  :)xyz


First, I'll grant you that famine likely improves some aspects of immune function (although see below). See this post on the recent Fontana paper (PMID: 25500208) showing anorexics have better immune system efficiency


But there is also a downside to CR's impact on the immune system. Specifically, when infections like flu/pneumonia are most likely to kill us (i.e. when we are old), a very thin CR practitioner might be somewhat less susceptible to contracting such an illness, but more susceptible to dying from it, due to fewer metabolic reserves to fight it once a serious infection is contracted. This hypothesis that CR may be a serious problem once infected, is supported by this recent rodent study [1], where more young and old CR mice than controls died when exposed to the flu. Fortunately, refeeding before the illness improved the ability of the mice to recover, but that sort of defeats the purpose of CR, and is likely to reverse the CR benefit of reduced susceptibility! So damned if you do, and damned if you don't. But perhaps another reason to consider backing off serious CR when one gets old... BTW, "flu and pneumonia" are the 3rd leading killer of centenarians. 


Also - sure relative to eating a crappy SAD diet CR seems likely to provide an immunity advantage. But it's not clear that the CR immunity advantage would be significant relative to an obesity-avoiding healthy diet and lifestyle.


And with vaccines and modern antibiotics, it might be argued that we're living more in sheltered laboratory conditions than the "wild" of our ancestors, where having a stronger immune system and thereby avoiding infections during famine via CR might have indeed been a win, since once you got infected in such a Hobbesian "state of nature", you were as good as dead, whether CRed or not - if not from the infection itself than from some bully coming and beating you to death to take your stuff.  :ph34r:


Finally, see my upcoming post on the cold exposure thread on cold exposure and immune system function. 





[1] J Nutr. 2010 Aug;140(8):1495-501. doi: 10.3945/jn.110.122408. Epub 2010 Jun 9.

Short-term re-feeding of previously energy-restricted C57BL/6 male mice restores
body weight and body fat and attenuates the decline in natural killer cell
function after primary influenza infection.

Clinthorne JF(1), Adams DJ, Fenton JI, Ritz BW, Gardner EM.

Author information:
(1)Department of Food Science and Human Nutrition, Michigan State University,
East Lansing, MI 48824, USA.

A hallmark of energy restriction (ER) is a decrease in total body fat, which is
thought to increase lifespan and maintain immune function. However, we have shown
that during primary influenza infection, ER induces rapid weight loss, impairs
natural killer (NK) cell function, and increases mortality in young and aged
mice. To determine whether influenza-induced NK cell function could be restored
in ER mice, young adult (6 mo) male C57BL/6 mice were fed an ER diet or re-fed
(RF) control diet ad libitum for 2 wk before infection with PR8 influenza A. An
initial hyperphagic response was observed in RF mice, characterized by increased
food intake, rapid weight gain, and restoration of body fat and fat depots by 5-7
d of re-feeding to levels comparable to control ad libitum (AL) mice. Re-feeding
improved survival and attenuated the decline in NK cell function during
infection, evidenced by increased numbers, percentages, and CD69 expression by d
3 postinfection in RF mice. Interestingly, an altered metabolic phenotype was
observed during infection of RF mice, with plasma leptin concentrations greater
than in ER mice but less than in AL mice. In contrast, adiponectin concentrations
of RF mice were lower than those of both ER and AL mice. These data suggest that
re-feeding for a defined period before, and perhaps throughout, influenza season
may provide the energy needed to counter the deleterious effects of ER on NK cell
function, especially during exposure to newly emerging strains of influenza, for
which vaccines are limited or unavailable.

PMCID: PMC2903303
PMID: 20534876

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  • 3 weeks later...



More evidence that once exposed to a virus, CR (and rapamycin) may negatively impact one's ability to fight it off. In this case, the organism is question is old mice, and the virus is the West Nile Flu Virus (WNV). As you can see from the figure below from [1], CR mice and rapamycin treated mice were less able to survive exposure to WNV than al lib fed controls.








[1] Aging Cell. 2015 Feb;14(1):130-8. doi: 10.1111/acel.12280. Epub 2014 Nov 26.

Lifespan-extending caloric restriction or mTOR inhibition impair adaptive
immunity of old mice by distinct mechanisms.

Goldberg EL(1), Romero-Aleshire MJ, Renkema KR, Ventevogel MS, Chew WM, Uhrlaub
JL, Smithey MJ, Limesand KH, Sempowski GD, Brooks HL, Nikolich-Žugich J.

Author information:
(1)Departments of Immunobiology and the Arizona Center on Aging, University of
Arizona College of Medicine, Tucson, AZ, USA; Department of Nutritional Sciences,
College of Agriculture and Life Sciences, University of Arizona, Tucson, AZ, USA.

Aging of the world population and a concomitant increase in age-related diseases
and disabilities mandates the search for strategies to increase healthspan, the
length of time an individual lives healthy and productively. Due to the
age-related decline of the immune system, infectious diseases remain among the
top 5-10 causes of mortality and morbidity in the elderly, and improving immune
function during aging remains an important aspect of healthspan extension.
Calorie restriction (CR) and more recently rapamycin (rapa) feeding have both
been used to extend lifespan in mice. Preciously few studies have actually
investigated the impact of each of these interventions upon in vivo immune
defense against relevant microbial challenge in old organisms. We tested how rapa
and CR each impacted the immune system in adult and old mice. We report that each
intervention differentially altered T-cell development in the thymus, peripheral
T-cell maintenance, T-cell function and host survival after West Nile virus
infection, inducing distinct but deleterious consequences to the aging immune
system. We conclude that neither rapa feeding nor CR, in the current
form/administration regimen, may be optimal strategies for extending healthy
immune function and, with it, lifespan.

© 2014 The Authors. Aging Cell published by the Anatomical Society and John Wiley
& Sons Ltd.

PMCID: PMC4326902
PMID: 25424641

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While I don't have the technical understanding of CR, or the background some people here have, I read the 2 above posts and thought something very obvious was overlooked.


The OP's question was "But why should CR and improved immunity be correlated?"  My understanding goes back to one of the basic ideas of CR. CR causes you to live longer, so that you'll have a greater chance to reproduce.  When calories are not abundant, it is not a good time to reproduce and it will enhance your chances of longevity via a myriad of pathways.  Therefore CR improves immunity so that you have greater likelihood of your DNA being passed on in the gene pool, no?  That is why CR and improved immunity should be correlated.  


A question in my mind then becomes, why isn't immunity enhanced all the time? And to that I don't have an answer.

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A question in my mind then becomes, why isn't immunity enhanced all the time? And to that I don't have an answer.


Your question can be interpreted in two ways - "why isn't immunity enhanced at all times in everyone?" or "why isn't immunity enhanced at all times in people practicing CR?"


But I think the answer to both comes down to the same thing, scarce resources - at least as the theory goes.


The theory says that resources are limited. You can't have both enhanced immunity while at the same time maximizing reproduction. So there is a tradeoff. In the case of normal (non-CR) people and other animals/organisms, they are more fecund than their CRed brethren, so in times of plenty they do better in passing on their genes. They trade off heightened immunity for heightened reproductive fitness.


As to why our (i.e. CRed folks) immunity (our ability to cope with infections and foreign invaders) isn't always enhanced by CR, contra the last couple studies I've posted, is that you can only do so so much with the limited fuel that CR'ed bodies get. Sometimes that isn't enough to mount an effective counterattack against foreign invaders once they've gotten a foothold in your body.



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  • 4 weeks later...

Al posted a rather alarming sounding new study [1], along with an even more sensationalist press release about CR with the headline:


Caloric restriction leads to fatale <sic> weakening of the immune system


The study is a rather complicated one, with many parts. Below is a brief summary of some of the highlights. From my reading of it, it basically reinforces the take-home message from the study I discussed a few posts up (PMID: 25424641), namely that CR may preserve the immune system both in a younger and a more quiescent state (e.g. your body is less inflammed - so needs fewer immune cells to put out the fire, so to speak). Both of which are good things. But it also provides limited, somewhat troubling additional evidence that once someone practicing CR gets an infection, they may have more difficulty fighting it off.


The vast majority of the paper focuses on the positive immune system changes exhibited in mice subjected to long-term DR (i.e. they simply cut the mice's food to 70% of AL, without extra supplements to make up for nutrient shortfalls, making it DR instead of CR, which isn't optimal, but which also isn't that uncommon in rodent CR experiments). More accurately, it wasn't so much that DR caused positive immune system changes, but the DR animals avoided the negative immune system changes that accompanied increasing age in the AL-fed animals. One way this benefit manifested itself was through hematopoietic stem cells (HSCs). From the abstract:


[Adult-onset] DR ameliorated HSC aging phenotypes, such as the increase in number of HSCs
and the skewing toward myeloid-biased HSCs during aging. Furthermore, DR increased 
HSC quiescence and improved the maintenance of the repopulation capacity of HSCs during aging.
So CR preserves immune system stem cells, which is a good thing. 
But on the downside was the following (headline stealing) result, described in this passage from the abstract:
In contrast to these beneficial effects, DR strongly impaired HSC differentiation into lymphoid lineages and
particularly inhibited the proliferation of lymphoid progenitors, resulting in decreased production of peripheral
B lymphocytes and impaired immune function.
So basically this seems to suggest that  CR preserves immune system stem cells, but for some reason they are unwilling/unable to "put out" - i.e. to raise a response to an immune system challenge by kicking off the sequence of events involved in generating infection-fighting lymphocytes.
But let's look "below the hood", at some of the details from the study to see if such a pessimistic interpretation is really justified. Here is what they actually did and found.
In short, they did a short-term experiment and found DR reduced the ability of mice to fight off infections. They (quite abruptly) put adult mice on 30% DR for 10 days, then injected them with a staph bacteria to cause an infection. A week later the DR mice had much higher staph bacteria level still circulating than did AL mice. Here is the comparison chart (figure 3H-K):
As you can see, the number of B lymphocytes (H), spleen weight (I), thymus weight (J) were all reduced dramatically after 10 days of abrupt onset DR. It appears along with other body tissues (e.g. fat mass, muscle mass) the DR mice were cannibalizing their spleen and thymus to compensate for their calorie deficit.
Since the spleen and thymus are important organs for generating immune cells, the DR mice were unable to mount a strong immune system response, and as a result the staph bacteria load of the DR mice (K) was much higher after a week than the AL group. In other words, the DR group was having a lot more trouble fighting off the staph infection.
But the authors themselves had already shown that such short-term CR is very bad for the immune system, and in particularly around 10 days is the nadir in immunocompetence, at least as measured by the number of B lymphocyte progenitor (pro-B) cells. Here is a graph of the pro-B cell count as a function of time on DR:
As you can see, at 2 weeks after DR onset, at the time the mice (in a separate experiment) got the staph injection/infection, the pro-B cells were at their lowest point. But also note that the pro-B count in the DR mice recovered some after that (months 1-4), and especially seemed to be bouncing back strongly at 9 months, when they ended the experiment. It appears the authors didn't subject long-term (i.e. 9 months+) DR mice to an immune system challenge to see how well they were able to fight off an infection. 
So it's not at all clear to me from this study to what degree, or even if, mice (or people) practicing long-term CR will have a compromised ability to fight off infections. It seems to tentatively support the idea that this might be a problem for CRers. But I don't think it is nearly as strong as the evidence from PMID: 25424641 discussed above which showed that old, long-term CR mice died from a (deliberate) infection with West Nile Flu virus more often than did AL mice.
In particular, the fact that short-term, abrupt onset DR compromises immunity isn't a surprise, and simply suggests to me you shouldn't go on a crash diet, and if you do, you should avoid getting sick while doing it.
This lack of relevance of their immunocompromise result to long-term CR (to say nothing of long-term CRON, vs the short-term DR in this study) coupled with the evidence they collected showing that the DR'ed mice had a younger-looking immune system, and preserved more immune system stem cells than AL mice as they aged, and coupled with the recovery of progenitor cell count they observed after an initial severe dip resulting from abrupt DR onset, makes their "CR compromises the immune system" claim a rather weak one, not nearly deserving of the sensationalist headline "Caloric restriction leads to fatale <sic> weakening of the immune system" that the authors and the media have used to portray it.
In fact, that headline really bugs me. The so-called "fatal(e)" weakening of the immune system was only fatal to the mice in the sense that a week after being deliberately infected, ALL the mice (DR & AL) were sacrificed to measure their immune system...
But having said that, I don't mean to suggest that the ability to fight off infections won't be compromised by CR in humans. It's just that the evidence this study provides that it will is pretty weak. Coupled with the West Nile Flu paper above, it seems reasonable to think that in fact it very well might. In other words, our immune system might look younger, but as a result of being so quiescent and has fewer metabolic resources to use to mount a defense, the immune system of CR animals and humans may indeed let us down when we need it most to fight off infections, in old age when such infections can easily be lethal.
really wish a certain long-time, relatively elderly CR practitioner lurking on these forums (whose initials are coincidentally quite familiar...) would pipe in here. He's been having troubles with infections and other health issues, and contacted me excitedly (off-forums) about this paper. His insights about the benefits and hazards of practicing CRON in one's elder years, after abusing one's body in youth, would be extremely valuable. But so far all he does is continue to lurk :-(
[1] J Exp Med. 2016 Mar 7. pii: jem.20151100. [Epub ahead of print]
Dietary restriction improves repopulation but impairs lymphoid
differentiation capacity of hematopoietic stem cells in early aging.
Tang D, Tao S, Chen Z, Koliesnik IO, Calmes PG, Hoerr V, Han B, Gebert N,
Z?rnig M, L?ffler B, Morita Y, Rudolph KL.
Dietary restriction (DR) improves health, delays tissue aging, and elongates
survival in flies and worms. However, studies on laboratory mice and
nonhuman primates revealed ambiguous effects of DR on lifespan despite
improvements in health parameters. In this study, we analyzed consequences
of adult-onset DR (24 h to 1 yr) on hematopoietic stem cell (HSC) function.
DR ameliorated HSC aging phenotypes, such as the increase in number of HSCs
and the skewing toward myeloid-biased HSCs during aging. Furthermore, DR
increased HSC quiescence and improved the maintenance of the repopulation
capacity of HSCs during aging. In contrast to these beneficial effects, DR
strongly impaired HSC differentiation into lymphoid lineages and
particularly inhibited the proliferation of lymphoid progenitors, resulting
in decreased production of peripheral B lymphocytes and impaired immune
function. The study shows that DR-dependent suppression of growth factors
and interleukins mediates these divergent effects caused by DR.
Supplementation of insulin-like growth factor 1 partially reverted the
DR-induced quiescence of HSCs, whereas IL-6/IL-7 substitutions rescued the
impairment of B lymphopoiesis exposed to DR. Together, these findings
delineate positive and negative effects of long-term DR on HSC functionality
involving distinct stress and growth signaling pathways.
PMID: 26951333
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I believe that it was Michael Rae who not long ago said that the *absolute* lymphocyte counts were the best CR marker.  With your low WBC counts Dean; that makes your absolute lymphocyte counts quite low. Lymphocytes for me in August of last year were 0.65 (1.5-4) and WBCs were 1.78 (4-8).  Lymphocytes thus were 37%. 


My immunologist's PHA stimulation test some years ago showed a response of 1.33 versus the normal 1, so my immune system responded strongly, although it was weak, as evidenced by very low blood immune cells that brought about the test. 

I have had severe and repeated lower respiratory tract infections, which I and doctors have attributed at least partially to my kyphosis, dowager's hump.  I now practice my previous doctor's advise and do breathing exercises, breathing in and mostly forcefully out to help bring up phlegm from my restricted and scarred lungs. 


My dental hygiene was very poor, and I ate great amounts of puffed wheat and rice, which made my ad lib baseline poor dental health much worse.  After much cajoling, I got my dentists to pull remaining top and later bottom teeth and have and am happy with dentures.  I did not really have infected gums much once I was persuaded to floss, but did have much chronic pain from toothache. 

Upper respiratory tract history was not good during severe CR, re especially laryngitis, to which I have always been prone.  I can also remember that as a child I was constantly having such colds.  I carried two large red handkerchiefs so that one would be soaked and could be dry by the time the second was soaked. They had the texture of cardboard before my colds were gone.


Lately, I went from a nadir of 80 pounds in 2003 to 104 pounds this morning and have a better than average upper respiratory tract infection history and no lower respiratory tract infections for 10 years.


Below is a part of my health history, which some may be interest in, as an example of a serious consequence of my earlier poor practicing of CR.



13 Apr 2003 1

Subject:      Alan Pater: Post Glucose Crisis Blood Tests


Hi All, Here for your information is a run-down of my blood test results

since my glucose crisis on March 13, 2003.   The results may be informative

regarding how CR might protect CRers from a severe stress event. 

My best guess is that I weighed about 88-90 pounds at the time,

having come down from an ad lib 157 or so.  I had a case of pretty

severe pneumonia. Overall, there seemed to me to be a shock wave

of abnormalities, most of which rapidly improved to the pre-crisis levels. 

Measures that showed no significant deviation from previous levels are

not mentioned below.


My glucose versus 3.5-5 reference range values were:


for the 13th at 626 (that is 6:26 am), 2.5; 1.1 at 1400 (2 pm);

Ø       6.1 until glucose intravenous stopped at 20:00 on the 14th;

Ø       3.8 on the 15th at 300 so I ate; 6.3 at 345; 6.6 at 614;

Ø       3.2 at 748; 5.1 after oatmeal at 840;

Ø       4.6 at 1100; okay the rest of the 15th;

Ø       on the 16th 5.1 at 310 and take oatmeal;

Ø       4.9 at 600;

Ø       on the 17th 4.5 at 635 and ate a little before fasting until 1100 for CAT

scan after which it was 2.2;

Ø       3.5 at 1100; 3.8 at 1245;

Ø       6.0 at 1322; 3.8 at 1457;

Ø       5.0 at 1550; the 18th at 640 3.7;

Ø       the next lows were at about 700 each day and about 4.0 with 3.5 on the



Of note, before my crisis my levels had remained above 4.0 after fasting as much as 16 hours on the latest glucose tolerance test on Nov, 7, 2002 when it was 4.4.


Creatinine was a little low from the 18th March until the 28th.


White blood cells (wbc) were relative to reference range 4.8-10.8 and my usual average of 2.2 over the last 2 years:


3.8 on Mar. 13 at 626 indicating they were elevated to fight the pneumonia; 3.0 on the 18th; 2.4 on the 19th; 2.0 on the 26th; 3.3 on the 28th; 1.8 on the 31st; 1.4 on the 2nd of April; and later values of 2.2, 1.4 and 1.6.


My neutrophils that they were more concerned about were versus reference range 2.0-7.5 and my average of 1.4:


3.3 on the 13th at 626 again indicating infection fighting;

2.5 on the 18th;

1.9 on the 19th;

1.2 on the 26th;

0.8 on the 31st;

1.4 on the 4th of April;

0.7 on the 7th;

and 0.9 on the 11th.


So, it seems to me that they were high for the infection and returned to low level when antibiotic was given and when the infection passed.


Monocytes showed somewhat similar but higher levels.


Lymphocytes were versus reference rang 1.5-4.0 and my usual about 0.5 over the last 3 years:


0.2 on Mar.

1.3 at 626;

0.3 on the 18th and 19th;

0.5 on the 26th;

1.1 on the 28th;

0.7 on the 31st;

0.5 on April 2nd;

and more of similar values thereafter.


My platelets were versus the reference range of 130-400 and normal slightly above or below the low in the reference range:


139 on the 13th at 626;

109 on the 18th;

103 on the 19th;

and return to ~a third above the low in the reference range thereafter.


 For liver damage markers were:


 PT versus reference range of 10.4-13.0 seconds:


19.6 on the 13th at 1519;

13.0 on the 17th;

and 2.6 on April 4th.


The INR versus reference range 0.80-1.20:

2.22 on the 13th;

1.21 on the 17th;

and 1.15 on April 4th.


The aspartate aminotransferase (AST) versus my traditional ? and reference range 0-37 values were:


64 at 1519 on the 13th of March;

335 later on the 13th; and

32-44 after the 30th.


The alanine aminotransferase (ALT) values versus my traditional values and 0-37 reference range were:


33 at 1519 on the 13th;

132 later on the 13th;

and ~28 on and after the 28th.


Not really for liver damage, but bilirubin went from lately normal levels to versus reference range 0-20:


35 on March 13 at 1519;

25 on the 18th;

and thereafter similar levels.


For heart damage marker, troponin I at 0 hours versus reference range 0-0.05 values were:


0.11 for 0 hours 13th of March at 1519;

0.29 at 1905 for 3 hours; and

0.01 on April 1st for 0 hours.

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  • 2 weeks later...

For anyone who is interested in immune function, but has given up on reading the cold exposure thread, you might want to check out this new post, where I discuss a new study showing exercise + cold exposure, or cold exposure alone, boosts immune system function and reduces cancer growth. Really cool stuff, and quite germane for anyone concerned with CR's potential negative effects on the immune system's ability to fight off invaders.



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Here is another post about immune function, and the optimal level for WBC to maximize health & longevity over on the thread where all the cool people are hanging out .


Brief Summary: Having a WBC count above 8 is bad because it's a marker of systemic inflammation. But having a WBC count < 4 is also bad, since it indicates one will likely have difficulty fighting off infections and killing rogue cancer cells.  A WBC somewhere in the range of 4-6 (i.e. low normal) looks like it might be the optimal range.



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  • 3 months later...


Here is discussion of a paper by Luigi Fontana et al on results from the CALERIE study, investigating the impact of mild CR on systemic inflammation and immunocompetence.
Brief summary - mild (9%) CR resulted in reduction in markers of inflammation (CRP, TNF-α, WBC) without compromising the body's ability to respond to acute immune challenges, as measured by response to vaccines.
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