Tuesday, July 28, 2009

Side effects of caloric restriction (CR): CR increases susceptibility to infections

See also:
-- 'Longevity Science' blog
-- 'Books Forum' blog


This is to invite you to discuss the side effects of caloric restriction (CR) that is often suggested for delaying aging and life extension. To initiate this discussion, a list of recent scientific publications is attached below (in reversed chronological order), which demonstrates that caloric restriction increases susceptibility to infections. You are most welcome to comment on these publications by clicking here, and to add more references to other studies on related topics. Thank you!

B. W. Ritz, I. Aktan, S. Nogusa, and E. M. Gardner (2008)
Energy Restriction Impairs Natural Killer Cell Function and Increases the Severity of Influenza Infection in Young Adult Male C57BL/6 Mice
J. Nutr., November 1, 2008; 138(11): 2269 - 2275.

Energy restriction (ER) without malnutrition extends lifespan in mice and postpones age-related changes in immunity. However, we have previously shown that aged (22 mo old) ER mice exhibit increased mortality, impaired viral clearance, and reduced natural killer (NK) cell cytotoxicity following influenza infection compared with aged mice that consumed food ad libitum (AL). To determine whether the detrimental effects of ER in response to influenza infection occur independently of advanced age, young adult (6 mo) male C57BL/6 mice consuming an AL or ER diet were infected with influenza A virus (H1N1, PR8). Young adult ER mice exhibited increased mortality (P < 0.05) and weight loss (P < 0.01) in response to infection. ER mice exhibited decreased total (P < 0.001) and NK1.1+ lymphocytes (P < 0.05) in lung and reduced influenza-induced NK cell cytotoxicity in both lung (P < 0.01) and spleen (P < 0.05). Importantly, the mRNA expression of interferon (IFN){alpha}/ß (P < 0.05) was also reduced in the lungs of ER mice in response to infection, and in vitro stimulation of NK cells from ER mice with type I IFN resulted in cytotoxicity comparable to that in NK cells from AL mice. In contrast, NK cell activation was enhanced in ER mice, determined as an increase in the percentage of NK cells expressing B220 (P < 0.001) and increased intracellular production of IFN{gamma} (P < 0.01). These data describe an age-independent and detrimental effect of ER on the innate immune response to influenza infection and suggest that a decrease in NK cell number and alterations in the NK cell-activating environment may contribute to decreased innate immunity in ER mice.

Deborah M. Kristan (2008)
Calorie restriction and susceptibility to intact pathogens
AGE, Volume 30, Numbers 2-3 / September, 2008, 147-156
Long-term calorie restriction (CR) causes numerous physiological changes that ultimately increase mean and maximum lifespan of most species examined to date. One physiological change that occurs with CR is enhanced immune function, as tested using antigens and mitogens to stimulate an immune response. Fewer studies have used intact pathogen exposure to test whether the enhanced capacity of the immune response during CR actually decreases susceptibility of hosts to their pathogens. So far, studies using intact bacteria, virus, and helminth worm exposure indicate that, despite similar or enhanced immune system function, CR hosts are more susceptible to infection by intact pathogens than their fully fed counterparts. Long-term CR studies that examine susceptibility to a variety of parasite taxa will help determine if direct CR or CR mimetics will be beneficial to people living in pathogen-rich environments.

Kristan DM (2007)
Chronic calorie restriction increases susceptibility of laboratory mice (Mus musculus) to a primary intestinal parasite infection.
Aging Cell, 2007, 6: 817–825.
Long-term calorie restriction (CR) has numerous benefits; however, effects of CR on susceptibility to intact pathogens are not well understood. Because CR enhances immune function of laboratory mice (Mus musculus), it was hypothesized that mice subjected to CR would be less susceptible to experimental infections of the intestinal parasite Heligmosomoides bakeri. Furthermore, because H. bakeri must combat a greater host immune response by CR mice compared to fully fed mice, it also was also hypothesized that (i) worms living in CR hosts would have lower reproduction than worms from ad libitum-fed mice, and (ii) CR mice would have a more female-biased sex ratio as male worms may be more vulnerable to host immune response than female worms. Mice were subjected to CR for 6.7 months and were then infected with H. bakeri for one additional month. As expected, CR mice had equal or enhanced immune response (eosinophils and immunoglobin G1 production) to H. bakeri infection compared to ad libitum-fed mice, and CR mice harbored a more female-biased sex ratio than ad libitum-fed mice. Contrary to predictions, CR mice had more worms than ad libitum-fed mice and the worms from CR mice produced more eggs than worms from ad libitum-fed mice. These data indicate that, despite the evidence that long-term CR enhances traditional measures of immune function, CR may actually increase susceptibility to intact parasite infection. Furthermore, changes in worm reproduction and differential survival of male vs. female worms may influence host-parasite transmission dynamics during long-term host CR.

Elizabeth M. Gardner (2005)
Caloric Restriction Decreases Survival of Aged Mice in Response to Primary Influenza Infection
The Journals of Gerontology Series A: Biological Sciences and Medical Sciences 60:688-694 (2005)
Caloric restriction (CR) extends life span of healthy rodents compared to those fed ad libitum. Previous studies have shown positive effects of CR on the immune response of aged mice after influenza immunization. To extend these studies, a mouse model of CR was used to determine if CR could modulate primary responses of aged mice to influenza. Although CR delayed the age-related decrease in mitogen-induced lymphoproliferation of aged mice, in stark contrast, CR decreased survival, increased virus titers, and reduced natural killer cell activity in lungs of aged mice after primary influenza infection. Thus, CR has differential effects on immunity of aged mice, as general indices of immune response are maintained, but primary responses to influenza infection are impaired. This suggests that, although CR may positively affect many long-term parameters of aging, increased susceptibility after primary exposure of aged mice to virus, such as influenza, may not be correctable by CR.

Karen Hopkin (2003)
Dietary Drawbacks
Sci. Aging Knowl. Environ., 26 February 2003, Vol. 2003, Issue 8, p. ns4
A growing number of researchers are finding that calorie restriction is not all it's cracked up to be. The regimen--long hailed as the only way to retard aging in a wide variety of animals--produces some distasteful side effects and doesn't always work.
The benefits of dietary restriction are well documented: Creatures that consume one-third fewer calories are leaner, livelier, and longer lived than their fully fed kin. But such drastic dieting also has a dark side. Restricted animals get chilled and pick up infections unusually easily, and they're less fertile than their more portly compatriots are. Furthermore, cutting calories doesn't enhance longevity in all animals, according to several studies. These observations have many researchers wondering what dietary restriction--or a drug that mimics its effects--might do for people who are hoping to live longer and healthier lives.
Lay down your fork and extend your life-span! It's not a scam but a sentiment that finds equal welcome in blockbuster diet books and gerontological journals. Backed by more than 6 decades of solid research, scientists tout calorie restriction (CR) as the only intervention that retards aging and lengthens life-span in a variety of creatures, from yeast and worms to laboratory mice and rats (see Masoro Review and "Aging Research Grows Up"). Although studies on primates are still in their infancy, some people interested in prolonging their lives are already putting the idea into practice.
But is this antiaging wonder diet really the greatest thing since saying no to sliced bread? Despite their enhanced longevity, animals consuming 20% to 40% fewer calories than their well-fed brethren might not be the picture of perfect health, according to a growing number of studies. The results suggest that dietary restriction has its drawbacks, and that researchers will need to separate its benefits from its less savory side effects before applying it to humans. At the same time, studies in Mediterranean fruit flies and certain strains of mice indicate that cutting calories does not guarantee long life in all animals, leading some scientists to question anew whether CR--or a pill that might mimic its effects on aging--would ever work in people.

Sun D, Muthukumar AR, Lawrence RA, Fernandes G (2001)
Effects of calorie restriction on polymicrobial peritonitis induced by cecum ligation and puncture in young C57BL/6 mice.
Clin Diagn Lab Immunol , 2001, 8: 1003–1011.
Calorie restriction (CR) is known to prolong the life span and maintain an active immune function in aged mice, but it is still not known if rodents under CR can respond optimally to bacterial infection. We report here on the influence of CR on the response of peritoneal macrophages to lipopolysaccharide, splenic NF-kappa B and NF-interleukin-6 (IL-6) activities, and mortality in polymicrobial sepsis induced by cecal ligation and puncture (CLP). Macrophages from 6-month-old C57BL/6 mice on a calorie-restricted diet were less responsive to lipopolysaccharide, as evidenced by lower levels of IL-12 and IL-6 protein and mRNA expression. Furthermore, in vitro lipopolysaccharide-stimulated macrophages from mice under CR also expressed decreased lipopolysaccharide receptor CD14 levels as well as Toll-like receptor 2 (TLR2) and TLR4 mRNA levels. In addition, the phagocytic capacity and class II (I-Ab) expression of macrophages were also found to be significantly lower in mice under CR. Mice under CR died earlier (P < 0.005) after sepsis induced by CLP, which appeared to be a result of increased levels in serum of the proinflammatory cytokines tumor necrosis factor alpha and IL-6 and splenic NF-kappa B and NF-IL-6 activation 4 h after CLP. However, mice under CR survived significantly (P < 0.005) longer than mice fed ad libitum when injected with paraquat, a free radical-inducing agent. These data suggest that young mice under CR may be protected against oxidative stress but may have delayed maturation of macrophage function and increased susceptibility to bacterial infection.

See also:
-- New Books on Caloric Restriction
-- Life Extension, Caloric Restriction and Scientific Philanthropy

Key words:
Caloric restriction, Calorie restriction, CR, Dietary restriction, DR, Energy Restriction, ER, susceptibility to infections, Influenza, pathogens, delaying aging,life extension

To read comments on this topic and to participate in further discussions by posting your own thoughts and suggestions, you are welcome to click here.

Health Studies Blog
Side effects of caloric restriction (CR): CR increases susceptibility to infections
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Matthew said...

A few people in my house, some friend had suspected, and 2 of them confirmed swine flu (it was spreading fast in my local community which is why doctors suspected swine flu for flu like illness reports). I have been on CR for a long time and I'm almost 25. I also developed similar symptoms to everyone else that caught the flu recently however mine was far milder, and it was over after 1 day with no other lingering symptoms. This is quite typical for me now whethre it be cold viruses or flu virses, 95% of the time they never develop into a full blown illness and ALWAYS i recover much faster than everyone else.

I've had far fewer colds and flu on CR than when I wasn't on it, and my BMI is 16.4

I think that having just a good quality diet in addition to the CR really helps. Whereas mice are fed standard diets which do not contain significant amoutns of polyphenols and other compounds that are thought to affect the immune system, and/or have a direct anti viral and anti bacterial effect. For example, green tea catechins are effective against many influenza viruses in vivo, and also the ability of the immune system to deal with the virus. I've talked about this on my blog and the CR lists which I noted my experience with the flu.

And it really wasn't a big deal. And if you ASK most of the people doing CR they will also tell you that they rare, if ever get sick anymore.

Paul McGlothin said...

I thank Dr. Leonid Gavrilov for raising the very important issue of how calorie restriction affects immunity. Meredith Averill, who is chairman of the board of the CR Society International and I, as its Vice President of Research are champions of the calorie restriction movement. We are also co-authors of The CR Way, a revolutionary approach to putting calorie restriction research into actual practice.

We have serious concerns about the relevance of mouse studies to human calorie restriction. If available, we prefer studies on monkeys or humans such as this one:

Messaoudi I, Lane MA, Roth GS, Ingram DK, Picker LJ. et al (2006)
Delay of T cell senescence by caloric restriction in aged long-lived nonhuman primates.
Proc Natl Acad Sci U S A. 2006 Dec 19;103(51):19448-53. Epub 2006 Dec 11.

… Here we show that long-term CR delays the adverse effects of aging on nonhuman primate T cells. CR effected a marked improvement in the maintenance and/or production of naïve T cells and the consequent preservation of T cell receptor repertoire diversity. Furthermore, CR also improved T cell function and reduced production of inflammatory cytokines by memory T cells. Our results provide evidence that CR can delay immune senescence in nonhuman primates, potentially contributing to an extended lifespan by reducing susceptibility to infectious disease.

In this study immune response to infectious disease, which is mediated in part by T cells, is preserved by calorie restriction. Recent studies on calorie-restricted humans, of which Meredith and I participated in the CR cohort, support this contention.

Further, humans who follow The CR Way are not bound by protocols followed by a strain of mouse in the studies cited. The CR Way encourages readers to consider dietary and lifestyle strategies that may enhance immune response. For example, Chapter 4 Glucose Control: The Sweet Spot in Longevity introduces many innovative approaches to keeping circulating glucose low to facilitate gluconeogenesis. This may activate the sirtuin genes, which have been found to play an important role in calorie restriction benefits. As it turns out, activating gluconeogenesis also enhances T-cell memory, as shown in the study below:

Pearce EL, Walsh MC, Cejas PJ, Harms GM, Shen H, Wang LS, Jones RG, Choi Y.
Enhancing CD8 T-cell memory by modulating fatty acid metabolism.
Nature. 2009 Jul 2;460(7251):103-7.

…Here we show that tumour necrosis factor (TNF) receptor-associated factor 6 (TRAF6), an adaptor protein in the TNF-receptor and interleukin-1R/Toll-like receptor superfamily, regulates CD8 T(M)-cell development after infection by modulating fatty acid metabolism. We show that mice with a T-cell-specific deletion of TRAF6 mount robust CD8 T(E)-cell responses, but have a profound defect in their ability to generate T(M) cells that is characterized by the disappearance of antigen-specific cells in the weeks after primary immunization.

Microarray analyses revealed that TRAF6-deficient CD8 T cells exhibit altered expression of genes that regulate fatty acid metabolism. Consistent with this, activated CD8 T cells lack
ing TRAF6 display defective AMP-activated kinase activation and mitochondrial fatty acid oxidation (FAO) in response to growth factor withdrawal. Administration of the anti-diabetic drug metformin restored FAO and CD8 T(M)-cell generation in the absence of TRAF6. This treatment also increased CD8 T(M) cells in wild-type mice, and consequently was able to considerably improve the efficacy of an experimental anti-cancer vaccine.

Paul McGlothin said...

Part II: Comment on "Side effects of caloric restriction (CR): CR increases susceptibility to infections."

The CR Way suggestion of meditation, which also enhances immune response.

Richard J. Davidson, PhD,et al.
Alterations in brain and immune function produced by mindfulness meditation.
Psychosom Med. 2003 Jul-Aug;65(4):564-70.

RESULTS: We report for the first time significant increases in left-sided anterior activation, a pattern previously associated with positive affect, in the meditators compared with the nonmeditators. We also found significant increases in antibody titers to influenza vaccine among subjects in the meditation compared with those in the wait-list control group. Finally, the magnitude of increase in left-sided activation predicted the magnitude of antibody titer rise to the vaccine.

CONCLUSIONS: …findings suggest that meditation may change brain and immune function in positive ways and underscore the need for additional research.

One of the cited studies induced sepsis by cecum venipuncture. An artificial protocol like this might provoke a poor immune system response in a calorie-restricted human. Normally, humans in the industrialized world consume very little total dietary fiber. However, a calorie-restricted human, following The CR Way may consume 70-80 grams of fiber per day. Overall that has tremendous health benefits. It would, however, create an environment that would cause suddenly introduced microbes to flourish. Fortunately, advances in probiotics have made it possible to beneficially alter the guts microbial balance – increasing beneficial immune responses. For example:

Schultz M, Linde HJ, Lehn N, Zimmermann K, Grossmann J, Falk W, Scholmerich J.
Immunomodulatory consequences of oral administration of Lactobacillus rhamnosus strain GG in healthy volunteers.
J Dairy Res. 2003 May;70(2):165-73.

Probiotic microorganisms, especially lactic acid bacteria, are effective in the treatment of infectious diarrhoeal diseases and experimental colitis. Although the mechanisms by which these organisms exert their anti-inflammatory effects are largely unknown, immunomodulating effects are suggested.

The objective of this study was to examine the effect of a 5-week oral administration of Lactobacillus rhamnosus subspecies GG (Lb. GG) on the cellular immune response to intestinal microorganisms in ten healthy volunteers.

Peripheral blood cells (PB) were stimulated with either 'self' or 'non-self' preparations of faecal samples and isolated Bacteroides fragilis group-organisms (Bfg) or Escherichia coli (E. coli), and pro- and anti-inflammatory cytokines (IL-10, IL-4, IL-6, IFN-gamma, TNF-alpha) were measured in the culture supernatant.

CD4+ T-lymphocyte activation was determined by measurement of intracellular ATP following lysis of the cells. The activational response of CD4+ T-lymphocytes towards isolated and heat-inactivated intestinal organisms was increased after the probiotic treatment. Additionally, TNF-alpha, IL-6, and in part IFN-gamma cytokine secretion by PB cells following stimulation with whole stool preparations and single members of the flora was significantly decreased, whereas the IL-10 and in part IL-4 cytokine secretion was increased at the end of the study. In contrast, the activational response of CD4+ T-lymphocytes following stimulation with whole 'non-self' intestinal flora was higher than by 'self' intestinal flora, but both responses showed a trend towards a reduction at the end of the study.
We think a few probiotics possess significant and beneficial effects on the gut’s immune responses. This too is discussed in The CR Way.

For too long calorie restriction has been judged by protocols used in mouse studies. The CR Way is designed for humans and includes many suggestions that enhance the benefits of the lifestyle. Strengthening immune response is one of them.

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