Messaoudi, I. et al. Delay of T cell senescence by caloric restriction in aged long-lived nonhuman primates. Proc. Natl Acad. Sci. USA 103, 19448-19453

Vaccine and Gene Therapy Institute and Oregon National Primate Research Center, Oregon Health and Science University, Beaverton, OR 97006, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 01/2007; 103(51):19448-53. DOI: 10.1073/pnas.0606661103
Source: PubMed


Caloric restriction (CR) has long been known to increase median and maximal lifespans and to decreases mortality and morbidity in short-lived animal models, likely by altering fundamental biological processes that regulate aging and longevity. In rodents, CR was reported to delay the aging of the immune system (immune senescence), which is believed to be largely responsible for a dramatic increase in age-related susceptibility to infectious diseases. However, it is unclear whether CR can exert similar effects in long-lived organisms. Previous studies involving 2- to 4-year CR treatment of long-lived primates failed to find a CR effect or reported effects on the immune system opposite to those seen in CR-treated rodents. 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.

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Available from: Ilhem Messaoudi
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    • "Sirt3 and mTOR are known as key regulators of energy metabolic homeostasis during fasting and calorie restriction [39,40], which has been linked to ameliorate diseases associate with aging [41,42]. Several studies have shown that calorie restriction can mitigate excessive immune response [43-46], but the mechanisms for this attenuation are still largely unknown. Prolonged restriction of calorie intake also leads to higher serum D-BHB concentrations [47-49]. "
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    ABSTRACT: Background Fasting is a rigorous type of dietary restriction that is associate with a number of health benefits. During fasting, ketone bodies significantly increase in blood and become major body fuels, thereby sparing glucose. In the present study, we investigated effects of fasting on hypersensitivity. In addition, we also investigated the possible role of D-beta-hydroxybutyrate provoked by fasting in the attenuation of immediate hypersensitivity by fasting. Methods Effects of fasting on systemic anaphylaxis were examined using rat model of toluene 2, 4-diisocyanate induced nasal allergy. In addition to food restriction, a ketogenic high-fat and low-carbohydrate diet that accelerates fatty acid oxidation and systemic instillation of D-beta-hydroxybutyrate were employed to elevate internal D-beta-hydroxybutyrate concentration. We assessed relationship between degranulation of rat peritoneal mast cells and internal D-beta-hydroxybutyrate concentration in each treatment. Changes in [Ca2+]i responses to compound 48/80 were analyzed in fura 2-loaded rat peritoneal mast cells derived from the ketogenic diet and fasting. Results Immediate hypersensitivity reaction was significantly suppressed by fasting. A significant reduction in mast cells degranulation, induced by mast cell activator compound 48/80, was observed in rat peritoneal mast cells delivered from the 24 hours fasting treatment. In addition, mast cells delivered from a ketogenic diet and D-beta-hydroxybutyrate infusion treatment also had reduced mast cell degranulation and systemic D-beta-hydroxybutyrate concentrations were elevated to similar extent as the fasting state. The peak increase in [Ca2+]i was significantly lower in the ketogenic diet and fasting group than that in the control diet group. Conclusions The results of the present study demonstrates that fasting suppress hypersensitivity reaction, and indicate that increased level of D-beta-hydroxybutyrate by fasting plays an important role, via the stabilization of mast cells, in suppression of hypersensitivity reaction.
    Full-text · Article · Aug 2014 · Nutrition & Metabolism
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    • "Interestingly, it has been recently reported that subjects genetically enriched for longevity are less susceptible to the characteristic CMV-associated antigen-driven immune alterations commonly considered to be the hallmarks of immunosenescence (Derhovanessian et al. 2010). Other factors independent from genetic predisposition could also play roles, such as: length of time from primary infection, distinct CMV viral strains (Pignatelli et al. 2010), site of viral persistence (Leng et al. 2011), degree of thymic involution and naive T cell reservoir faced with primary infection (Pitcher et al. 2002; Sauce et al. 2009), different individual behaviours regarding physical exercise (Turner et al. 2010) and/or caloric intake (Messaoudi et al. 2006), prior events of lymphodepletion counteracted by T lymphocyte homeostatic mechanisms (Fagnoni et al. 2002). Regardless of origin(s) of individual variability, we have seen that CMV-driven CD8+ T cell reactivity is correlated with increasing numbers of late differentiated CD28 − CD8+ T cells. "
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    ABSTRACT: Alterations in the circulating CD8+ T cell pool, with a loss of naïve and accumulation of effector/effector memory cells, are pronounced in older adults. However, homeostatic forces that dictate such changes remain incompletely understood. This observational cross-sectional study explored the basis for variability of CD8+ T cell number and composition of its main subsets: naïve, central memory and effector memory T cells, in 131 cytomegalovirus (CMV) seropositive subjects aged over 60 years. We found great heterogeneity of CD8+ T cell numbers, which was mainly due to variability of the CD8 + CD28− T cell subset regardless of age. Analysis, by multiple regression, of distinct factors revealed that age was a predictor for the loss in absolute number of naïve T cells, but was not associated with changes in central or effector memory CD8+ T cell subsets. By contrast, the size of CD8+ T cells specific to pp65 and IE-1 antigens of CMV, predicted CD28 − CD8+ T cell, antigen-experienced CD8+ T cell, and even total CD8+ T cell numbers, but not naïve CD8+ T cell loss. These results indicate a clear dichotomy between the homeostasis of naïve and antigen-experienced subsets of CD8+ T cells which are independently affected, in human later life, by age and antigen-specific responses to CMV, respectively. Electronic supplementary material The online version of this article (doi:10.1007/s11357-013-9594-z) contains supplementary material, which is available to authorized users.
    Full-text · Article · Dec 2013 · Age
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    • "Dietary restriction (DR) extends life span across a vast diversity of taxa, ranging from unicellular yeast (Lin et al. 2002) to primates (Messaoudi et al. 2006; Colman et al. 2008, 2009), supporting the idea that an evolutionary conserved mechanism may underpin this phenomenon. Substantial research has been devoted to identifying the mechanisms involved, especially in the nematode worm Caenorhabditis elegansi (Kimura et al. 1997; Lakowski and Hekimi 1998; Dillin et al. 2002), the fruit fly Drosophila melanogaster (Chapman and Partridge 1996; Clancy et al. 2001; Mair et al. 2003; Marden et al. 2003), and the mouse Mus musculus (Hursting et al. 1994; Bluher et al. 2003; Harrison et al. 2009). "
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    ABSTRACT: Dietary restriction extends life span across a vast diversity of taxa, but significant challenges remain in elucidating the underlying mechanisms. Distinguishing between caloric and nutrient effects is an essential step. Recent studies with Drosophila and tephritid fruit flies have reported increased life span as dietary yeast-to-sugar ratios decreased and these effects have been attributed to changes in protein-to-carbohydrate (P:C) ratios of the diets rather than calories. However, yeast is a complex mix of macronutrients and micronutrients, and hence changes in yeast content of the diet necessarily alters other nutrients in lockstep. To explicitly test whether studies using yeast are justified in attributing results to diet protein content rather than correlated nutrients, we developed a chemically defined diet allowing manipulation of just the ratio of protein (free amino acids) to carbohydrate (sucrose) levels of diets while holding other nutrients constant. Mated, female Queensland fruit flies (Q-flies) were fed 1 of 18 diets varying in P:C ratios and diet concentration. Diet consumption, egg production, and life span were recorded for each fly. In close concordance with recent studies using yeast diets, flies had increased life span as P:C ratios decreased, and caloric restriction did not extend life span. Similarly, egg production was maximized on high P:C ratios, but lifetime egg production was maximized on intermediate P:C ratios, indicating a life history trade-off between life span and egg production rate. Finally, Q-flies adjusted their diet intake in response to P:C ratios and diet concentration. Our results substantiate recent claims that P:C ratios significantly modulate life span in flies.
    Full-text · Article · Sep 2011 · Age
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