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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: 9.81). 01/2007; 103(51):19448-53. DOI: 10.1073/pnas.0606661103
Source: PubMed

ABSTRACT 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, Aug 14, 2015
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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.
    Age 09/2011; 34(6). DOI:10.1007/s11357-011-9308-3 · 3.45 Impact Factor
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    • "We next evaluated the effect of ovariectomy on the frequency of inflammatory cytokine-producing T cells. We previously showed that increased production of inflammatory cytokines by memory T cells following polyclonal stimulation is a hallmark of immune senescence in rhesus macaques (Jankovic et al. 2003; Messaoudi et al. 2006). To that end, we measured the frequency of CM and EM CD4 and CD8 T cells that secreted IFNγ and TNFα following polyclonal stimulation with anti-CD3 using intracellular cytokine staining (ICS) as shown in Fig. 2a. "
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    ABSTRACT: Aging is associated with a general dysregulation in immune function, commonly referred to as "immune senescence". Several studies have shown that female sex steroids can modulate the immune response. However, the impact of menopause-associated loss of estrogen and progestins on immune senescence remains poorly understood. To help answer this question, we examined the effect of ovariectomy on T-cell homeostasis and function in adult and aged female rhesus macaques. Our data show that in adult female rhesus macaques, ovariectomy increased the frequency of naïve CD4 T cells. In contrast, ovariectomized (ovx) aged female rhesus macaques had increased frequency of terminally differentiated CD4 effector memory T cells and inflammatory cytokine-secreting memory T cells. Moreover, ovariectomy reduced the immune response (T-cell cytokine and IgG production) following vaccination with modified vaccinia ankara in both adult and aged female rhesus macaques compared to ovary-intact age-matched controls. Interestingly, hormone therapy (estradiol alone or in conjunction with progesterone) partially improved the T-cell response to vaccination in aged ovariectomized female rhesus macaques. These data suggest that the loss of ovarian steroids, notably estradiol and progesterone, may contribute to reduced immune function in post-menopausal women and that hormone therapy may improve immune response to vaccination in this growing segment of the population.
    Age 09/2011; 33(3):275-89. DOI:10.1007/s11357-010-9178-0 · 3.45 Impact Factor
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    • "NHP T cell subsets change with age in ways that are similar to the changes that occur in rodents and humans: naïve CD4 and CD8 T cell numbers decline and memory cells increase, limiting fl exibility in responsiveness to new infections. An exciting fi nding from studies of the monkeys in the NIA project indicated that naïve cell populations were preserved in animals that began CR in early adulthood compared to age-matched controls (Messaoudi et al. 2006). Subsequent analysis of the younger and older cohorts, however, revealed that CR begun earlier in life (1-2 years of age) or when the animals were older adolescents (3-5 years old) had the opposite effect, increasing T cell senescence or producing lymphopenia and reduced proliferative capacity, respectively (Messaoudi et al. 2008). "
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    ABSTRACT: In the 75 years since the seminal observation of Clive McCay that restriction of calorie intake extends the lifespan of rats, a great deal has been learned about the effects of calorie restriction (CR; reduced intake of a nutritious diet) on aging in various short-lived animal models. Studies have demonstrated many beneficial effects of CR on health, the rate of aging, and longevity. Two prospective investigations of the effects of CR on long-lived nonhuman primate (NHP) species began nearly 25 years ago and are still under way. This review presents the design, methods, and main findings of these and other important contributing studies, which have generally revealed beneficial effects of CR on physiological function and the retardation of disease consistent with studies in other species. Specifically, prolonged CR appears to extend the lifespan of rhesus monkeys, which exhibited lower body fat; slower rate of muscle loss with age; lower incidence of neoplasia, cardiovascular disease, type 2 diabetes mellitus, and endometriosis; improved insulin sensitivity and glucose tolerance; and no apparent adverse effect on bone health, as well as a reduction in total energy expenditure. In addition, there are no reports of deleterious effects of CR on reproductive endpoints, and brain morphology is preserved by CR. Adrenal and thyroid hormone profiles are inconsistently affected. More research is needed to delineate the mechanisms of the desirable outcomes of CR and to develop interventions that can produce similar beneficial outcomes for humans. This research offers tremendous potential for producing novel insights into aging and risk of disease.
    ILAR journal / National Research Council, Institute of Laboratory Animal Resources 02/2011; 52(1):66-77. DOI:10.1093/ilar.52.1.66 · 1.05 Impact Factor
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