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Linda Partridge - One of the best experts on this subject based on the ideXlab platform.

  • Dietary Restriction and aging a unifying perspective
    Cell Metabolism, 2011
    Co-Authors: Matthew D W Piper, Linda Partridge, David Raubenheimer, Stephen J. Simpson
    Abstract:

    Dietary Restriction (DR) and mutations in nutrient signaling pathways can extend healthy life span in diverse organisms. Studying the interaction between these interventions should reveal mechanisms of aging, but has yielded some apparently contradictory results. A multidimensional representation of nutrition, called the geometric framework, can better describe the responses of life span and other traits, including metabolism, and can reconcile these apparent contradictions. We provide examples showing that it is more informative to analyze DR in terms of Dietary balance and that Dietary optimization for life span is critical for studies examining the biology of aging and other traits.

  • Dietary Restriction: Standing Up for Sirtuins Response
    Science, 2010
    Co-Authors: Luigi Fontana, Linda Partridge
    Abstract:

    Baur et al. quote our statement that our Review aimed to “consider the role of nutrient-sensing signaling pathways in mediating the beneficial effects of Dietary Restriction.” However, they failed to quote the next sentence: “We focus on processes that are evolutionarily conserved in multiple

  • amino acid imbalance explains extension of lifespan by Dietary Restriction in drosophila
    Nature, 2009
    Co-Authors: Richard C. Grandison, Matthew D W Piper, Linda Partridge
    Abstract:

    In a number of organisms, Dietary Restriction has been shown to extend lifespan at the expense of reduced fecundity. An example of competition for limited resources, the thinking generally goes, as nutrients are reallocated from reproduction to somatic maintenance. Grandison et al. now demonstrate that, in Drosophila, Dietary Restriction does not induce reallocation, because different amino acids limit lifespan and fecundity. They find that fecundity in long-life flies can be rescued by the addition of methionine alone. Long lifespan and high fecundity can thus occur simultaneously, without Dietary Restriction itself, by adjustment of the ratio of amino acids in the diet. These findings imply that humans might be able to enjoy the benefits of reduced food intake, without the downsides, by adjustment of Dietary nutrients. Dietary Restriction extends healthy lifespan in diverse organisms but reduces fecundity; this is thought to be because of an adaptive reallocation of nutrients from reproduction to somatic maintenance. Here, the nutrients producing the responses of lifespan and fecundity to Dietary Restriction in Drosophila are identified. Adding essential amino acids to the Dietary Restriction condition increased fecundity and decreased lifespan; furthermore, addition of methionine alone rescued fecundity. Dietary Restriction extends healthy lifespan in diverse organisms and reduces fecundity1,2. It is widely assumed to induce adaptive reallocation of nutrients from reproduction to somatic maintenance, aiding survival of food shortages in nature3,4,5,6. If this were the case, long life under Dietary Restriction and high fecundity under full feeding would be mutually exclusive, through competition for the same limiting nutrients. Here we report a test of this idea in which we identified the nutrients producing the responses of lifespan and fecundity to Dietary Restriction in Drosophila. Adding essential amino acids to the Dietary Restriction condition increased fecundity and decreased lifespan, similar to the effects of full feeding, with other nutrients having little or no effect. However, methionine alone was necessary and sufficient to increase fecundity as much as did full feeding, but without reducing lifespan. Reallocation of nutrients therefore does not explain the responses to Dietary Restriction. Lifespan was decreased by the addition of amino acids, with an interaction between methionine and other essential amino acids having a key role. Hence, an imbalance in Dietary amino acids away from the ratio optimal for reproduction shortens lifespan during full feeding and limits fecundity during Dietary Restriction. Reduced activity of the insulin/insulin-like growth factor signalling pathway extends lifespan in diverse organisms7, and we find that it also protects against the shortening of lifespan with full feeding. In other organisms, including mammals, it may be possible to obtain the benefits to lifespan of Dietary Restriction without incurring a reduction in fecundity, through a suitable balance of nutrients in the diet.

  • Amino-acid imbalance explains extension of lifespan by Dietary Restriction in Drosophila
    Nature, 2009
    Co-Authors: Richard C. Grandison, Matthew D W Piper, Linda Partridge
    Abstract:

    Dietary Restriction extends healthy lifespan in diverse organisms and reduces fecundity(1,2). It is widely assumed to induce adaptive reallocation of nutrients from reproduction to somatic maintenance, aiding survival of food shortages in nature(3-6). If this were the case, long life under Dietary Restriction and high fecundity under full feeding would be mutually exclusive, through competition for the same limiting nutrients. Here we report a test of this idea in which we identified the nutrients producing the responses of lifespan and fecundity to Dietary Restriction in Drosophila. Adding essential amino acids to the Dietary Restriction condition increased fecundity and decreased lifespan, similar to the effects of full feeding, with other nutrients having little or no effect. However, methionine alone was necessary and sufficient to increase fecundity as much as did full feeding, but without reducing lifespan. Reallocation of nutrients therefore does not explain the responses to Dietary Restriction. Lifespan was decreased by the addition of amino acids, with an interaction between methionine and other essential amino acids having a key role. Hence, an imbalance in Dietary amino acids away from the ratio optimal for reproduction shortens lifespan during full feeding and limits fecundity during Dietary Restriction. Reduced activity of the insulin/insulin-like growth factor signalling pathway extends lifespan in diverse organisms(7), and we find that it also protects against the shortening of lifespan with full feeding. In other organisms, including mammals, it may be possible to obtain the benefits to lifespan of Dietary Restriction without incurring a reduction in fecundity, through a suitable balance of nutrients in the diet.

  • demography of Dietary Restriction and death in drosophila
    Science, 2003
    Co-Authors: William B Mair, Scott D Pletcher, Patrick Goymer, Linda Partridge
    Abstract:

    Dietary Restriction (DR) increases life-span in organisms from yeast to mammals, presumably by slowing the accumulation of aging-related damage. Here we show that in Drosophila, DR extends life-span entirely by reducing the short-term risk of death. Two days after the application of DR at any age for the first time, previously fully fed flies are no more likely to die than flies of the same age that have been subjected to long-term DR. DR of mammals may also reduce short-term risk of death, and hence DR instigated at any age could generate a full reversal of mortality.

Donald K Ingram - One of the best experts on this subject based on the ideXlab platform.

  • Dietary Restriction slows age pigment accumulation in the retinal pigment epithelium
    Investigative Ophthalmology and Visual Science, 1993
    Co-Authors: M. L. Katz, C L Gao, H. A. White, G. S. Roth, Joseph J Knapka, Donald K Ingram
    Abstract:

    PURPOSE. The accumulation of age pigment, or lipofuscin, in postmitotic cells appears to be a universal feature of the aging process in animals. In mammals, the lipofuscin content of the retinal pigment epithelium (RPE) increases progressively during senescence. Dietary Restriction has been shown to slow the rate at which many biologic parameters change during aging. Experiments were conducted to determine if Dietary Restriction alters the rate of age pigment accumulation in the RPE. METHODS. Male Wistar rats were placed on one of three Dietary regimens starting at weaning. One group was fed a nutritionally complete diet ad libitum. Another group was fed the same diet but was only allowed to consume 60% as much food daily as the ad libitum group ate. The final group was fed ad libitum a nutritionally complete diet that had a lower caloric density per gram than the diets fed to the other animals primarily because of the replacement of carbohydrate with oat fiber. Ultrastructural morphometric analysis was used to determine the RPE age pigment content in the first group at 6 months of age, and in all of the groups at 18 months of age. RESULTS. Dietary Restriction, achieved either by reducing total food intake or by reducing the caloric content of the diet, resulted in significant decreases in RPE lipofuscin accumulation. CONCLUSIONS. Dietary Restriction provides a relatively simple means by which RPE age pigment content can be modulated. This should prove useful in assessing the role of RPE lipofuscin accumulation in age-related retinal disorders. That the oat fiber diet fed ad libitum was almost as effective as Restriction of total food intake in slowing RPE age pigment accumulation indicates that the effect of restricted caloric intake is not mediated by almost constant hunger.

  • Neuroendocrine Effects of Lifelong Dietary Restriction by Intermittent Feeding in Mice
    Biomedical Advances in Aging, 1990
    Co-Authors: Barbara J. Davis, Robert W. Hamill, Thomas H. Mcneill, Elaine L. Bresnahan, Donald K Ingram
    Abstract:

    Lifelong Dietary Restriction has been shown to increase mean and maximum life span and to delay the onset of pathophysiologic changes associated with aging in rodents (Barrows and Kokkonen, 1978). The mechanisms underlying the modulation of aging by Dietary Restriction remain unknown. Based on studies using several levels of Dietary Restriction in mice, Weindruch et al. (1986) suggested that increased metabolic efficiency may be related to longevity, since the longest-lived mice at each level of Dietary Restriction studies also were the heaviest. Although a number of studies support the hypothesis that increased body weight is associated with increased longevity in dietarily restricted rodents, (reviewed by Ingram and Reynolds, 1987), the relationship between body weight and life span is complex, and it is difficult to make generalized statements relating longevity to body weight.

Chris Kenyon - One of the best experts on this subject based on the ideXlab platform.

  • A role for autophagy in the extension of lifespan by Dietary Restriction in C. elegans
    PLoS Genetics, 2008
    Co-Authors: Malene Hansen, Monica Driscoll, Laura L. Mitic, Brian Onken, Abha Chandra, Chris Kenyon
    Abstract:

    In many organisms, Dietary Restriction appears to extend lifespan, at least in part, by down-regulating the nutrient-sensor TOR (Target Of Rapamycin). TOR inhibition elicits autophagy, the large-scale recycling of cytoplasmic macromolecules and organelles. In this study, we asked whether autophagy might contribute to the lifespan extension induced by Dietary Restriction in C. elegans. We find that Dietary Restriction and TOR inhibition produce an autophagic phenotype and that inhibiting genes required for autophagy prevents Dietary Restriction and TOR inhibition from extending lifespan. The longevity response to Dietary Restriction in C. elegans requires the PHA-4 transcription factor. We find that the autophagic response to Dietary Restriction also requires PHA-4 activity, indicating that autophagy is a transcriptionally regulated response to food limitation. In spite of the rejuvenating effect that autophagy is predicted to have on cells, our findings suggest that autophagy is not sufficient to extend lifespan. Long-lived daf-2 insulin/IGF-1 receptor mutants require both autophagy and the transcription factor DAF-16/FOXO for their longevity, but we find that autophagy takes place in the absence of DAF-16. Perhaps autophagy is not sufficient for lifespan extension because although it provides raw material for new macromolecular synthesis, DAF-16/FOXO must program the cells to recycle this raw material into cell-protective longevity proteins.

  • A Role for Autophagy Genes in the Extension of Lifespan by Dietary Restriction in C. elegans
    PLoS Genetics, 2005
    Co-Authors: Malene Hansen, Monica Driscoll, Laura L. Mitic, Brian Onken, Abha Chandra, Chris Kenyon
    Abstract:

    In many organisms, Dietary Restriction appears to extend lifespan, at least in part, by down-regulating the nutrient-sensor TOR (Target Of Rapamycin). TOR inhibition elicits autophagy, the large-scale recycling of cytoplasmic macromolecules and organelles. In this study, we asked whether autophagy might contribute to the lifespan extension induced by Dietary Restriction in C. elegans. We find that Dietary Restriction and TOR inhibition produce an autophagic phenotype, and that inhibiting genes required for autophagy prevents Dietary Restriction and TOR inhibition from extending lifespan. The longevity response to Dietary Restriction in C. elegans requires the PHA-4 transcription factor. We find that the autophagic response to Dietary Restriction also requires PHA-4 activity, indicating that autophagy is a transcriptionally-regulated response to food limitation. In spite of the rejuvenating effect that autophagy is predicted to have on cells, our findings suggest that autophagy is not sufficient to extend lifespan. Long-lived daf-2 insulin/IGF-1 receptor mutants require both autophagy and the transcription factor DAF-16/FOXO for their longevity, but we find that autophagy takes place in the absence of DAF-16. Perhaps autophagy is not sufficient for lifespan extension because although it provides raw material for new macromolecular synthesis, DAF-16/FOXO must program the cells to recycle this raw material into cell-protective longevity proteins.

Byung Pal Yu - One of the best experts on this subject based on the ideXlab platform.

  • Protection of DNA damage by Dietary Restriction.
    Free Radical Biology and Medicine, 2003
    Co-Authors: Myung Hee Chung, Hiroshi Kasai, Susumu Nishimura, Byung Pal Yu
    Abstract:

    Abstract Dietary Restriction is known to retard the aging processes and delay the onset of age-related neoplastic diseases. The mechanisms underlying these remarkable actions of nutritional intervention are now known in spite of recently intensified research efforts. However, the last couple of years' research on Dietary Restriction produced strong evidence indicating that its effective antiaging actions might be related to its ability to modulate free radical damage. In the present study, DNA damage and attenuation of the damage by Dietary Restriction were asessed by measuring 8-hydroxydeoxyguanosine 8-OH dG) in both nuclear DNA (nuDNA) and mitochondrial DNA (mitDNA) fractions. The data show that substantially more damage (∼ 15 times) occurred in mitDNA compared to nuDNA. More interestingly, the DNA damage was significantly attenuated in dietarily restricted rats.

  • aging and oxidative stress modulation by Dietary Restriction
    Free Radical Biology and Medicine, 1996
    Co-Authors: Byung Pal Yu
    Abstract:

    Abstract Aging is an inevitable biological process that affects most living organisms. Despite the enormous consequences associated with the aging process, until recently, relatively little systematic effort has been expended on the scientific understanding of this important life process. Society, however, urged by an ever increasing older population, is challenging scientists from many disciplines to explore one of nature's most complex phenomena-biological aging. For the past two decades, research directed toward the basic understanding of biological aging mechanisms and possible aging interventions have given us new insights into the molecular bases and the biological events that contribute to age-related deterioration. To further investigate the aging processes, one probe uniquely suited to exploring the progression of aging in animal models is Dietary Restriction, currently the only antiaging intervention accepted by gerontologists and nutritionists. Recent research renders a better understanding of how reduced Dietary intake extends the life span, supplying evidence that Dietary Restriction is a diverse and effective modulator of oxidative stress. It has been proposed that this antioxidative mechanism is the underlying anti-aging action of Dietary Restriction.

  • Dietary Restriction retards onset but not progression of leukemia in male F344 rats.
    The Journals of Gerontology, 1993
    Co-Authors: Isao Shimokawa, Byung Pal Yu, Yoshikazu Higami, Takayoshi Ikeda, Edward J. Masoro
    Abstract:

    : The objective of this study was to determine the effect of Dietary Restriction on the spontaneous occurrence and the progression of leukemia in male F344 rats. The analysis involved both sacrificed rats and those that died spontaneously. These rats had been either ad libitum fed (AL) or restricted to approximately 60% of the ad libitum intake (DR) from 6 weeks of age. Dietary Restriction delayed spontaneous death due to this disease by delaying the occurrence of leukemia. However, Dietary Restriction did not retard its progression, i.e., the time between occurrence and death.

David M Sabatini - One of the best experts on this subject based on the ideXlab platform.

  • tumours with pi3k activation are resistant to Dietary Restriction
    Nature, 2009
    Co-Authors: Nada Y Kalaany, David M Sabatini
    Abstract:

    Dietary Restriction delays the incidence and decreases the growth of various types of tumours, but the mechanisms underlying the sensitivity of tumours to food Restriction remain unknown. Here we show that certain human cancer cell lines, when grown as tumour xenografts in mice, are highly sensitive to the anti-growth effects of Dietary Restriction, whereas others are resistant. Cancer cells that form Dietary-Restriction-resistant tumours carry mutations that cause constitutive activation of the phosphatidylinositol-3-kinase (PI3K) pathway and in culture proliferate in the absence of insulin or insulin-like growth factor 1. Substitution of an activated mutant allele of PI3K with wild-type PI3K in otherwise isogenic cancer cells, or the restoration of PTEN expression in a PTEN-null cancer cell line, is sufficient to convert a Dietary-Restriction-resistant tumour into one that is Dietary-Restriction-sensitive. Dietary Restriction does not affect a PTEN-null mouse model of prostate cancer, but it significantly decreases tumour burden in a mouse model of lung cancer lacking constitutive PI3K signalling. Thus, the PI3K pathway is an important determinant of the sensitivity of tumours to Dietary Restriction, and activating mutations in the pathway may influence the response of cancers to Dietary Restriction-mimetic therapies. It has been known for decades that Dietary Restriction has anticancer effects in rodents, yet surprisingly little is known about the molecular mechanisms that determine whether a given tumour responds to the regime or not. Nada Kalaany and David Sabatini report that certain human cancer cell lines, when grown as tumour xenografts in mice, are very sensitive to the antigrowth effects of Dietary Restriction, while others are resistant. The cause of the differential sensitivities of the tumours has now been identified as the activation state of the phosphatidylinositol-3-kinase (PI3K)/Akt signalling pathway. Thus the status of this pathway may serve as a predictor of which tumours might respond to therapies that mimic Dietary Restriction. The authors show that mouse or human tumours in which the PI3K/Akt pathway is constitutively activated are resistant to Dietary Restriction whereas other tumours are sensitive. The authors also implicate the Akt target gene FOXO1 in the response to Dietary Restriction.