Kelvin Yen - Academia.edu (original) (raw)

Papers by Kelvin Yen

Preface The Role of Hormesis in Life Extension by Dietary Restriction: Masoro, E.J. Metabolic Rep... more Preface The Role of Hormesis in Life Extension by Dietary Restriction: Masoro, E.J. Metabolic Reprogramming in Dietary Restriction: Anderson, R.M. Weindruch, R. Secrets of the Iac Operon. Glucose Hysteresis as a Mechanism in Dietary Restriction, Aging and Disease: Mobbs, C.V. Mastaitis, J.W. Zhang, M. Isoda, F. Cheng, H. Yen, K. Effects of Dietary Restriction on the Expression of Insulin-Signaling-Related Genes in Long-Lived Mutant Mice: Bartke, A. Masternak, M.M. Al-Regaiey, K.A. Bonkowski, M.S. Anti-Inflammatory Mechanisms of Dietary Restriction in Slowing Aging Processes: Morgan, T.E. Wong, A.M. Finch, C.E. Dietary Restriction in the Nematode Caenorhabditis elegans: Houthoofd, K. Gems, D. Johnson, T.E. Vanfleteren, J.R. Diet Restriction in Drosophila melanogaster. Design and Analysis: Tatar, M. Dietary Restriction in Aging Nonhuman Primates: Mattison, J.A. Roth, G.S. Lane, M.A. Ingram, D.K. Caloric Intake and Alzheimer's Disease. Experimental Approaches and Therapeutic Implic...

Physiology & Behavior, 2005

Since nutrition-sensitive feedback signals normally act to maintain relatively stable levels of b... more Since nutrition-sensitive feedback signals normally act to maintain relatively stable levels of both available and stored nutritional resources, failure in one or more of these feedback signals could plausibly lead to obese phenotypes. The glucostatic hypothesis in its original form posited that glucose serves as a physiological satiety factor (in the sense that post-prandial increases in plasma glucose cause meal termination), but in this form the hypothesis has been difficult to prove, and, especially since the discovery of leptin, the glucostatic hypothesis has largely been abandoned. Nevertheless, reduction of plasma glucose levels or glucose signaling produces a profile of neuroendocrine responses similar to those produced by leptin deficiency. Since leptin is not a physiological satiety factor (because it does not increase before meal termination), yet leptin deficiency causes obesity, we suggest that the glucostatic hypothesis be re-formulated without reference to satiety (i.e., short-term effects on food intake). Instead we argue that like leptin signaling, glucose signaling regulates long-term energy balance, in part by regulating metabolic rate but also by chronically regulating food intake. We further speculate that high-fat diets produce obesity in part because carbohydrates are, per calorie, more effective than lipids to reduce food intake and increase metabolic rate. In support of this glucoadipostatic hypothesis, the 5 present review examines evidence that obesity and the metabolic syndrome may be due to reduction in neuroendocrine sensitivity to glucose leading to increased metabolic efficiency.

Neurochemical Research, 2004

DNA microarray analysis has been used to investigate relative changes in the level of gene expres... more DNA microarray analysis has been used to investigate relative changes in the level of gene expression in the CNS, including changes that are associated with disease, injury, psychiatric disorders, drug exposure or withdrawal, and memory formation. We have used oligonucleotide microarrays to identify hypothalamic genes that respond to nutritional manipulation. In addition to commonly used microarray analysis based on criteria such as fold-regulation, we have also found that simply carrying out multiple t tests then sorting by P value constitutes a highly reliable method to detect true regulation, as assessed by real-time polymerase chain reaction (PCR), even for relatively low abundance genes or relatively low magnitude of regulation. Such analyses directly suggested novel mechanisms that mediate effects of nutritional state on neuroendocrine function and are being used to identify regulated gene products that may elucidate the metabolic pathology of obese ob/ob, lean Vgf-/Vgf-, and other models with profound metabolic impairments.

Mechanisms of Ageing and Development, 2009

Experimental Gerontology, 2004

Experimental Gerontology, 2008

A key goal of gerontology is to discover the factors that influence the rate of senescence, which... more A key goal of gerontology is to discover the factors that influence the rate of senescence, which in this context refers to the age-dependent acceleration of mortality, inversely related to the morality rate doubling time. In contrast factors that influence only initial mortality rate are thought to be less relevant to the fundamental processes of aging. To resolve these two determinants of mortality rate and lifespan, initial morality rate and rate of senescence are calculated using the Gompertz equation. Despite theoretical and empirical evidence that the Gompertz parameters are most consistently and reliably estimated by maximum-likelihood techniques, and somewhat less so by non-linear regression, many researchers continue to use linear regression on the log-transformed hazard rate. The present study compares these three methods in the analysis of several published studies. Estimates of the mortality rate parameters were then used to compare the theoretical values to the actual values of the following parameters: maximal lifespan, 50% survival times, variance in control groups and agreement with the distribution of deaths. These comparisons indicate that maximum-likelihood and non-linear regression estimates provide better estimates of mortality rate parameters than log-linear regression. Of particular interest, the improved estimates indicate that most genetic manipulations in mice that increase lifespan do so by decreasing initial mortality rate, not rate of senescence, whereas most genetic manipulations that decrease lifespan surprisingly do so by increasing the rate of senescence, not initial mortality rate.

Experimental Gerontology, 2008

Both caloric and chemosensory mechanisms influence lifespan, but the relative importance of each ... more Both caloric and chemosensory mechanisms influence lifespan, but the relative importance of each of these mechanisms in mediating effects of dietary restriction on lifespan has been unclear. Here we demonstrate that chemosensory mechanisms consistently influence initial mortality rate, whereas caloric mechanisms consistently influence age-dependent acceleration of mortality rate. Based on this analysis, life-extending effects of dietary restriction are mediated primarily by caloric mechanisms in rats and nematodes and by both mechanisms in mice and flies.

Cell Death & Differentiation, 2012

The insulin/IGF-1 pathway controls a number of physiological processes in the nematode worm Caeno... more The insulin/IGF-1 pathway controls a number of physiological processes in the nematode worm Caenorhabditis elegans, including development, aging and stress response. We previously found that the Akt/PKB ortholog AKT-1 dampens the apoptotic response to genotoxic stress in the germline by negatively regulating the p53-like transcription factor CEP-1. Here, we report unexpected rearrangements to the insulin/IGF-1 pathway, whereby the insulin-like receptor DAF-2 and 3-phosphoinositidedependent protein kinase PDK-1 oppose AKT-1 to promote DNA damage-induced apoptosis. While DNA damage does not affect phosphorylation at the PDK-1 site Thr350/Thr308 of AKT-1, it increased phosphorylation at Ser517/Ser473. Although ablation of daf-2 or pdk-1 completely suppressed akt-1-dependent apoptosis, the transcriptional activation of CEP-1 was unaffected, suggesting that daf-2 and pdk-1 act independently or downstream of cep-1 and akt-1. Ablation of the akt-1 paralog akt-2 or the downstream target of the insulin/IGF-1 pathway daf-16 (a FOXO transcription factor) restored sensitivity to damage-induced apoptosis in daf-2 and pdk-1 mutants. In addition, daf-2 and pdk-1 mutants have reduced levels of phospho-MPK-1/ERK in their germ cells, indicating that the insulin/IGF-1 pathway promotes Ras signaling in the germline. Ablation of the Ras effector gla-3, a negative regulator of mpk-1, restored sensitivity to apoptosis in daf-2 mutants, suggesting that gla-3 acts downstream of daf-2. In addition, the hypersensitivity of let-60/Ras gain-of-function mutants to damage-induced apoptosis was suppressed to wild-type levels by ablation of daf-2. Thus, insulin/IGF-1 signaling selectively engages AKT-2/DAF-16 to promote DNA damage-induced germ cell apoptosis downstream of CEP-1 through the Ras pathway.

Appetite, 2007

High-fat diets produce obesity in part because, per calorie, glucose produces greater post-prandi... more High-fat diets produce obesity in part because, per calorie, glucose produces greater post-prandial thermogenesis than lipids, an effect probably mediated by glucose-sensing neurons. A very low-carbohydrate/high-fat/high-protein Atkins-type diet produces obesity but is marginally ketogenic in mice. In contrast, high-sucrose/low-fat diets, and very low-carbohydrate/high-fat/low-protein (anti-epileptic) ketogenic diets reverse diet-induced obesity independent of caloric intake. We propose that a non-ketogenic high-fat diet reduces glucose metabolism and signaling in glucose-sensing neurons, thereby reducing post-prandial thermogenesis, and that a ketogenic high-fat diet does not reduce glucose signaling, thereby preventing and/or reversing obesity.

American Journal of Physiology-Endocrinology and Metabolism, 2012

To discover hypothalamic genes that might play a role in regulating energy balance, we carried ou... more To discover hypothalamic genes that might play a role in regulating energy balance, we carried out a microarray screen for genes induced by a 48-h fast in male C57Bl/6J mouse hypothalamus. One such gene was Fkbp51 (FK506 binding protein 5; Locus NP_034350). The product of this gene is of interest because it blocks glucocorticoid action, suggesting that fasting-induced elevation of this gene in the hypothalamus may reduce glucocorticoid negative feedback, leading to elevated glucocorticoid levels, thus promoting obese phenotypes. Subsequent analysis demonstrated that a 48-h fast induces Fkbp51 in ventromedial, paraventricular, and arcuate hypothalamic nuclei of mice and rats. To assess if hypothalamic Fkbp51 promotes obesity, the gene was transferred to the hypothalamus via an adeno-associated virus vector. Within 2 wk following Fkbp51 overexpression, mice on a high-fat diet exhibited elevated body weight, without hyperphagia, relative to mice receiving the control mCherry vector. Bo...

This is the data for the figures in this paper.

Aging, 2020

INTRODUCTION Mitochondria are central to several theories of aging as they are the major producer... more INTRODUCTION Mitochondria are central to several theories of aging as they are the major producer of both energy and free radicals, they regulate cell apoptosis, and their dysfunction is central to the observed physiological declines that occur during the aging process [1-5]. Similarly, mitochondrial dysfunction is found in many www.aging-us.com

Translational Medicine of Aging, 2020

Recent advancements in genomic, transcriptomic, proteomic, and metabolomic techniques have prompt... more Recent advancements in genomic, transcriptomic, proteomic, and metabolomic techniques have prompted fresh inquiry in the field of aging. Here, we outline the application of these techniques in the context of the mitochondrial genome and suggest their potential for use in exploring the biological mechanisms of the aging immune system.

Preface The Role of Hormesis in Life Extension by Dietary Restriction: Masoro, E.J. Metabolic Rep... more Preface The Role of Hormesis in Life Extension by Dietary Restriction: Masoro, E.J. Metabolic Reprogramming in Dietary Restriction: Anderson, R.M. Weindruch, R. Secrets of the Iac Operon. Glucose Hysteresis as a Mechanism in Dietary Restriction, Aging and Disease: Mobbs, C.V. Mastaitis, J.W. Zhang, M. Isoda, F. Cheng, H. Yen, K. Effects of Dietary Restriction on the Expression of Insulin-Signaling-Related Genes in Long-Lived Mutant Mice: Bartke, A. Masternak, M.M. Al-Regaiey, K.A. Bonkowski, M.S. Anti-Inflammatory Mechanisms of Dietary Restriction in Slowing Aging Processes: Morgan, T.E. Wong, A.M. Finch, C.E. Dietary Restriction in the Nematode Caenorhabditis elegans: Houthoofd, K. Gems, D. Johnson, T.E. Vanfleteren, J.R. Diet Restriction in Drosophila melanogaster. Design and Analysis: Tatar, M. Dietary Restriction in Aging Nonhuman Primates: Mattison, J.A. Roth, G.S. Lane, M.A. Ingram, D.K. Caloric Intake and Alzheimer's Disease. Experimental Approaches and Therapeutic Implic...

Physiology & Behavior, 2005

Since nutrition-sensitive feedback signals normally act to maintain relatively stable levels of b... more Since nutrition-sensitive feedback signals normally act to maintain relatively stable levels of both available and stored nutritional resources, failure in one or more of these feedback signals could plausibly lead to obese phenotypes. The glucostatic hypothesis in its original form posited that glucose serves as a physiological satiety factor (in the sense that post-prandial increases in plasma glucose cause meal termination), but in this form the hypothesis has been difficult to prove, and, especially since the discovery of leptin, the glucostatic hypothesis has largely been abandoned. Nevertheless, reduction of plasma glucose levels or glucose signaling produces a profile of neuroendocrine responses similar to those produced by leptin deficiency. Since leptin is not a physiological satiety factor (because it does not increase before meal termination), yet leptin deficiency causes obesity, we suggest that the glucostatic hypothesis be re-formulated without reference to satiety (i.e., short-term effects on food intake). Instead we argue that like leptin signaling, glucose signaling regulates long-term energy balance, in part by regulating metabolic rate but also by chronically regulating food intake. We further speculate that high-fat diets produce obesity in part because carbohydrates are, per calorie, more effective than lipids to reduce food intake and increase metabolic rate. In support of this glucoadipostatic hypothesis, the 5 present review examines evidence that obesity and the metabolic syndrome may be due to reduction in neuroendocrine sensitivity to glucose leading to increased metabolic efficiency.

Neurochemical Research, 2004

DNA microarray analysis has been used to investigate relative changes in the level of gene expres... more DNA microarray analysis has been used to investigate relative changes in the level of gene expression in the CNS, including changes that are associated with disease, injury, psychiatric disorders, drug exposure or withdrawal, and memory formation. We have used oligonucleotide microarrays to identify hypothalamic genes that respond to nutritional manipulation. In addition to commonly used microarray analysis based on criteria such as fold-regulation, we have also found that simply carrying out multiple t tests then sorting by P value constitutes a highly reliable method to detect true regulation, as assessed by real-time polymerase chain reaction (PCR), even for relatively low abundance genes or relatively low magnitude of regulation. Such analyses directly suggested novel mechanisms that mediate effects of nutritional state on neuroendocrine function and are being used to identify regulated gene products that may elucidate the metabolic pathology of obese ob/ob, lean Vgf-/Vgf-, and other models with profound metabolic impairments.

Mechanisms of Ageing and Development, 2009

Experimental Gerontology, 2004

Experimental Gerontology, 2008

A key goal of gerontology is to discover the factors that influence the rate of senescence, which... more A key goal of gerontology is to discover the factors that influence the rate of senescence, which in this context refers to the age-dependent acceleration of mortality, inversely related to the morality rate doubling time. In contrast factors that influence only initial mortality rate are thought to be less relevant to the fundamental processes of aging. To resolve these two determinants of mortality rate and lifespan, initial morality rate and rate of senescence are calculated using the Gompertz equation. Despite theoretical and empirical evidence that the Gompertz parameters are most consistently and reliably estimated by maximum-likelihood techniques, and somewhat less so by non-linear regression, many researchers continue to use linear regression on the log-transformed hazard rate. The present study compares these three methods in the analysis of several published studies. Estimates of the mortality rate parameters were then used to compare the theoretical values to the actual values of the following parameters: maximal lifespan, 50% survival times, variance in control groups and agreement with the distribution of deaths. These comparisons indicate that maximum-likelihood and non-linear regression estimates provide better estimates of mortality rate parameters than log-linear regression. Of particular interest, the improved estimates indicate that most genetic manipulations in mice that increase lifespan do so by decreasing initial mortality rate, not rate of senescence, whereas most genetic manipulations that decrease lifespan surprisingly do so by increasing the rate of senescence, not initial mortality rate.

Experimental Gerontology, 2008

Both caloric and chemosensory mechanisms influence lifespan, but the relative importance of each ... more Both caloric and chemosensory mechanisms influence lifespan, but the relative importance of each of these mechanisms in mediating effects of dietary restriction on lifespan has been unclear. Here we demonstrate that chemosensory mechanisms consistently influence initial mortality rate, whereas caloric mechanisms consistently influence age-dependent acceleration of mortality rate. Based on this analysis, life-extending effects of dietary restriction are mediated primarily by caloric mechanisms in rats and nematodes and by both mechanisms in mice and flies.

Cell Death & Differentiation, 2012

The insulin/IGF-1 pathway controls a number of physiological processes in the nematode worm Caeno... more The insulin/IGF-1 pathway controls a number of physiological processes in the nematode worm Caenorhabditis elegans, including development, aging and stress response. We previously found that the Akt/PKB ortholog AKT-1 dampens the apoptotic response to genotoxic stress in the germline by negatively regulating the p53-like transcription factor CEP-1. Here, we report unexpected rearrangements to the insulin/IGF-1 pathway, whereby the insulin-like receptor DAF-2 and 3-phosphoinositidedependent protein kinase PDK-1 oppose AKT-1 to promote DNA damage-induced apoptosis. While DNA damage does not affect phosphorylation at the PDK-1 site Thr350/Thr308 of AKT-1, it increased phosphorylation at Ser517/Ser473. Although ablation of daf-2 or pdk-1 completely suppressed akt-1-dependent apoptosis, the transcriptional activation of CEP-1 was unaffected, suggesting that daf-2 and pdk-1 act independently or downstream of cep-1 and akt-1. Ablation of the akt-1 paralog akt-2 or the downstream target of the insulin/IGF-1 pathway daf-16 (a FOXO transcription factor) restored sensitivity to damage-induced apoptosis in daf-2 and pdk-1 mutants. In addition, daf-2 and pdk-1 mutants have reduced levels of phospho-MPK-1/ERK in their germ cells, indicating that the insulin/IGF-1 pathway promotes Ras signaling in the germline. Ablation of the Ras effector gla-3, a negative regulator of mpk-1, restored sensitivity to apoptosis in daf-2 mutants, suggesting that gla-3 acts downstream of daf-2. In addition, the hypersensitivity of let-60/Ras gain-of-function mutants to damage-induced apoptosis was suppressed to wild-type levels by ablation of daf-2. Thus, insulin/IGF-1 signaling selectively engages AKT-2/DAF-16 to promote DNA damage-induced germ cell apoptosis downstream of CEP-1 through the Ras pathway.

Appetite, 2007

High-fat diets produce obesity in part because, per calorie, glucose produces greater post-prandi... more High-fat diets produce obesity in part because, per calorie, glucose produces greater post-prandial thermogenesis than lipids, an effect probably mediated by glucose-sensing neurons. A very low-carbohydrate/high-fat/high-protein Atkins-type diet produces obesity but is marginally ketogenic in mice. In contrast, high-sucrose/low-fat diets, and very low-carbohydrate/high-fat/low-protein (anti-epileptic) ketogenic diets reverse diet-induced obesity independent of caloric intake. We propose that a non-ketogenic high-fat diet reduces glucose metabolism and signaling in glucose-sensing neurons, thereby reducing post-prandial thermogenesis, and that a ketogenic high-fat diet does not reduce glucose signaling, thereby preventing and/or reversing obesity.

American Journal of Physiology-Endocrinology and Metabolism, 2012

To discover hypothalamic genes that might play a role in regulating energy balance, we carried ou... more To discover hypothalamic genes that might play a role in regulating energy balance, we carried out a microarray screen for genes induced by a 48-h fast in male C57Bl/6J mouse hypothalamus. One such gene was Fkbp51 (FK506 binding protein 5; Locus NP_034350). The product of this gene is of interest because it blocks glucocorticoid action, suggesting that fasting-induced elevation of this gene in the hypothalamus may reduce glucocorticoid negative feedback, leading to elevated glucocorticoid levels, thus promoting obese phenotypes. Subsequent analysis demonstrated that a 48-h fast induces Fkbp51 in ventromedial, paraventricular, and arcuate hypothalamic nuclei of mice and rats. To assess if hypothalamic Fkbp51 promotes obesity, the gene was transferred to the hypothalamus via an adeno-associated virus vector. Within 2 wk following Fkbp51 overexpression, mice on a high-fat diet exhibited elevated body weight, without hyperphagia, relative to mice receiving the control mCherry vector. Bo...

This is the data for the figures in this paper.

Aging, 2020

INTRODUCTION Mitochondria are central to several theories of aging as they are the major producer... more INTRODUCTION Mitochondria are central to several theories of aging as they are the major producer of both energy and free radicals, they regulate cell apoptosis, and their dysfunction is central to the observed physiological declines that occur during the aging process [1-5]. Similarly, mitochondrial dysfunction is found in many www.aging-us.com

Translational Medicine of Aging, 2020

Recent advancements in genomic, transcriptomic, proteomic, and metabolomic techniques have prompt... more Recent advancements in genomic, transcriptomic, proteomic, and metabolomic techniques have prompted fresh inquiry in the field of aging. Here, we outline the application of these techniques in the context of the mitochondrial genome and suggest their potential for use in exploring the biological mechanisms of the aging immune system.