Daesung Hwangbo | University of Louisville (original) (raw)

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Papers by Daesung Hwangbo

Life-span extension in Drosophila brought about by a down-regulation of insulin-like signaling system (ISS)

ABSTRACT The insulin-like signaling system (ISS) is known to play an important role not only in t... more ABSTRACT The insulin-like signaling system (ISS) is known to play an important role not only in the regulation of biochemical metabolism but also in the control of other important biological processes such as growth and differentiation. In the nematode, it has been shown that down-regulation of the ISS results in a significant extension of the adult life-span. Studies on body and organ size control suggest that ISS is conserved in the fruit fly. Thus, I hypothesized that a down-regulation of the ISS in Drosophila would significantly extend the adult life-span. This hypothesis was tested using a genetic approach where single or double heterozygous mutants for the components of ISS were constructed. Significant extension of life-span in some of the ISS mutants including the heterozygous mutants for the insulin-like receptor gene (InR) was observed. Further tests were done using the constructed ISS mutants to determine if (a) increased antioxidant activity is associated with their extended longevity; and (b) whether the altered ISS activities result in certain metabolic changes. Body weight shift and up-regulation of a system for oxidative stress resistance, which is thought to bring about the life-span extension, were also observed. (Abstract shortened by UMI.) ^

PLoS Genetics, 2012

Epithelial homeostasis in the posterior midgut of Drosophila is maintained by multipotent intesti... more Epithelial homeostasis in the posterior midgut of Drosophila is maintained by multipotent intestinal stem cells (ISCs). ISCs self-renew and produce enteroblasts (EBs) that differentiate into either enterocytes (ECs) or enteroendocrine cells (EEs) in response to differential Notch (N) activation. Various environmental and growth signals dynamically regulate ISC activity, but their integration with differentiation cues in the ISC lineage remains unclear. Here we identify Notch-mediated repression of Tuberous Sclerosis Complex 2 (TSC2) in EBs as a required step in the commitment of EBs into the EC fate. The TSC1/2 complex inhibits TOR signaling, acting as a tumor suppressor in vertebrates and regulating cell growth. We find that TSC2 is expressed highly in ISCs, where it maintains stem cell identity, and that N-mediated repression of TSC2 in EBs is required and sufficient to promote EC differentiation. Regulation of TSC/TOR activity by N signaling thus emerges as critical for maintenance and differentiation in somatic stem cell lineages.

Experimental Gerontology, 2011

Cellular responses to extrinsic and intrinsic insults have to be carefully regulated to properly ... more Cellular responses to extrinsic and intrinsic insults have to be carefully regulated to properly coordinate cytoprotection, repair processes, cell proliferation and apoptosis. Stress signaling pathways, most prominently the Jun-N-terminal Kinase (JNK) pathway, are critical regulators of such cellular responses and have accordingly been implicated in the regulation of lifespan in various organisms. JNK signaling promotes cytoprotective gene expression, but also interacts with the insulin signaling pathway to influence growth, metabolism, stress tolerance and regeneration. Here, we review recent studies in Drosophila that elucidate the tissue-specific and systemic consequences of JNK activation that ultimately impact lifespan of the organism.

Annals of the New York Academy of Sciences, 2006

Evolutionary theories suggest that the expression of extended longevity depends on the organism's... more Evolutionary theories suggest that the expression of extended longevity depends on the organism's ability to shift energy from reproduction to somatic maintenance. New data led us to reexamine our older data and integrate the two into a larger picture of the genetic and metabolic alterations required if the animal is to live long. Our Ra normal-lived control strain can express any one of three different extended longevity phenotypes, only one of which involves significant and proportional increases in both mean and maximum longevity and thus a delayed onset of senescence. This phenotype is dependent on the up-regulation of the antioxidant defense system (ADS) genes and enzymes. Animals that express this phenotype typically have a pattern of altered specific activities in metabolically important enzymes, suggesting they are necessary to support the NAD + /NADP + reducing system required for the continued high ADS enzyme activities. Fecundity data suggests that the energy required for this higher level of somatic maintenance initially came from a reduced egg production. This was only transient, however, for the females significantly increased their fecundity in later generations while still maintaining their longevity. The energy required for this enhanced fecundity was probably obtained from an increased metabolic efficiency, for the mitochondria of the La long-lived strain are metabolically more efficient and have a lower leakage of reactive oxygen species (ROS) to the cytosol. Selection pressures that do not lead to these shifts in energy allocations result in extended longevity phenotypes characterized by increased early survival or increased late survival but not by a delayed onset of senescence.

Ageing Research Reviews, 2002

The antagonistic pleiotropy theory of the evolution of aging is shown to be too simple to fully a... more The antagonistic pleiotropy theory of the evolution of aging is shown to be too simple to fully apply to the situation in which Drosophila are selected directly for delayed female fecundity and indirectly for extended longevity. We re-evaluated our own previously reported selection experiments using previously unreported data, as well as new data from the literature. The facts that led to this re-evaluation were: (1) the recognition that there are at least three different extended longevity phenotypes; (2) the existence of metabolic and mitochondrial differences between normal-and long-lived organisms; and most importantly; (3) the observation that animals selected for extended longevity are both more fecund and longer-lived than their progenitor control animals. This latter observation appears to contradict the theory. A revised interpretation of the events underlying the selection process indicates that there is a two-step change in energy allocations leading to a complex phenotype. Initial selection first allows the up-regulation of the antioxidant defense system genes and a shift to the use of the pentose shunt. This is later followed by alterations in mitochondrial fatty acid composition and other changes necessary to reduce the leakage of H 2 O 2 from the mitochondria into the cytosol. The recaptured energy available from the latter step is diverted from somatic maintenance back into reproduction, resulting in animals that are both long-lived and fecund. Literature review suggests the involvement of mitochon

Nature, 2004

amino-acid pair distances 15. Subdivision of rat-mouse-human codon triplets into classes represen... more amino-acid pair distances 15. Subdivision of rat-mouse-human codon triplets into classes represented in Tables 1-3 easily follows from the genetic code table. All suitable triplets of bacterial genomes were obtained from the NCBI Entrez database and processed analogously. All alignments are available at ftp://ftp.ncbi.nih.gov/pub/kondrashov/ RatMouse/. Fluctuating negative selection We assumed that negative selection at a codon switches off and on at random moments. The expected waiting times (in units of time since rat-mouse divergence) for off to on and on to off switches are T and bT, respectively. Thus, negative selection is present with a probability of b/(1 þ b). If the total duration of episodes of absent negative selection in rat and mouse lineages were f r and f m , respectively, at a two-substitution codon P 0 ¼ r 2 , P 1 ¼ 2r(1 2 r) and P 2 ¼ (1 2 r) 2 , where r ¼ f r /(f r þ f m). This model was studied by Monte-Carlo simulations. For each pair of values of Tand b, we performed 1,000,000 runs. Initially, negative selection in both rat and mouse lineages was off with probability 1/(1 þ b) and on with probability b/(1 þ b). Then, switches of negative selection and accumulation of substitutions in the two lineages occurred independently. For each run, we calculated the probability that at a codon exactly two substitutions took place in rat and mouse lineages, assuming that substitutions occur independently, only when negative selection is off, with the instant rate 0.2 (the value of rat-mouse K s). After this, the probability of pattern 1 was calculated within two-substitution codons.

Life-span extension in Drosophila brought about by a down-regulation of insulin-like signaling system (ISS)

ABSTRACT The insulin-like signaling system (ISS) is known to play an important role not only in t... more ABSTRACT The insulin-like signaling system (ISS) is known to play an important role not only in the regulation of biochemical metabolism but also in the control of other important biological processes such as growth and differentiation. In the nematode, it has been shown that down-regulation of the ISS results in a significant extension of the adult life-span. Studies on body and organ size control suggest that ISS is conserved in the fruit fly. Thus, I hypothesized that a down-regulation of the ISS in Drosophila would significantly extend the adult life-span. This hypothesis was tested using a genetic approach where single or double heterozygous mutants for the components of ISS were constructed. Significant extension of life-span in some of the ISS mutants including the heterozygous mutants for the insulin-like receptor gene (InR) was observed. Further tests were done using the constructed ISS mutants to determine if (a) increased antioxidant activity is associated with their extended longevity; and (b) whether the altered ISS activities result in certain metabolic changes. Body weight shift and up-regulation of a system for oxidative stress resistance, which is thought to bring about the life-span extension, were also observed. (Abstract shortened by UMI.) ^

PLoS Genetics, 2012

Epithelial homeostasis in the posterior midgut of Drosophila is maintained by multipotent intesti... more Epithelial homeostasis in the posterior midgut of Drosophila is maintained by multipotent intestinal stem cells (ISCs). ISCs self-renew and produce enteroblasts (EBs) that differentiate into either enterocytes (ECs) or enteroendocrine cells (EEs) in response to differential Notch (N) activation. Various environmental and growth signals dynamically regulate ISC activity, but their integration with differentiation cues in the ISC lineage remains unclear. Here we identify Notch-mediated repression of Tuberous Sclerosis Complex 2 (TSC2) in EBs as a required step in the commitment of EBs into the EC fate. The TSC1/2 complex inhibits TOR signaling, acting as a tumor suppressor in vertebrates and regulating cell growth. We find that TSC2 is expressed highly in ISCs, where it maintains stem cell identity, and that N-mediated repression of TSC2 in EBs is required and sufficient to promote EC differentiation. Regulation of TSC/TOR activity by N signaling thus emerges as critical for maintenance and differentiation in somatic stem cell lineages.

Experimental Gerontology, 2011

Cellular responses to extrinsic and intrinsic insults have to be carefully regulated to properly ... more Cellular responses to extrinsic and intrinsic insults have to be carefully regulated to properly coordinate cytoprotection, repair processes, cell proliferation and apoptosis. Stress signaling pathways, most prominently the Jun-N-terminal Kinase (JNK) pathway, are critical regulators of such cellular responses and have accordingly been implicated in the regulation of lifespan in various organisms. JNK signaling promotes cytoprotective gene expression, but also interacts with the insulin signaling pathway to influence growth, metabolism, stress tolerance and regeneration. Here, we review recent studies in Drosophila that elucidate the tissue-specific and systemic consequences of JNK activation that ultimately impact lifespan of the organism.

Annals of the New York Academy of Sciences, 2006

Evolutionary theories suggest that the expression of extended longevity depends on the organism's... more Evolutionary theories suggest that the expression of extended longevity depends on the organism's ability to shift energy from reproduction to somatic maintenance. New data led us to reexamine our older data and integrate the two into a larger picture of the genetic and metabolic alterations required if the animal is to live long. Our Ra normal-lived control strain can express any one of three different extended longevity phenotypes, only one of which involves significant and proportional increases in both mean and maximum longevity and thus a delayed onset of senescence. This phenotype is dependent on the up-regulation of the antioxidant defense system (ADS) genes and enzymes. Animals that express this phenotype typically have a pattern of altered specific activities in metabolically important enzymes, suggesting they are necessary to support the NAD + /NADP + reducing system required for the continued high ADS enzyme activities. Fecundity data suggests that the energy required for this higher level of somatic maintenance initially came from a reduced egg production. This was only transient, however, for the females significantly increased their fecundity in later generations while still maintaining their longevity. The energy required for this enhanced fecundity was probably obtained from an increased metabolic efficiency, for the mitochondria of the La long-lived strain are metabolically more efficient and have a lower leakage of reactive oxygen species (ROS) to the cytosol. Selection pressures that do not lead to these shifts in energy allocations result in extended longevity phenotypes characterized by increased early survival or increased late survival but not by a delayed onset of senescence.

Ageing Research Reviews, 2002

The antagonistic pleiotropy theory of the evolution of aging is shown to be too simple to fully a... more The antagonistic pleiotropy theory of the evolution of aging is shown to be too simple to fully apply to the situation in which Drosophila are selected directly for delayed female fecundity and indirectly for extended longevity. We re-evaluated our own previously reported selection experiments using previously unreported data, as well as new data from the literature. The facts that led to this re-evaluation were: (1) the recognition that there are at least three different extended longevity phenotypes; (2) the existence of metabolic and mitochondrial differences between normal-and long-lived organisms; and most importantly; (3) the observation that animals selected for extended longevity are both more fecund and longer-lived than their progenitor control animals. This latter observation appears to contradict the theory. A revised interpretation of the events underlying the selection process indicates that there is a two-step change in energy allocations leading to a complex phenotype. Initial selection first allows the up-regulation of the antioxidant defense system genes and a shift to the use of the pentose shunt. This is later followed by alterations in mitochondrial fatty acid composition and other changes necessary to reduce the leakage of H 2 O 2 from the mitochondria into the cytosol. The recaptured energy available from the latter step is diverted from somatic maintenance back into reproduction, resulting in animals that are both long-lived and fecund. Literature review suggests the involvement of mitochon

Nature, 2004

amino-acid pair distances 15. Subdivision of rat-mouse-human codon triplets into classes represen... more amino-acid pair distances 15. Subdivision of rat-mouse-human codon triplets into classes represented in Tables 1-3 easily follows from the genetic code table. All suitable triplets of bacterial genomes were obtained from the NCBI Entrez database and processed analogously. All alignments are available at ftp://ftp.ncbi.nih.gov/pub/kondrashov/ RatMouse/. Fluctuating negative selection We assumed that negative selection at a codon switches off and on at random moments. The expected waiting times (in units of time since rat-mouse divergence) for off to on and on to off switches are T and bT, respectively. Thus, negative selection is present with a probability of b/(1 þ b). If the total duration of episodes of absent negative selection in rat and mouse lineages were f r and f m , respectively, at a two-substitution codon P 0 ¼ r 2 , P 1 ¼ 2r(1 2 r) and P 2 ¼ (1 2 r) 2 , where r ¼ f r /(f r þ f m). This model was studied by Monte-Carlo simulations. For each pair of values of Tand b, we performed 1,000,000 runs. Initially, negative selection in both rat and mouse lineages was off with probability 1/(1 þ b) and on with probability b/(1 þ b). Then, switches of negative selection and accumulation of substitutions in the two lineages occurred independently. For each run, we calculated the probability that at a codon exactly two substitutions took place in rat and mouse lineages, assuming that substitutions occur independently, only when negative selection is off, with the instant rate 0.2 (the value of rat-mouse K s). After this, the probability of pattern 1 was calculated within two-substitution codons.