Cancer cells have elevated energy demands to sustain continuous growth and other malignant proces... more Cancer cells have elevated energy demands to sustain continuous growth and other malignant processes and undergo extensive metabolic reprogramming to meet these demands. One element of this reprogramming in many cancer subtypes is elevated synthesis of nicotinamide adenine dinucleotide (NAD+), a critical co-enzyme that supports energy production through both glycolysis and the TCA cycle. The kynurenine metabolic pathway is the evolutionarily conserved means by which cells produce NAD+ de novo from tryptophan. NAD+ levels drop with age, a contributing factor to many forms of age-related disease. While interventions that increase NAD+ have been shown to extend lifespan, previous work from our lab demonstrates that knockdown of several kynurenine pathway enzymes, thus decreasing de novo NAD+ production, results in increased longevity of Caenorhabditis elegans by 20-30%. To address this apparent contradiction, we propose that kynurenine pathway inhibition may produce metabolic feedback ...
Select kynurenine pathway interventions extend lifespan in invertebrate models and are of interes... more Select kynurenine pathway interventions extend lifespan in invertebrate models and are of interest in treating age-associated diseases. Kynurenine pathway activity is responsive to inflammatory signaling, and we are evaluating the potential for these interventions to increase pathogen resistance and curtail age-associated immune decline in Caenorhabditis elegans and mammals. The kynurenine pathway facilitates the catabolism of tryptophan to nicotinamide adenine dinucleotide (NAD). Our lab has found that supplementing the kynurenine metabolite 3-hydroxyanthranilic acid (3HAA) or inhibiting the enzyme 3HAA dioxygenase (HAAO) extends lifespan in C. elegans. 3HAA has demonstrated pro/anti-inflammatory properties in mammals, suggesting a potential role in immune function. C. elegans have a primitive immune system that lacks an adaptive element, but it recapitulates aspects of innate immune signaling and pathogen response. I hypothesize kynurenine pathway interventions that impact C. eleg...
SummaryThe metabolism of tryptophan to nicotinamide adenine dinucleotide (NAD+) through the kynur... more SummaryThe metabolism of tryptophan to nicotinamide adenine dinucleotide (NAD+) through the kynurenine pathway is increasingly linked to aging and age-associated disease. Kynurenine pathway enzymes and metabolites influence a range of molecular processes critical to healthy aging, including regulation of inflammatory and immune responses, cellular redox homeostasis, and energy production. Aberrant kynurenine metabolism is observed during normal aging and has been implicated in a range of age-associated pathologies, including chronic inflammation, atherosclerosis, neurodegeneration, and cancer. In previous work, we and others identified three genes—kynu-1, tdo-2, and acsd-1—encoding kynurenine pathway enzymes for which decreasing expression extends lifespan in invertebrate models. Here we report that knockdown of haao-1, a fourth kynurenine pathway gene encoding the enzyme 3-hydroxyanthranilic acid dioxygenase (HAAO), extends lifespan by ~30% and delays age-associated decline in heal...
Aging is characterized by a progressive decline in the normal physiological functions of an organ... more Aging is characterized by a progressive decline in the normal physiological functions of an organism, ultimately leading to mortality. Metabolic changes throughout the aging process disrupt the balance and homeostasis of the cell. The kynurenine metabolic pathway is the sole de novo biosynthetic pathway for producing NAD+ from ingested tryptophan. Altered kynurenine pathway activity is associated with both aging and a variety of age-associated diseases, and kynurenine-based interventions can extend lifespan in Caenorhabditis elegans. Our laboratory recently demonstrated knockdown of the kynurenine pathway enzymes kynureninase (KYNU) or 3-hydroxyanthranilic acid dioxygenase (HAAO) increases lifespan by 20-30% in C elegans. However, the mechanism of how these interventions may modulate response against different stressors during the aging process has yet to be explored. Fluorescent reporter strains show the stress-responsive transcription factors skn-1 (ortholog of NRF2/NFE2L2; oxidat...
Cellular stress is a fundamental component of age-associated disease. Cells experience many forms... more Cellular stress is a fundamental component of age-associated disease. Cells experience many forms of stress (oxidative, heavy metal, etc.), and as we age the burden of stress and resulting damage increases while our cells’ ability to deal with the consequences becomes diminished due to dysregulation of cellular stress response pathways. By understanding how cells respond to stress we aim to slow age-associated deterioration and develop treatment targets for age-associated disease. The majority of past work has focused on understanding responses to individual stressors. In contrast, how pathology and stress responses differ in the presence of multiple stressors is relatively unknown; we investigate that here. We cultured worms on agar plates with different combinations of arsenic, copper, and DTT (which create oxidative/proteotoxic, heavy metal, and endoplasmic reticulum (ER) stress, respectively) at doses that result in 20% lifespan reduction individually and measured the effect on ...
Aberrant kynurenine pathway metabolism is increasingly linked to aging and age-associated disease... more Aberrant kynurenine pathway metabolism is increasingly linked to aging and age-associated disease. Kynurenine metabolic activity increases with age and becomes dysregulated during various forms of age-associated pathology in humans. By manipulating one or more kynurenine pathway enzymes and metabolites, we have extended lifespan up to 40% in Caenorhabditis elegans. In particular, elevating physiological levels of the kynurenine pathway metabolite 3-hydroxyanthranilic acid (3HAA) by directly supplementing 3HAA or inhibiting the enzyme 3HAA dioxygenase (HAAO) extends C. elegans lifespan by ~30%. 3HAA delivered chronically in chow similarly extends lifespan in aged C57BL/6 mice. In ongoing work, we are investigating the mechanisms underlying the benefits of multiple kynurenine pathway interventions using tools in C. elegans, mice, and human cell culture. We have preliminary evidence for activation of broad-spectrum cellular stress response, enhanced immune function, and reduced inflamm...
Cells are constantly subjected to a variety of intrinsic and extrinsic stresses—oxidative, protei... more Cells are constantly subjected to a variety of intrinsic and extrinsic stresses—oxidative, protein misfolding, osmotic—and respond by activating a range of molecular pathways to mitigate and repair damage—oxidative stress response, unfolded protein response, osmotic stress response. While individual stress response pathways have been described in detail, and some interventions improve resistance to multiple forms of stress (e.g. dietary restriction, insulin signaling inhibition), surprisingly little is known about how these responses differ when cells are challenged with multiple types of stress simultaneously. The molecular architecture underlying multi-stress response has broad implications for aging and age-associated disease. One characteristic of aging is a progressive increase in multiple categories of cellular stress accompanied by a decline in cellular stress response capability. Human diseases rarely involve a single form of stress—Alzheimer’s disease is characterized by ne...
Cellular stress is an ever-present aspect of aging and a primary driver of many common age-associ... more Cellular stress is an ever-present aspect of aging and a primary driver of many common age-associated diseases such as cancer, diabetes, or neurodegenerative diseases. As we age, stress-induced damage accumulates over time, along with reduced efficacy of stress response pathways at combatting such damage. Molecular stress response pathways are well studied in the context of individual stressors, but there is a lack of understanding of how these responses change when multiple stressors are encountered at the same time. The goal of our work is to explore the impact of multiple simultaneous stressors on health and survival, and to investigate the underlying molecular pathways involved. To accomplish this, we utilize the nematode Caenorhabditis elegans to monitor lifespan changes in response to various stressors. We simultaneously exposed C. elegans to high concentrations of sodium chloride and cadmium chloride, known to induce osmotic and heavy metal stress, respectively. We found that...
Hepatocellular carcinoma (HCC) is the most prevalent cancer in the liver. The majority of ingeste... more Hepatocellular carcinoma (HCC) is the most prevalent cancer in the liver. The majority of ingested tryptophan is processed in the liver through the kynurenine pathway, the endpoint of which is de novo NAD+ biosynthesis. Dysregulation of tryptophan-kynurenine metabolism and NAD+ synthesis may promote mitochondrial malfunction, tumor reprogramming, and carcinogenesis. Using a publicly available gene expression dataset from liver hepatocellular carcinoma (LIHC) samples available through The Cancer Genome Atlas (TCGA; n = 371), we employed Principal Component Analysis (PCA), hierarchical clustering, gene-pattern expression profiling, and survival analysis to cluster patients and determine overall survival. Our analysis of genes encoding kynurenine pathway enzymes determined that patients with high QPRT expression had a poor prognosis with decreased median survival, with no effect on the maximum survival. There is a significant difference in the survival between patients with high QPRT e...
This session will focus on interventions to delay biological aging with the goal of in increasing... more This session will focus on interventions to delay biological aging with the goal of in increasing lifespan and healthspan.
The kynurenine pathway, the major route for tryptophan catabolism, becomes dysregulated with age ... more The kynurenine pathway, the major route for tryptophan catabolism, becomes dysregulated with age and in many age-associated pathologies in humans. Interventions targeting kynurenine metabolism are being pursued for neurodegeneration, cardiovascular disease, and chronic kidney disease. By manipulating kynurenine pathway enzymes and metabolites, we have extended lifespan up to 40% in Caenorhabditis elegans. Our most promising single target is the metabolite 3-hydroxyanthranilic acid dioxygenase (3HAA). Elevating physiological 3HAA by directly supplementing 3HAA or inhibiting the enzyme 3HAA dioxygenase (HAAO) extends worm lifespan by ~30% while reducing oxidative stress by directly degrading hydrogen peroxide. In rodents, anti-inflammatory activity of 3HAA improves outcomes in models of cardiovascular disease, asthma, and autoimmune encephalomyelitis. We are now beginning to validate our C. elegans work in mice and investigating a mechanistic model in which 3HAA acts to extend healthy...
Young Caenorhabditis elegans hermaphrodites use their own sperm to protect against the negative c... more Young Caenorhabditis elegans hermaphrodites use their own sperm to protect against the negative consequences of mating.
Understanding the biological mechanisms behind aging, lifespan and healthspan is becoming increas... more Understanding the biological mechanisms behind aging, lifespan and healthspan is becoming increasingly important as the proportion of the world's population over the age of 65 grows, along with the cost and complexity of their care. BigData oriented approaches and analysis methods for integrative functional genomics enable current and future bio-gerontologists to synthesize, distill and interpret vast, heterogeneous data. GeneWeaver is an analysis system for integration of data that allows investigators to store, search, and analyze immense amounts of data including user-submitted experimental data, data from primary publications, and data in other databases. Aging related genome-wide gene sets from primary publications were curated into this system in concert with data from other model-organism and aging-specific databases, and used in several application using GeneWeavers analysis tools. For example, we identified Cd63 as a frequently represented gene among aging-related genom...
Understanding the biological mechanisms behind aging, lifespan and healthspan is becoming increas... more Understanding the biological mechanisms behind aging, lifespan and healthspan is becoming increasingly important as the proportion of the world's population over the age of 65 grows, along with the cost and complexity of their care. BigData oriented approaches and analysis methods enable current and future bio-gerontologists to synthesize, distill and interpret vast, heterogeneous data from functional genomics studies of aging. GeneWeaver is an analysis system for integration of data that allows investigators to store, search, and analyze immense amounts of data including user-submitted experimental data, data from primary publications, and data in other databases. Aging related genome-wide gene sets from primary publications were curated into this system in concert with data from other modelorganism and aging-specific databases, and applied to several questions in genrontology using. For example, we identified Cd63 as a frequently represented gene among agingrelated genome-wide results. To evaluate the role of Cd63 in aging, we performed RNAi knockdown of the C. elegans ortholog, tsp-7, demonstrating that this manipulation is capable of extending lifespan. The tools in GeneWeaver enable aging researchers to make new discoveries into the associations between the genes, normal biological processes, and diseases that affect aging, healthspan, and lifespan.
As in other poikilotherms, longevity in C. elegans varies inversely with temperature; worms are l... more As in other poikilotherms, longevity in C. elegans varies inversely with temperature; worms are longer-lived at lower temperatures. While this observation may seem intuitive based on thermodynamics, the molecular and genetic basis for this phenomenon is not well understood. Several recent reports have argued that lifespan changes across temperatures are genetically controlled by temperature-specific gene regulation. Here, we provide data that both corroborate those studies and suggest that temperature-specific longevity is more the rule than the exception. By measuring the lifespans of worms with single modifications reported to be important for longevity at 15, 20, or 25°C, we find that the effect of each modification on lifespan is highly dependent on temperature. Our results suggest that genetics play a major role in temperature-associated longevity and are consistent with the hypothesis that while aging in C. elegans is slowed by decreasing temperature, the major cause(s) of death may also be modified, leading to different genes and pathways becoming more or less important at different temperatures. These differential mechanisms of age-related death are not unlike what is observed in humans, where environmental conditions lead to development of different diseases of aging.
We report a systematic RNAi longevity screen of 82 Caenorhabditis elegans genes selected based on... more We report a systematic RNAi longevity screen of 82 Caenorhabditis elegans genes selected based on orthology to human genes differentially expressed with age. We find substantial enrichment in genes for which knockdown increased lifespan. This enrichment is markedly higher than published genomewide longevity screens in C. elegans and similar to screens that preselected candidates based on longevity-correlated metrics (e.g., stress resistance). Of the 50 genes that affected lifespan, 46 were previously unreported. The five genes with the greatest impact on lifespan (>20% extension) encode the enzyme kynureninase (kynu-1), a neuronal leucine-rich repeat protein (iglr-1), a tetraspanin (tsp-3), a regulator of calcineurin (rcan-1), and a voltage-gated calcium channel subunit (unc-36). Knockdown of each gene extended healthspan without impairing reproduction. kynu-1(RNAi) alone delayed pathology in C. elegans models of Alzheimer's disease and Huntington's disease. Each gene dis...
Animals, particularly poikilotherms, exhibit distinct physiologies at different environmental tem... more Animals, particularly poikilotherms, exhibit distinct physiologies at different environmental temperatures. Here, we hypothesized that temperature-based differences in physiology could affect the amount of variation in complex quantitative traits. Specifically, we examined, in Caenorhabditis elegans, how different temperatures (15°C, 20°C, and 25°C) affected the amount of interindividual variation in life span and also expression of three reporter genes-transcriptional reporters for vit-2, gpd-2, and hsp-16.2 (a life-span biomarker). We found the expected inverse relationship between temperature and average life span. Surprisingly, we found that at the highest temperature, there were fewer differences between individuals in life span and less interindividual variation in expression of all three reporters. We suggest that growth at 25°C might canalize (reduce interindividual differences in) life span and expression of some genes by eliciting a small constitutive heat shock response. Growth at 25°C requires wild-type hsf-1, which encodes the main heat shock response transcriptional activator. We speculate that increased chaperone activity at 25°C may reduce interindividual variation in gene expression by increasing protein folding efficiency. We hypothesize that reduced variation in gene expression may ultimately cause reduced variation in life span.
Cancer cells have elevated energy demands to sustain continuous growth and other malignant proces... more Cancer cells have elevated energy demands to sustain continuous growth and other malignant processes and undergo extensive metabolic reprogramming to meet these demands. One element of this reprogramming in many cancer subtypes is elevated synthesis of nicotinamide adenine dinucleotide (NAD+), a critical co-enzyme that supports energy production through both glycolysis and the TCA cycle. The kynurenine metabolic pathway is the evolutionarily conserved means by which cells produce NAD+ de novo from tryptophan. NAD+ levels drop with age, a contributing factor to many forms of age-related disease. While interventions that increase NAD+ have been shown to extend lifespan, previous work from our lab demonstrates that knockdown of several kynurenine pathway enzymes, thus decreasing de novo NAD+ production, results in increased longevity of Caenorhabditis elegans by 20-30%. To address this apparent contradiction, we propose that kynurenine pathway inhibition may produce metabolic feedback ...
Select kynurenine pathway interventions extend lifespan in invertebrate models and are of interes... more Select kynurenine pathway interventions extend lifespan in invertebrate models and are of interest in treating age-associated diseases. Kynurenine pathway activity is responsive to inflammatory signaling, and we are evaluating the potential for these interventions to increase pathogen resistance and curtail age-associated immune decline in Caenorhabditis elegans and mammals. The kynurenine pathway facilitates the catabolism of tryptophan to nicotinamide adenine dinucleotide (NAD). Our lab has found that supplementing the kynurenine metabolite 3-hydroxyanthranilic acid (3HAA) or inhibiting the enzyme 3HAA dioxygenase (HAAO) extends lifespan in C. elegans. 3HAA has demonstrated pro/anti-inflammatory properties in mammals, suggesting a potential role in immune function. C. elegans have a primitive immune system that lacks an adaptive element, but it recapitulates aspects of innate immune signaling and pathogen response. I hypothesize kynurenine pathway interventions that impact C. eleg...
SummaryThe metabolism of tryptophan to nicotinamide adenine dinucleotide (NAD+) through the kynur... more SummaryThe metabolism of tryptophan to nicotinamide adenine dinucleotide (NAD+) through the kynurenine pathway is increasingly linked to aging and age-associated disease. Kynurenine pathway enzymes and metabolites influence a range of molecular processes critical to healthy aging, including regulation of inflammatory and immune responses, cellular redox homeostasis, and energy production. Aberrant kynurenine metabolism is observed during normal aging and has been implicated in a range of age-associated pathologies, including chronic inflammation, atherosclerosis, neurodegeneration, and cancer. In previous work, we and others identified three genes—kynu-1, tdo-2, and acsd-1—encoding kynurenine pathway enzymes for which decreasing expression extends lifespan in invertebrate models. Here we report that knockdown of haao-1, a fourth kynurenine pathway gene encoding the enzyme 3-hydroxyanthranilic acid dioxygenase (HAAO), extends lifespan by ~30% and delays age-associated decline in heal...
Aging is characterized by a progressive decline in the normal physiological functions of an organ... more Aging is characterized by a progressive decline in the normal physiological functions of an organism, ultimately leading to mortality. Metabolic changes throughout the aging process disrupt the balance and homeostasis of the cell. The kynurenine metabolic pathway is the sole de novo biosynthetic pathway for producing NAD+ from ingested tryptophan. Altered kynurenine pathway activity is associated with both aging and a variety of age-associated diseases, and kynurenine-based interventions can extend lifespan in Caenorhabditis elegans. Our laboratory recently demonstrated knockdown of the kynurenine pathway enzymes kynureninase (KYNU) or 3-hydroxyanthranilic acid dioxygenase (HAAO) increases lifespan by 20-30% in C elegans. However, the mechanism of how these interventions may modulate response against different stressors during the aging process has yet to be explored. Fluorescent reporter strains show the stress-responsive transcription factors skn-1 (ortholog of NRF2/NFE2L2; oxidat...
Cellular stress is a fundamental component of age-associated disease. Cells experience many forms... more Cellular stress is a fundamental component of age-associated disease. Cells experience many forms of stress (oxidative, heavy metal, etc.), and as we age the burden of stress and resulting damage increases while our cells’ ability to deal with the consequences becomes diminished due to dysregulation of cellular stress response pathways. By understanding how cells respond to stress we aim to slow age-associated deterioration and develop treatment targets for age-associated disease. The majority of past work has focused on understanding responses to individual stressors. In contrast, how pathology and stress responses differ in the presence of multiple stressors is relatively unknown; we investigate that here. We cultured worms on agar plates with different combinations of arsenic, copper, and DTT (which create oxidative/proteotoxic, heavy metal, and endoplasmic reticulum (ER) stress, respectively) at doses that result in 20% lifespan reduction individually and measured the effect on ...
Aberrant kynurenine pathway metabolism is increasingly linked to aging and age-associated disease... more Aberrant kynurenine pathway metabolism is increasingly linked to aging and age-associated disease. Kynurenine metabolic activity increases with age and becomes dysregulated during various forms of age-associated pathology in humans. By manipulating one or more kynurenine pathway enzymes and metabolites, we have extended lifespan up to 40% in Caenorhabditis elegans. In particular, elevating physiological levels of the kynurenine pathway metabolite 3-hydroxyanthranilic acid (3HAA) by directly supplementing 3HAA or inhibiting the enzyme 3HAA dioxygenase (HAAO) extends C. elegans lifespan by ~30%. 3HAA delivered chronically in chow similarly extends lifespan in aged C57BL/6 mice. In ongoing work, we are investigating the mechanisms underlying the benefits of multiple kynurenine pathway interventions using tools in C. elegans, mice, and human cell culture. We have preliminary evidence for activation of broad-spectrum cellular stress response, enhanced immune function, and reduced inflamm...
Cells are constantly subjected to a variety of intrinsic and extrinsic stresses—oxidative, protei... more Cells are constantly subjected to a variety of intrinsic and extrinsic stresses—oxidative, protein misfolding, osmotic—and respond by activating a range of molecular pathways to mitigate and repair damage—oxidative stress response, unfolded protein response, osmotic stress response. While individual stress response pathways have been described in detail, and some interventions improve resistance to multiple forms of stress (e.g. dietary restriction, insulin signaling inhibition), surprisingly little is known about how these responses differ when cells are challenged with multiple types of stress simultaneously. The molecular architecture underlying multi-stress response has broad implications for aging and age-associated disease. One characteristic of aging is a progressive increase in multiple categories of cellular stress accompanied by a decline in cellular stress response capability. Human diseases rarely involve a single form of stress—Alzheimer’s disease is characterized by ne...
Cellular stress is an ever-present aspect of aging and a primary driver of many common age-associ... more Cellular stress is an ever-present aspect of aging and a primary driver of many common age-associated diseases such as cancer, diabetes, or neurodegenerative diseases. As we age, stress-induced damage accumulates over time, along with reduced efficacy of stress response pathways at combatting such damage. Molecular stress response pathways are well studied in the context of individual stressors, but there is a lack of understanding of how these responses change when multiple stressors are encountered at the same time. The goal of our work is to explore the impact of multiple simultaneous stressors on health and survival, and to investigate the underlying molecular pathways involved. To accomplish this, we utilize the nematode Caenorhabditis elegans to monitor lifespan changes in response to various stressors. We simultaneously exposed C. elegans to high concentrations of sodium chloride and cadmium chloride, known to induce osmotic and heavy metal stress, respectively. We found that...
Hepatocellular carcinoma (HCC) is the most prevalent cancer in the liver. The majority of ingeste... more Hepatocellular carcinoma (HCC) is the most prevalent cancer in the liver. The majority of ingested tryptophan is processed in the liver through the kynurenine pathway, the endpoint of which is de novo NAD+ biosynthesis. Dysregulation of tryptophan-kynurenine metabolism and NAD+ synthesis may promote mitochondrial malfunction, tumor reprogramming, and carcinogenesis. Using a publicly available gene expression dataset from liver hepatocellular carcinoma (LIHC) samples available through The Cancer Genome Atlas (TCGA; n = 371), we employed Principal Component Analysis (PCA), hierarchical clustering, gene-pattern expression profiling, and survival analysis to cluster patients and determine overall survival. Our analysis of genes encoding kynurenine pathway enzymes determined that patients with high QPRT expression had a poor prognosis with decreased median survival, with no effect on the maximum survival. There is a significant difference in the survival between patients with high QPRT e...
This session will focus on interventions to delay biological aging with the goal of in increasing... more This session will focus on interventions to delay biological aging with the goal of in increasing lifespan and healthspan.
The kynurenine pathway, the major route for tryptophan catabolism, becomes dysregulated with age ... more The kynurenine pathway, the major route for tryptophan catabolism, becomes dysregulated with age and in many age-associated pathologies in humans. Interventions targeting kynurenine metabolism are being pursued for neurodegeneration, cardiovascular disease, and chronic kidney disease. By manipulating kynurenine pathway enzymes and metabolites, we have extended lifespan up to 40% in Caenorhabditis elegans. Our most promising single target is the metabolite 3-hydroxyanthranilic acid dioxygenase (3HAA). Elevating physiological 3HAA by directly supplementing 3HAA or inhibiting the enzyme 3HAA dioxygenase (HAAO) extends worm lifespan by ~30% while reducing oxidative stress by directly degrading hydrogen peroxide. In rodents, anti-inflammatory activity of 3HAA improves outcomes in models of cardiovascular disease, asthma, and autoimmune encephalomyelitis. We are now beginning to validate our C. elegans work in mice and investigating a mechanistic model in which 3HAA acts to extend healthy...
Young Caenorhabditis elegans hermaphrodites use their own sperm to protect against the negative c... more Young Caenorhabditis elegans hermaphrodites use their own sperm to protect against the negative consequences of mating.
Understanding the biological mechanisms behind aging, lifespan and healthspan is becoming increas... more Understanding the biological mechanisms behind aging, lifespan and healthspan is becoming increasingly important as the proportion of the world's population over the age of 65 grows, along with the cost and complexity of their care. BigData oriented approaches and analysis methods for integrative functional genomics enable current and future bio-gerontologists to synthesize, distill and interpret vast, heterogeneous data. GeneWeaver is an analysis system for integration of data that allows investigators to store, search, and analyze immense amounts of data including user-submitted experimental data, data from primary publications, and data in other databases. Aging related genome-wide gene sets from primary publications were curated into this system in concert with data from other model-organism and aging-specific databases, and used in several application using GeneWeavers analysis tools. For example, we identified Cd63 as a frequently represented gene among aging-related genom...
Understanding the biological mechanisms behind aging, lifespan and healthspan is becoming increas... more Understanding the biological mechanisms behind aging, lifespan and healthspan is becoming increasingly important as the proportion of the world's population over the age of 65 grows, along with the cost and complexity of their care. BigData oriented approaches and analysis methods enable current and future bio-gerontologists to synthesize, distill and interpret vast, heterogeneous data from functional genomics studies of aging. GeneWeaver is an analysis system for integration of data that allows investigators to store, search, and analyze immense amounts of data including user-submitted experimental data, data from primary publications, and data in other databases. Aging related genome-wide gene sets from primary publications were curated into this system in concert with data from other modelorganism and aging-specific databases, and applied to several questions in genrontology using. For example, we identified Cd63 as a frequently represented gene among agingrelated genome-wide results. To evaluate the role of Cd63 in aging, we performed RNAi knockdown of the C. elegans ortholog, tsp-7, demonstrating that this manipulation is capable of extending lifespan. The tools in GeneWeaver enable aging researchers to make new discoveries into the associations between the genes, normal biological processes, and diseases that affect aging, healthspan, and lifespan.
As in other poikilotherms, longevity in C. elegans varies inversely with temperature; worms are l... more As in other poikilotherms, longevity in C. elegans varies inversely with temperature; worms are longer-lived at lower temperatures. While this observation may seem intuitive based on thermodynamics, the molecular and genetic basis for this phenomenon is not well understood. Several recent reports have argued that lifespan changes across temperatures are genetically controlled by temperature-specific gene regulation. Here, we provide data that both corroborate those studies and suggest that temperature-specific longevity is more the rule than the exception. By measuring the lifespans of worms with single modifications reported to be important for longevity at 15, 20, or 25°C, we find that the effect of each modification on lifespan is highly dependent on temperature. Our results suggest that genetics play a major role in temperature-associated longevity and are consistent with the hypothesis that while aging in C. elegans is slowed by decreasing temperature, the major cause(s) of death may also be modified, leading to different genes and pathways becoming more or less important at different temperatures. These differential mechanisms of age-related death are not unlike what is observed in humans, where environmental conditions lead to development of different diseases of aging.
We report a systematic RNAi longevity screen of 82 Caenorhabditis elegans genes selected based on... more We report a systematic RNAi longevity screen of 82 Caenorhabditis elegans genes selected based on orthology to human genes differentially expressed with age. We find substantial enrichment in genes for which knockdown increased lifespan. This enrichment is markedly higher than published genomewide longevity screens in C. elegans and similar to screens that preselected candidates based on longevity-correlated metrics (e.g., stress resistance). Of the 50 genes that affected lifespan, 46 were previously unreported. The five genes with the greatest impact on lifespan (>20% extension) encode the enzyme kynureninase (kynu-1), a neuronal leucine-rich repeat protein (iglr-1), a tetraspanin (tsp-3), a regulator of calcineurin (rcan-1), and a voltage-gated calcium channel subunit (unc-36). Knockdown of each gene extended healthspan without impairing reproduction. kynu-1(RNAi) alone delayed pathology in C. elegans models of Alzheimer's disease and Huntington's disease. Each gene dis...
Animals, particularly poikilotherms, exhibit distinct physiologies at different environmental tem... more Animals, particularly poikilotherms, exhibit distinct physiologies at different environmental temperatures. Here, we hypothesized that temperature-based differences in physiology could affect the amount of variation in complex quantitative traits. Specifically, we examined, in Caenorhabditis elegans, how different temperatures (15°C, 20°C, and 25°C) affected the amount of interindividual variation in life span and also expression of three reporter genes-transcriptional reporters for vit-2, gpd-2, and hsp-16.2 (a life-span biomarker). We found the expected inverse relationship between temperature and average life span. Surprisingly, we found that at the highest temperature, there were fewer differences between individuals in life span and less interindividual variation in expression of all three reporters. We suggest that growth at 25°C might canalize (reduce interindividual differences in) life span and expression of some genes by eliciting a small constitutive heat shock response. Growth at 25°C requires wild-type hsf-1, which encodes the main heat shock response transcriptional activator. We speculate that increased chaperone activity at 25°C may reduce interindividual variation in gene expression by increasing protein folding efficiency. We hypothesize that reduced variation in gene expression may ultimately cause reduced variation in life span.
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Papers by George Sutphin