George L Sutphin

Interests

Research

I am interested in understanding the molecular basis of aging. Individual age is the primary risk factor for the majority of the top causes of death in the United States and other developed nations. As our population grows older, aging is increasingly a central problem for both individual quality of life and the economics of societal health. Understanding the molecular architecture that drives aging will reveal key intervention points to extend healthy human lifespan, simultaneously delay onset of multiple categories of age-associated disease, and develop targeted treatments for specific pathologies. I use a combination of systems biology, comparative genetics, and molecular physiology to understand the molecular processes that underlie aging and drive age-associated disease.

Courses

Scholarly Contributions

Journals/Publications

• Sutphin, G. L. (2017). Caenorhabditis elegans orthologs of human genes differentially expressed with age are enriched for determinants of longevity. Aging Cell.
• Sutphin, G. L. (2017). Environmental Canalization of Life Span and Gene Expression in Caenorhabditis elegans. The Journals of Gerontology: Series A.
• Sutphin, G. L. (2017). Genetic interaction with temperature is an important determinant of nematode longevity. Aging Cell.
• Sutphin, G. L. (2016). Age-associated vulval integrity is an important marker of nematode healthspan. AGE.
• Sutphin, G. L. (2016). WORMHOLE: Novel Least Diverged Ortholog Prediction through Machine Learning. PLOS Computational Biology.
• Sutphin, G. L. (2015). A Comprehensive Analysis of Replicative Lifespan in 4,698 Single-Gene Deletion Strains Uncovers Conserved Mechanisms of Aging.. Cell metabolism.
• Sutphin, G. L. (2015). Corrigendum: Transcription errors induce proteotoxic stress and shorten cellular lifespan. Nature Communications.
• Sutphin, G. L. (2015). Sorbitol treatment extends lifespan and induces the osmotic stress response in Caenorhabditis elegans. Frontiers in Genetics.
• Sutphin, G. L. (2015). Transcription errors induce proteotoxic stress and shorten cellular lifespan. Nature Communications.
• Sutphin, G. L. (2014). Inactivation of Yeast Isw2 Chromatin Remodeling Enzyme Mimics Longevity Effect of Calorie Restriction via Induction of Genotoxic Stress Response. Cell Metabolism.
• Sutphin, G. L. (2013). Dietary restriction and mitochondrial function link replicative and chronological aging in Saccharomyces cerevisiae.. Experimental gerontology.
• Sutphin, G. L. (2013). End-of-life cell cycle arrest contributes to stochasticity of yeast replicative aging.. FEMS yeast research.
• Sutphin, G. L. (2013). Molecular mechanisms underlying genotype-dependent responses to dietary restriction.. Aging cell.
• Sutphin, G. L. (2013). Stress profiling of longevity mutants identifies Afg3 as a mitochondrial determinant of cytoplasmic mRNA translation and aging.. Aging cell.
• Sutphin, G. L. (2012). Caffeine extends life span, improves healthspan, and delays age-associated pathology in Caenorhabditis elegans. Longevity & Healthspan.
• Sutphin, G. L. (2012). pH neutralization protects against reduction in replicative lifespan following chronological aging in yeast.. Cell cycle (Georgetown, Tex.).
• Sutphin, G. L. (2011). Absence of effects of Sir2 overexpression on lifespan in C. elegans and Drosophila.. Nature.
• Sutphin, G. L. (2011). Elevated proteasome capacity extends replicative lifespan in Saccharomyces cerevisiae.. PLoS Genetics.
• Sutphin, G. L. (2011). Sir2 deletion prevents lifespan extension in 32 long-lived mutants.. Aging cell.
• Sutphin, G. L. (2009). Measuring Caenorhabditis elegans Life Span on Solid Media. Journal of Visualized Experiments.
• Sutphin, G. L. (2009). Proteasomal regulation of the hypoxic response modulates aging in C. elegans.. Science (New York, N.Y.).
• Sutphin, G. L. (2008). Dietary restriction by bacterial deprivation increases life span in wild-derived nematodes. Experimental Gerontology.
• Sutphin, G. L. (2008). Dietary restriction suppresses proteotoxicity and enhances longevity by an hsf-1-dependent mechanism in Caenorhabditis elegans. Aging Cell.

Proceedings Publications

• Sutphin, G. L. (2004, July). Investigation of Enhanced Vortex Tube Air Separators for Advanced Space Transportation. In 40th AIAA/ASME/SAE/ASEE Joint Propulsion Conference and Exhibit.

Presentations

• Sutphin, G. L. (2018, 2018-04-18). 3-Hydroxyanthranilic Acid—A Novel Molecular Target to Extend Lifespan and Treat Neurodegeneration in the Kynurenine Pathway. Invited Seminar, University of Pennsylvania. Philadelphia, PA: Departments of Bioengineering and Neuroscience.
  More info

  Identifying novel genetic factors that can be targeted to beneficially influence longevity, healthspan, and age-associated disease is an ongoing area of focus in aging science. In a recent study, we selected 82 Caenorhabditis elegans genes based on orthology to 125 human genes differentially expressed with age and conducted an RNAi lifespan screen. The clear outlier was kynu-1, encoding the kynurenine pathway enzyme kynureninase. RNAi knockdown of kynu-1 extended lifespan by >20%. Kynurenine pathway gene expression and metabolite abundance is perturbed in individuals with a number of age-associated diseases, including neurodegenerative disease. Many intermediate kynurenine pathway metabolites have neuroactive or antioxidant properties, and pharmacological interventions targeting kynurenine pathway enzymes are being pursued for Alzheimer’s and Huntington’s disease. In an expanded survey of the kynurenine pathway, we identified two additional genes for which knockdown results in a similar degree of lifespan extension to kynu-1(RNAi)—haao-1 and tdo-2. Knockdown of kynu-1, haao-1, or tdo-2 extended healthspan and delayed pathology in C. elegans models of Alzheimer’s and Huntington’s disease. Knockdown of haao-1 alone achieved these benefits without impairing reproduction or development. haao-1 encodes the enzyme 3-hydroxyanthraniate 3,4-dioxygenase, which converts the metabolite 3-hydroxyanthranilic acid (3HAA) into 2-amino-3-carboxymuconate semialdehyde. Worms lacking haao-1 have highly elevated 3HAA, which is thought to have both direct and indirect antioxidant properties. In ongoing work, we find that treatment of worms with 3HAA phenocopies reduced haao-1 in the context of aging and neurodegenerative pathology in C. elegans, suggesting that it may represent a potent metabolic target for treating age-associated cognitive disease.
• Sutphin, G. L. (2018, November). Systemic elevation of 3-hydroxyanthranilic acid (3HAA) to extend lifespan and delay Alzheimer’s pathology. Gerontological Society of America 2018 Annual Scientific Meeting. Boston, MA: Gerontological Society of America.
  More info

  Dysregulation of the kynurenine pathway, the major route for tryptophan metabolism, is linked to a wide range of age-associated pathologies in humans. Interventions targeting different aspects of kynurenine metabolism are being pursued for several diseases of aging, including Alzheimer’s disease. We have identified the metabolite 3-hydroxyanthranilic acid (3HAA) as a particularly promising molecular target. In Caenorhabditis elegans, elevating 3HAA through either direct supplementation or inhibition of 3HAA dioxygenase (HAAO), the primary enzyme that degrades 3HAA, robustly increases lifespan and improves health with age. In mice, short-term treatment with 3HAA is protective in acute models of atherosclerosis, spinal cord injury, and autoimmune encephalomyelitis. Preliminary evidence suggests that the beneficial effects of 3HAA are mediated by reduced oxidative stress and improved protein homeostasis with age. We are now testing the hypothesis that chronic 3HAA elevation in mice will extend lifespan and delay functional decline with age. We are further assessing 3HAA via HAAO inhibition as a therapeutic strategy for Alzheimer’s disease. 3HAA is predicted to directly bind amyloid-beta (Aβ) and prevents aggregation in vitro. 3HAA supplementation or HAAO inhibition delays paralysis in a C. elegans Alzheimer’s disease model expressing amyloid-beta in body-wall muscle. Elevating 3HAA by inhibition HAAO has the further benefit of limiting production of the downstream metabolite quinolinic acid (QA). QA is a proposed mediator of tau hyperphosphorylation in response to neuroinflammation, an early step in the formation of neurofibrillary tangles (NFTs). HAAO inhibition can potentially limit formation of both Aβ plaques and NFTs, two hallmark pathologies in Alzheimer’s disease.Funding: This work is supported by the State of Arizona Technology and Research Initiative Fund (TRIF).
• Sutphin, G. L. (2017, 2017-06-09). The JAX Aging Center Translational Core: Combining Systems and Comparative Genetics to Identify Novel Molecular Targets for Longevity and Age-Associated Disease. 46th Annual Meeting of the American Aging Association. Brooklyn, NY: American Aging Association (AGE).
  More info

  Identifying novel genetic factors that can be targeted to beneficially influence longevity, healthspan, and age-associated disease is an ongoing area of focus in aging science. In a recent study, we selected 82 Caenorhabditis elegans genes based on orthology to 125 human genes differentially expressed with age and conducted an RNAi lifespan screen. The clear outlier was kynu-1, encoding the kynurenine pathway enzyme kynureninase. RNAi knockdown of kynu-1 extended lifespan by >20%. Kynurenine pathway gene expression and metabolite abundance is perturbed in individuals with a number of age-associated diseases, including neurodegenerative disease. Many intermediate kynurenine pathway metabolites have neuroactive or antioxidant properties, and pharmacological interventions targeting kynurenine pathway enzymes are being pursued for Alzheimer’s and Huntington’s disease. In an expanded survey of the kynurenine pathway, we identified two additional genes for which knockdown results in a similar degree of lifespan extension to kynu-1(RNAi)—haao-1 and tdo-2. Knockdown of kynu-1, haao-1, or tdo-2 extended healthspan and delayed pathology in C. elegans models of Alzheimer’s and Huntington’s disease. Knockdown of haao-1 alone achieved these benefits without impairing reproduction or development. haao-1 encodes the enzyme 3-hydroxyanthraniate 3,4-dioxygenase, which converts the metabolite 3-hydroxyanthranilic acid (3HAA) into 2-amino-3-carboxymuconate semialdehyde. Worms lacking haao-1 have highly elevated 3HAA, which is thought to have both direct and indirect antioxidant properties. In ongoing work, we find that treatment of worms with 3HAA phenocopies reduced haao-1 in the context of aging and neurodegenerative pathology in C. elegans, suggesting that it may represent a potent metabolic target for treating age-associated cognitive disease.
• Sutphin, G. L. (2016, 2016-11-17). Kynurenine Pathway Genes Influence Aging through Multiple Distinct Molecular Mechanisms. 2016 Gerontological Society of America Annual Scientific Meeting.
  More info

  Identifying and characterizing novel genetic factors that can be targeted to beneficially influence longevity, healthspan, and age-associated disease is an ongoing area of focus in aging science. In this study, we selected 82 Caenorhabditis elegans genes based on orthology to 125 human genes differentially expressed with age in whole blood from a recent study by the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium and screened for lifespan phenotypes. This set was enriched in genes for which RNAi knockdown increased lifespan, compared to a randomly selected set of 60 genes. Of the 50 genes found to influence C. elegans lifespan, 46 were previously unreported. The clear positive outlier in our screen was flu-2, encoding the kynurenine pathway enzyme kynureninase. RNAi knockdown of flu-2 extended lifespan by >20%. In detailed follow up, we observed a similar degree of lifespan extension in response to knockdown of either of two additional kynurenine pathway genes—haao-1, encoding 3-hydroxyanthraniate 3,4-dioxygenase, or tdo-2, encoding tryptophan 2,3-dyoxygenase. Knockdown of flu-2, haao-1, or tdo-2 extended healthspan and delayed pathology in C. elegans models of Alzheimer’s and Huntington’s disease. In contrast, knockdown of tdo-2 alone resulted in a substantial reduction in body size and reproduction. Each examined kynurenine pathway gene displayed a distinct and temperature-dependent pattern of epistatic interaction with known aging pathways, including insulin/IGF signaling, dietary restriction, mTOR signaling, and sirtuins. The observed phenotypic pattern suggests that the kynurenine pathway influences aging through multiple molecular mechanisms that are closely linked to environmental context, and that specific phenotypes and molecular pathways can be differentially affected by targeting different kynurenine pathway enzymes.

Poster Presentations

• Sutphin, G. L. (2018, 2018-06-30). 3-Hydroxyanthranilic Acid—A Novel Molecular Target for Lifespan Extension in the Kynurenine Pathway. 47th Annual Meeting of the American Aging Association. Philadelphia, PA: American Aging Association (AGE).
  More info

  Identifying novel genetic factors that can be targeted to beneficially influence longevity, healthspan, and age-associated disease is an ongoing area of focus in aging science. In a recent study, we selected 82 Caenorhabditis elegans genes based on orthology to 125 human genes differentially expressed with age and conducted an RNAi lifespan screen. The clear outlier was kynu-1, encoding the kynurenine pathway enzyme kynureninase. RNAi knockdown of kynu-1 extended lifespan by >20%. Kynurenine pathway gene expression and metabolite abundance is perturbed in individuals with a number of age-associated diseases, including neurodegenerative disease. Many intermediate kynurenine pathway metabolites have neuroactive or antioxidant properties, and pharmacological interventions targeting kynurenine pathway enzymes are being pursued for Alzheimer’s and Huntington’s disease. In an expanded survey of the kynurenine pathway, we identified two additional genes for which knockdown results in a similar degree of lifespan extension to kynu-1(RNAi)—haao-1 and tdo-2. Knockdown of kynu-1, haao-1, or tdo-2 extended healthspan and delayed pathology in C. elegans models of Alzheimer’s and Huntington’s disease. Knockdown of haao-1 alone achieved these benefits without impairing reproduction or development. haao-1 encodes the enzyme 3-hydroxyanthraniate 3,4-dioxygenase, which converts the metabolite 3-hydroxyanthranilic acid (3HAA) into 2-amino-3-carboxymuconate semialdehyde. Worms lacking haao-1 have highly elevated 3HAA, which is thought to have both direct and indirect antioxidant properties. In ongoing work, we find that treatment of worms with 3HAA phenocopies reduced haao-1 in the context of aging and neurodegenerative pathology in C. elegans, suggesting that it may represent a potent metabolic target for treating age-associated cognitive disease.
• Sutphin, G. L. (2017, June). 3-Hydroxyanthranilic Acid—A Novel Molecular Target for Lifespan Extension in the Kynurenine Pathway. Innovation in Aging.

Others

• Sutphin, G. L. (2016). Longevity as a Complex Genetic Trait. Handbook of the Biology of Aging.
• Sutphin, G. L. (2014). Replicative Life Span Analysis in Budding Yeast. Yeast Genetics.
• Sutphin, G. L. (2011). Comparative Genetics of Aging. Handbook of the Biology of Aging.
• Sutphin, G. L. (2011). Genome-Wide Analysis of Yeast Aging. Aging Research in Yeast.
• Sutphin, G. L. (2009). Aging: Evolutionary Theory Meets Genomic Approaches. Evolutionary Biology.