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. A major current focus of my work is on understanding the role of tryptophan metabolism through the kynurenine pathway in the aging process, particularly the interaction with stress resistance, inflammation, and NAD metabolism. A second focus of the lab is understanding molecular mechanisms governing cellular and organismal response to multiple, simultaneous external stressors.

Teaching

I am interested in teaching theoretical and practical concepts related to the biology of aging and age-associated disease, including evolution of aging, molecular and cellular mechanisms of aging, systems and comparative biology of aging, aging genetics, and biostatistics related to survival analysis. Beyond aging, there is a growing need for foundational instruction in both both computational biology and biostastistics at both the undergraduate and graduate level. I am interested in promoting required course work, either as stand-alone courses or as material integrated into established course offerings, in both subject areas.

Courses

Scholarly Contributions

Chapters

• Sutphin, G. L., & Korstanje, R. (2021). Longevity as a Complex Genetic Trait. In Handbook of the Biology of Aging 9th Edition(pp 3-42). Academic Press.
• Sutphin, G. L., & Korstanje, R. (2016). Longevity as a Complex Genetic Trait. In Handbook of the Biology of Aging 8th Edition(pp 3-54). Academic Press.
• Sutphin, G. L., Delaney, J. R., & Kaeberlein, M. (2014). Replicative Life Span Analysis in Budding Yeast. In Yeast Genetics(pp 341-357). Springer. doi:10.1007/978-1-4939-1363-3
• Sutphin, G. L., Olsen, B. A., Kennedy, B. K., & Kaeberlein, M. (2012). Genome-Wide Analysis of Yeast Aging. In Aging Research in Yeast(pp 251-289). Springer.
• Sutphin, G. L., & Kaeberlein, M. (2011). Comparative Genetics of Aging. In Handbook of the Biology of Aging(pp 215-242). Academic Press.
• Sutphin, G. L., & Kennedy, B. K. (2009). Aging: Evolutionary Theory Meets Genomic Approaches. In Evolutionary Biology: Concept, Modeling, and Application(pp 339-360). Springer.

Journals/Publications

• Bubier, J. A., Sutphin, G. L., Reynolds, T. J., Korstanje, R., Fuksman-Kumpa, A., Baker, E. J., Langston, M. A., & Chesler, E. J. (2019). Integration of heterogeneous functional genomics data in gerontology research identifies genes and pathway underlying aging across species. PLoS One.
• 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. (2020, January). A comparative systems genetics pipeline to identify new anti-aging targets: Our path to kynurenine metabolism. MD/PhD Colloquium Faculty Data Blitz. Tucson, AZ: MD/PhD Program, University of Arizona.
• Sutphin, G. L. (2020, March). Targeting kynurenine metabolism in aging and age-associated disease. Animal and Comparative Biomedical Sciences (ACBS) Seminar Series. Tucson, AZ: Animal and Comparative Biomedical Sciences (ACBS), University of Arizona.
• Sutphin, G. L. (2019, April). Targeting kynurenine metabolism in aging and age-associated. Biological and Biomedical Joint Seminar Series. Tucson, AZ: Department of Molecular & Cellular Biology, University of Arizona.
• Sutphin, G. L. (2019, December). Elevating systemic 3-hydroxyanthranilic acid toimprove sepsis recovery in aged mice. Resilience and Independence in Aging Seminar Series. Tucson, AZ: Consortium to Hasten recovery from Injury and Infection in older adults Leading to Independence (CHiiLi) Project, University of Arizona.
• Sutphin, G. L. (2019, July). Targeting kynurenine metabolism in aging. Undergraduate Biology Research Program (UBRP) Summer Seminar. Tucson, AZ: Undergraduate Biology Research Program (UBRP), University of Arizona.
• Sutphin, G. L. (2019, November). Expanding the GeroScience Network: Report from the Biological Sciences Presidential Symposium. 2019 Gerontological Society of America Annual Scientific Meeting. Austin, TX: Gerontological Society of America (GSA).
• Sutphin, G. L. (2019, November). Targeting Kynurenine Metabolism in Age-Associated Disease. 2019 Gerontological Society of America Annual Scientific Meeting. Austin, TX: Gerontological Society of America (GSA).
• Sutphin, G. L. (2019, October). Targeting kynurenine metabolism in aging and age-associated disease. Invited Seminar, Medical University of South Carolina. Charleston, SC: Medical University of South Carolina.
• 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. (2019, February). Identification of 3-hydroxyanthranilic acid as a novel pro-longevity metabolite. Conversations with Faculty. Tucson, AZ: Undergraduate Biology Research Program (UBRP), University of Arizona.
• 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. (2019, July). Targeting tryptophan-kynurenine metabolism to extend healthy lifespan. 2019 Biology of Aging Conference. Newry, ME: Gordon Research Conferences (GRC).
• Sutphin, G. L. (2019, June). Targeting tryptophan-kynurenine metabolism to extend lifespan and treat age-associated disease. 48th Annual Meeting of the American Aging Association. San Francisco, CA: American Aging Association (AGE).
  More info

  The kynurenine pathway, the major route for tryptophan catabolism, becomes dysregulated with age and during many age-associated diseases 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 C. elegans 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 lifespan by slowing age-associated accumulation of oxidative damage and repressing chronic inflammation.
• 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.

Reviews

• Castro-Portuguez, R., & Sutphin, G. L. (2020. Kynurenine Pathway, NAD + Synthesis, and Mitochondrial Function: Targeting Tryptophan Metabolism to Promote Longevity and Healthspan(p. 14).
  More info

  Aging is characterized by a progressive decline in the normal physiological functions of an organism, ultimately leading to mortality. Nicotinamide adenine dinucleotide (NAD+) is an essential cofactor that plays a critical role in mitochondrial energy production as well as many enzymatic redox reactions. Age-associated decline in NAD+ is implicated as a driving factor in several categories of age-associated disease, including metabolic and neurodegenerative disease, as well as deficiency in the mechanisms of cellular defense against oxidative stress. The kynurenine metabolic pathway is the sole de novo NAD+ biosynthetic pathway, generating NAD+ from ingested tryptophan. Altered kynurenine pathway activity is associated with both aging and a variety of age-associated diseases. Kynurenine pathway interventions can extend lifespan in both fruit flies and nematodes, and altered NAD+ metabolism represents one potential mediating mechanism. Recent studies demonstrate that supplementation with NAD+ or NAD+-precursors increase longevity and promote healthy aging in fruit flies, nematodes, and mice. NAD+ levels and the intrinsic relationship to mitochondrial function have been widely studied in the context of aging. Mitochondrial function and dynamics have both been implicated in longevity determination in a range of organisms from yeast to humans, at least in part due to their intimate link to regulating an organism's cellular energy economy and capacity to resist oxidative stress. Recent findings support the idea that complex communication between the mitochondria and the nucleus orchestrates a series of events and stress responses involving mitophagy, mitochondrial number, mitochondrial unfolded protein response (UPRmt), and mitochondria fission and fusion events. In this review, we discuss how mitochondrial morphological changes and dynamics operate during aging, and how altered metabolism of tryptophan to NAD+ through the kynurenine pathway interacts with these processes.