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 worldwide. 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 stressors. Development of novel methods in robotics, imaging, image analysis, and machine learning have become an integral part of my approach to solving new problems in aging biology.

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 (Ninth Edition)(pp 3-42). Academic Press. doi:10.1016/b978-0-12-815962-0.00001-9
• Sutphin, G. L., & Korstanje, R. (2016). Longevity as a Complex Genetic Trait. In Handbook of the Biology of Aging (Eighth Edition)(pp 3-54). Academic Press. doi:10.1016/b978-0-12-411596-5.00001-0
• 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 (Seventh Edition)(pp 215-241). Academic Press. doi:10.1016/b978-0-12-378638-8.00010-5
• 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

• Espejo, L., Hull, B., Chang, L. M., DeNicola, D., Freitas, S., Silbar, V., Haskins, A., Turner, E. A., & Sutphin, G. L. (2022). Long-Term Culture of Individual Caenorhabditis elegans on Solid Media for Longitudinal Fluorescence Monitoring and Aversive Interventions. Journal of visualized experiments : JoVE.
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  Caenorhabditis elegans are widely used to study aging biology. The standard practice in C. elegans aging studies is to culture groups of worms on solid nematode growth media (NGM), allowing the efficient collection of population-level data for survival and other physiological phenotypes, and periodic sampling of subpopulations for fluorescent biomarker quantification. Limitations to this approach are the inability to (1) follow individual worms over time to develop age trajectories for phenotypes of interest and (2) monitor fluorescent biomarkers directly in the context of the culture environment. Alternative culture approaches use liquid culture or microfluidics to monitor individual animals over time, in some cases including fluorescence quantification, with the tradeoff that the culture environment is contextually distinct from solid NGM. The WorMotel is a previously described microfabricated multi-well device for culturing isolated worms on solid NGM. Each worm is maintained in a well containing solid NGM surrounded by a moat filled with copper sulfate, a contact repellent for C. elegans, allowing longitudinal monitoring of individual animals. We find copper sulfate insufficient to prevent worms from fleeing when subjected to aversive interventions common in aging research, including dietary restriction, pathogenic bacteria, and chemical agents that induce cellular stress. The multi-well devices are also molded from polydimethylsiloxane, which produces high background artifacts in fluorescence imaging. This protocol describes a new approach for culturing isolated roundworms on solid NGM using commercially available polystyrene microtrays, originally designed for human leukocyte antigen (HLA) typing, allowing the measurement of survival, physiological phenotypes, and fluorescence across the lifespan. A palmitic acid barrier prevents worms from fleeing, even in the presence of aversive conditions. Each plate can culture up to 96 animals and easily adapts to a variety of conditions, including dietary restriction, RNAi, and chemical additives, and is compatible with automated systems for collecting lifespan and activity data.
• Gardea, E. A., DeNicola, D., Freitas, S., Peterson, W., Dang, H., Shuck, K., Fang-Yen, C., & Sutphin, G. L. (2022). Long-Term Culture and Monitoring of Isolated Caenorhabditis elegans on Solid Media in Multi-Well Devices. Journal of visualized experiments : JoVE.
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  The nematode Caenorhabditis elegans is among the most common model systems used in aging research owing to its simple and inexpensive culture techniques, rapid reproduction cycle (~3 days), short lifespan (~3 weeks), and numerous available tools for genetic manipulation and molecular analysis. The most common approach for conducting aging studies in C. elegans, including survival analysis, involves culturing populations of tens to hundreds of animals together on solid nematode growth media (NGM) in Petri plates. While this approach gathers data on a population of animals, most protocols do not track individual animals over time. Presented here is an optimized protocol for the long-term culturing of individual animals on microfabricated polydimethylsiloxane (PDMS) devices called WorMotels. Each device allows up to 240 animals to be cultured in small wells containing NGM, with each well isolated by a copper sulfate-containing moat that prevents the animals from fleeing. Building on the original WorMotel description, this paper provides a detailed protocol for molding, preparing, and populating each device, with descriptions of common technical complications and advice for troubleshooting. Within this protocol are techniques for the consistent loading of small-volume NGM, the consistent drying of both the NGM and bacterial food, options for delivering pharmacological interventions, instructions for and practical limitations to reusing PDMS devices, and tips for minimizing desiccation, even in low-humidity environments. This technique allows the longitudinal monitoring of various physiological parameters, including stimulated activity, unstimulated activity, body size, movement geometry, healthspan, and survival, in an environment similar to the standard technique for group culture on solid media in Petri plates. This method is compatible with high-throughput data collection when used in conjunction with automated microscopy and analysis software. Finally, the limitations of this technique are discussed, as well as a comparison of this approach to a recently developed method that uses microtrays to culture isolated nematodes on solid media.
• Castro-Portuguez, R., & Sutphin, G. L. (2020). Kynurenine pathway, NAD synthesis, and mitochondrial function: Targeting tryptophan metabolism to promote longevity and healthspan. Experimental gerontology, 132, 110841.
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  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 (UPR), 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.
• 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. (2019). A new defense in the battle of the sexes. eLife, 8.
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  Young hermaphrodites use their own sperm to protect against the negative consequences of mating.
• Sutphin, G. L. (2019). Decision letter: Insulin-like peptides and the mTOR-TFEB pathway protect Caenorhabditis elegans hermaphrodites from mating-induced death. eLife. doi:10.7554/elife.46413.030
• Sutphin, G. L., & Kaeberlein, M. (2019). Decision letter: Self-sperm induce resistance to the detrimental effects of sexual encounters with males in hermaphroditic nematodes. eLife. doi:10.7554/elife.46418.028
• Sutphin, G. L., Petrascheck, M., Petrascheck, M., Sutphin, G. L., Petrascheck, M., & Kaeberlein, M. (2019). Decision letter: Metabolic stress is a primary pathogenic event in transgenic Caenorhabditis elegans expressing pan-neuronal human amyloid beta. eLife. doi:10.7554/elife.50069.032
• Sutphin, G. L. (2017). Genetic interaction with temperature is an important determinant of nematode longevity. Aging Cell.
• Sutphin, G. L., Brent, R., Johnson, T. E., Kaeberlein, M., Tedesco, P. M., Leiser, S. F., Crane, M. M., & Mendenhall, A. (2017). Environmental Canalization of Life Span and Gene Expression in Caenorhabditis elegans. The Journals of Gerontology. doi:10.1093/gerona/glx017
• Sutphin, G. L., Korstanje, R., Johnson, A. D., Murabito, J. M., Meurs, J. B., Peters, M., Liu, T. T., Corban, C., Bean, S., Sheehan, S., & Backer, G. (2017). Caenorhabditis elegans orthologs of human genes differentially expressed with age are enriched for determinants of longevity. Aging Cell. doi:10.1111/acel.12595
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  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 displayed a distinct pattern of interaction with known aging pathways. In the context of published work, kynu-1, tsp-3, and rcan-1 are of particular interest for immediate follow-up. kynu-1 is an understudied member of the kynurenine metabolic pathway with a mechanistically distinct impact on lifespan. Our data suggest that tsp-3 is a novel modulator of hypoxic signaling and rcan-1 is a context-specific calcineurin regulator. Our results validate C. elegans as a comparative tool for prioritizing human candidate aging genes, confirm age-associated gene expression data as valuable source of novel longevity determinants, and prioritize select genes for mechanistic follow-up.
• Sutphin, G. L., Kaeberlein, M., Fletcher, M., Leonard, A., Dong, J., Primitivo, M., Jafari, G., & Leiser, S. F. (2016). Age-associated vulval integrity is an important marker of nematode healthspan. Age. doi:10.1007/s11357-016-9936-8
• Sutphin, G. L., Korstanje, R., Walton, D. O., Sheppard, K. S., & Mahoney, J. M. (2016). WORMHOLE: Novel Least Diverged Ortholog Prediction through Machine Learning. PLOS Computational Biology. doi:10.1371/journal.pcbi.1005182
• Sutphin, G. L. (2015). Corrigendum: Transcription errors induce proteotoxic stress and shorten cellular lifespan. Nature Communications.
• Sutphin, G. L., Blangero, J., Turner, S. T., Montgomery, G. W., Tracy, R. P., Psaty, B. M., Oyston, L. J., Neely, G. G., Bakhshi, N., Raj, T., Bean, S., Hollander, W. d., Helmer, Q., Slagboom, P. E., Kloppenburg, M., Houwing-Duistermaat, J. J., Chen, Y. I., Rotter, J. I., Brody, J. A., , Enquobahrie, D. A., et al. (2015). The transcriptional landscape of age in human peripheral blood. Nature Communications. doi:10.1038/ncomms9570
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  Disease incidences increase with age, but the molecular characteristics of ageing that lead to increased disease susceptibility remain inadequately understood. Here we perform a whole-blood gene expression meta-analysis in 14,983 individuals of European ancestry (including replication) and identify 1,497 genes that are differentially expressed with chronological age. The age-associated genes do not harbor more age-associated CpG-methylation sites than other genes, but are instead enriched for the presence of potentially functional CpG-methylation sites in enhancer and insulator regions that associate with both chronological age and gene expression levels. We further used the gene expression profiles to calculate the 'transcriptomic age' of an individual, and show that differences between transcriptomic age and chronological age are associated with biological features linked to ageing, such as blood pressure, cholesterol levels, fasting glucose, and body mass index. The transcriptomic prediction model adds biological relevance and complements existing epigenetic prediction models, and can be used by others to calculate transcriptomic age in external cohorts.
• Sutphin, G. L., Kaeberlein, M., Smith, E. D., Shamieh, L. S., Le, A., Chen, S., Ocampo, B. R., Park, S., Choi, H., & Chandler-Brown, D. (2015). Sorbitol treatment extends lifespan and induces the osmotic stress response in Caenorhabditis elegans. Frontiers in Genetics. doi:10.3389/fgene.2015.00316
• Sutphin, G. L., Kennedy, B. K., Kaeberlein, M., Zhou, Z., Suh, Y., Liu, X., Brem, R. B., Westman, E. A., Welton, K. L., Wang, D., Wende, H. V., Ting, M. K., Tchao, B. N., Steffen, K. K., Spector, B. L., Solanky, A., Snead, K., Smith, E. D., Singh, M. K., , Sage, M., et al. (2015). A Comprehensive Analysis of Replicative Lifespan in 4,698 Single-Gene Deletion Strains Uncovers Conserved Mechanisms of Aging. Cell Metabolism. doi:10.1016/j.cmet.2015.09.008
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  Many genes that affect replicative lifespan (RLS) in the budding yeast Saccharomyces cerevisiae also affect aging in other organisms such as C. elegans and M. musculus. We performed a systematic analysis of yeast RLS in a set of 4,698 viable single-gene deletion strains. Multiple functional gene clusters were identified, and full genome-to-genome comparison demonstrated a significant conservation in longevity pathways between yeast and C. elegans. Among the mechanisms of aging identified, deletion of tRNA exporter LOS1 robustly extended lifespan. Dietary restriction (DR) and inhibition of mechanistic Target of Rapamycin (mTOR) exclude Los1 from the nucleus in a Rad53-dependent manner. Moreover, lifespan extension from deletion of LOS1 is nonadditive with DR or mTOR inhibition, and results in Gcn4 transcription factor activation. Thus, the DNA damage response and mTOR converge on Los1-mediated nuclear tRNA export to regulate Gcn4 activity and aging.
• 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., Sutphin, G. L., Delaney, J. R., Delaney, J. R., & Kaeberlein, M. (2014). Replicative life span analysis in budding yeast.. Methods in molecular biology (Clifton, N.J.), 1205, 341-57. doi:10.1007/978-1-4939-1363-3_20
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  Identifying and characterizing the factors that modulate longevity is central to understanding the basic mechanisms of aging. Among model organisms used for research related to aging, the budding yeast has proven to be an important system for defining pathways that influence life span. Replicative life span is defined by the number of daughter cells a mother cell can produce before senescing. Over the past 10 years, we have performed replicative life span analysis on several thousand yeast strains, identifying several hundred genes that influence replicative longevity. In this chapter we describe our method for determining replicative life span. Individual cells are grown on solid media and monitored from their initial undivided state until they undergo senescence. Daughter cells are manually removed using a fiber optic needle and quantified to determine the total number of times each mother cell divides.
• Sutphin, G. L. (2013). End-of-life cell cycle arrest contributes to stochasticity of yeast replicative aging.. FEMS yeast research.
• Sutphin, G. L., Kaeberlein, M., Kennedy, B. K., Han, J. J., MacCoss, M. J., Rabinovitch, P. S., Jelic, M., Fletcher, M., An, E. H., Wende, H. V., Spector, B., Singh, M., Ros, V., Rai, D., Pruett, D., Pradeep, P., Pollard, T., Peng, Z., Olsen, B., , Miller, H., et al. (2013). Molecular mechanisms underlying genotype-dependent responses to dietary restriction. Aging Cell. doi:10.1111/acel.12130
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  Dietary restriction (DR) increases lifespan and attenuates age-related phenotypes in many organisms; however, the effect of DR on longevity of individuals in genetically heterogeneous populations is not well characterized. Here, we describe a large-scale effort to define molecular mechanisms that underlie genotype-specific responses to DR. The effect of DR on lifespan was determined for 166 single gene deletion strains in Saccharomyces cerevisiae. Resulting changes in mean lifespan ranged from a reduction of 79% to an increase of 103%. Vacuolar pH homeostasis, superoxide dismutase activity, and mitochondrial proteostasis were found to be strong determinants of the response to DR. Proteomic analysis of cells deficient in prohibitins revealed induction of a mitochondrial unfolded protein response (mtUPR), which has not previously been described in yeast. Mitochondrial proteotoxic stress in prohibitin mutants was suppressed by DR via reduced cytoplasmic mRNA translation. A similar relationship between prohibitins, the mtUPR, and longevity was also observed in Caenorhabditis elegans. These observations define conserved molecular processes that underlie genotype-dependent effects of DR that may be important modulators of DR in higher organisms.
• Sutphin, G. L., Kaeberlein, M., Kennedy, B. K., Wende, H. V., Singh, M., Ros, V., Rai, D., Peng, Z., Muller, B., Klum, S., Jelic, M., Higgins, S., Fletcher, M., Castanza, A. S., An, E. H., Schleit, J., Murakami, C. J., Carr, D. B., Sim, S., , Chou, A. Y., et al. (2013). Stress profiling of longevity mutants identifies Afg3 as a mitochondrial determinant of cytoplasmic mRNA translation and aging. Aging Cell. doi:10.1111/acel.12032
• Sutphin, G. L., Kaeberlein, M., Olsen, B., Wasko, B. M., Wang, A. M., Wende, H. V., Spector, B., Singh, M., Schuster, A., Ros, V., Rai, D., Pruett, D., Pradeep, P., Pollard, T., Peng, Z., Moller, R. M., Miller, H., Lo, W., Lin, M. Z., , Liao, E. C., et al. (2013). Dietary restriction and mitochondrial function link replicative and chronological aging in Saccharomyces cerevisiae. Experimental Gerontology. doi:10.1016/j.exger.2012.12.001
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  Chronological aging of budding yeast cells results in a reduction in subsequent replicative life span through unknown mechanisms. Here we show that dietary restriction during chronological aging delays the reduction in subsequent replicative life span up to at least 23days of chronological age. We further show that among the viable portion of the control population aged 26days, individual cells with the lowest mitochondrial membrane potential have the longest subsequent replicative lifespan. These observations demonstrate that dietary restriction modulates a common molecular mechanism linking chronological and replicative aging in yeast and indicate a critical role for mitochondrial function in this process.
• Sutphin, G. L. (2012). An Exploration of the Genetics and Molecular Mechanisms Underlying Conserved Longevity Interventions. University of Washington Dissertation.
• Sutphin, G. L. (2012). Caffeine extends life span, improves healthspan, and delays age-associated pathology in Caenorhabditis elegans. Longevity & Healthspan.
• Sutphin, G. L., Kaeberlein, M., Olsen, B., Wasko, B. M., Wang, A. M., Wende, H. V., Spector, B. L., Singh, M., Schuster, A., Ros, V., Rai, D., Pruett, D., Pradeep, P., Pollard, T., Peng, Z. J., Moller, R. M., Miller, H., Lo, W., Lin, M. S., , Liao, E. C., et al. (2012). pH neutralization protects against reduction in replicative lifespan following chronological aging in yeast. Cell Cycle. doi:10.4161/cc.21465
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  Chronological and replicative aging have been studied in yeast as alternative paradigms for post-mitotic and mitotic aging, respectively. It has been known for more than a decade that cells of the S288C background aged chronologically in rich medium have reduced replicative lifespan relative to chronologically young cells. Here we report replication of this observation in the diploid BY4743 strain background. We further show that the reduction in replicative lifespan from chronological aging is accelerated when cells are chronologically aged under standard conditions in synthetic complete medium rather than rich medium. The loss of replicative potential with chronological age is attenuated by buffering the pH of the chronological aging medium to 6.0, an intervention that we have previously shown can extend chronological lifespan. These data demonstrate that extracellular acidification of the culture medium can cause intracellular damage in the chronologically aging population that is asymmetrically segregated by the mother cell to limit subsequent replicative lifespan.
• Sutphin, G. L., Olsen, B. A., Kennedy, B. K., & Kaeberlein, M. (2012). Genome-wide analysis of yeast aging.. Sub-cellular biochemistry, 57, 251-89. doi:10.1007/978-94-007-2561-4_12
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  In the past several decades the budding yeast Saccharomyces cerevisiae has emerged as a prominent model for aging research. The creation of a single-gene deletion collection covering the majority of open reading frames in the yeast genome and advances in genomic technologies have opened yeast research to genome-scale screens for a variety of phenotypes. A number of screens have been performed looking for genes that modify secondary age-associated phenotypes such as stress resistance or growth rate. More recently, moderate-throughput methods for measuring replicative life span and high-throughput methods for measuring chronological life span have allowed for the first unbiased screens aimed at directly identifying genes involved in determining yeast longevity. In this chapter we discuss large-scale life span studies performed in yeast and their implications for research related to the basic biology of aging.
• Sutphin, G. L., Gems, D., Partridge, L., Soti, C., Kaeberlein, M., Bedalov, A., Neri, C., Howard, K., Riesen, M., Vinti, G., Au, C., Ackerman, D., Orfila, A., Vázquez-Manrique, R. P., McElwee, J. J., Leko, V., Hoddinott, M. P., Piper, M. D., Somogyvári, M., , Goss, M., et al. (2011). Absence of effects of Sir2 overexpression on lifespan in C. elegans and Drosophila. Nature. doi:10.1038/nature10296
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  Overexpression of sirtuins (NAD(+)-dependent protein deacetylases) has been reported to increase lifespan in budding yeast (Saccharomyces cerevisiae), Caenorhabditis elegans and Drosophila melanogaster. Studies of the effects of genes on ageing are vulnerable to confounding effects of genetic background. Here we re-examined the reported effects of sirtuin overexpression on ageing and found that standardization of genetic background and the use of appropriate controls abolished the apparent effects in both C. elegans and Drosophila. In C. elegans, outcrossing of a line with high-level sir-2.1 overexpression abrogated the longevity increase, but did not abrogate sir-2.1 overexpression. Instead, longevity co-segregated with a second-site mutation affecting sensory neurons. Outcrossing of a line with low-copy-number sir-2.1 overexpression also abrogated longevity. A Drosophila strain with ubiquitous overexpression of dSir2 using the UAS-GAL4 system was long-lived relative to wild-type controls, as previously reported, but was not long-lived relative to the appropriate transgenic controls, and nor was a new line with stronger overexpression of dSir2. These findings underscore the importance of controlling for genetic background and for the mutagenic effects of transgene insertions in studies of genetic effects on lifespan. The life-extending effect of dietary restriction on ageing in Drosophila has also been reported to be dSir2 dependent. We found that dietary restriction increased fly lifespan independently of dSir2. Our findings do not rule out a role for sirtuins in determination of metazoan lifespan, but they do cast doubt on the robustness of the previously reported effects of sirtuins on lifespan in C. elegans and Drosophila.
• Sutphin, G. L., Kaeberlein, M., Kennedy, B. K., Liu, X., Zhou, Z., Suh, Y., Raabe, C., Johnson, S. C., Tsuchiyama, S., Tsuchiya, M., Steffen, K. K., Solanky, A., Sage, M., Pham, K. M., Peng, Z. J., Peng, Q., Pak, D. N., Moller, R. M., Lockshon, D., , Liu, B., et al. (2011). Sir2 deletion prevents lifespan extension in 32 long-lived mutants. Aging Cell. doi:10.1111/j.1474-9726.2011.00742.x
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  Activation of Sir2 orthologs is proposed to increase lifespan downstream of dietary restriction. Here, we describe an examination of the effect of 32 different lifespan-extending mutations and four methods of DR on replicative lifespan (RLS) in the short-lived sir2Δ yeast strain. In every case, deletion of SIR2 prevented RLS extension; however, RLS extension was restored when both SIR2 and FOB1 were deleted in several cases, demonstrating that SIR2 is not directly required for RLS extension. These findings indicate that suppression of the sir2Δ lifespan defect is a rare phenotype among longevity interventions and suggest that sir2Δ cells senesce rapidly by a mechanism distinct from that of wild-type cells. They also demonstrate that failure to observe lifespan extension in a short-lived background, such as cells or animals lacking sirtuins, should be interpreted with caution.
• Sutphin, G. L., Schmidt, M., Kennedy, B. K., Kaeberlein, M., Dittmar, G., Tar, K., Carr, D. B., Schleit, J., Murakami, C. J., Tsuchiyama, S., Tsuchiya, M., Kotireddy, S., Delaney, J. R., Kahlert, G., Dange, T., Robison, B., & Kruegel, U. (2011). Elevated Proteasome Capacity Extends Replicative Lifespan in Saccharomyces cerevisiae. PLOS Genetics. doi:10.1371/journal.pgen.1002253
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  Aging is characterized by the accumulation of damaged cellular macromolecules caused by declining repair and elimination pathways. An integral component employed by cells to counter toxic protein aggregates is the conserved ubiquitin/proteasome system (UPS). Previous studies have described an age-dependent decline of proteasomal function and increased longevity correlates with sustained proteasome capacity in centenarians and in naked mole rats, a long-lived rodent. Proof for a direct impact of enhanced proteasome function on longevity, however, is still lacking. To determine the importance of proteasome function in yeast aging, we established a method to modulate UPS capacity by manipulating levels of the UPS-related transcription factor Rpn4. While cells lacking RPN4 exhibit a decreased non-adaptable proteasome pool, loss of UBR2, an ubiquitin ligase that regulates Rpn4 turnover, results in elevated Rpn4 levels, which upregulates UPS components. Increased UPS capacity significantly enhances replicative lifespan (RLS) and resistance to proteotoxic stress, while reduced UPS capacity has opposing consequences. Despite tight transcriptional co-regulation of the UPS and oxidative detoxification systems, the impact of proteasome capacity on lifespan is independent of the latter, since elimination of Yap1, a key regulator of the oxidative stress response, does not affect lifespan extension of cells with higher proteasome capacity. Moreover, since elevated proteasome capacity results in improved clearance of toxic huntingtin fragments in a yeast model for neurodegenerative diseases, we speculate that the observed lifespan extension originates from prolonged elimination of damaged proteins in old mother cells. Epistasis analyses indicate that proteasome-mediated modulation of lifespan is at least partially distinct from dietary restriction, Tor1, and Sir2. These findings demonstrate that UPS capacity determines yeast RLS by a mechanism that is distinct from known longevity pathways and raise the possibility that interventions to promote enhanced proteasome function will have beneficial effects on longevity and age-related disease in humans.
• Sutphin, G. L. (2009). Measuring Caenorhabditis elegans Life Span on Solid Media. Journal of Visualized Experiments.
• Sutphin, G. L., Kaeberlein, M., Chandler-Brown, D., Davis, C., Huh, A., Shamieh, L. S., Ramos, F. J., Steinkraus, K. A., & Mehta, R. (2009). Proteasomal Regulation of the Hypoxic Response Modulates Aging in C. elegans. Science. doi:10.1126/science.1173507
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  Anti-Aging Several human neurodegenerative diseases, such as Alzheimer's and Huntington's, are caused by aberrant protein aggregation. These disorders typically develop after the fifth decade of life, suggesting a connection with the aging process. In a number of different species, life span can be extended by dietary restriction and reduced insulin and insulin-like growth factor–1 (IGF-1) signaling. These pathways can also decrease toxic protein aggregation, mechanistically linking aging with proteotoxic diseases. While searching for regulators of proteotoxicity in Caenorhabditis elegans , Mehta et al. (p. 1196 , published online 16 April) found that reduction of the von Hippel–Lindau tumor suppressor homolog VHL-1 significantly increased life span and enhanced resistance to proteotoxicity. VHL-1 is an E3 ubiquitin ligase that negatively regulates the hypoxic response, and animals grown under hypoxic conditions lived longer. This alternative longevity pathway was distinct from both dietary restriction and insulin/IGF-1–like signaling.
• Sutphin, G. L. (2008). Dietary restriction by bacterial deprivation increases life span in wild-derived nematodes. Experimental Gerontology.
• Sutphin, G. L., Kaeberlein, M., Kennedy, B. K., Pendergrass, W. R., Carr, D. B., Davis, C., Smith, E. D., & Steinkraus, K. A. (2008). Dietary restriction suppresses proteotoxicity and enhances longevity by an hsf-1-dependent mechanism in Caenorhabditis elegans. Aging Cell. doi:10.1111/j.1474-9726.2008.00385.x
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  Dietary restriction increases lifespan and slows the onset of age-associated disease in organisms from yeast to mammals. In humans, several age-related diseases are associated with aberrant protein folding or aggregation, including neurodegenerative disorders such as Alzheimer's, Parkinson's, and Huntington's diseases. We report here that dietary restriction dramatically suppresses age-associated paralysis in three nematode models of proteotoxicity. Similar to its longevity-enhancing properties, dietary restriction protects against proteotoxicity by a mechanism distinct from reduced insulin/IGF-1-like signaling. Instead, the heat shock transcription factor, hsf-1, is required for enhanced thermotolerance, suppression of proteotoxicity, and lifespan extension by dietary restriction. These findings demonstrate that dietary restriction confers a general protective effect against proteotoxicity and promotes longevity by a mechanism involving hsf-1.

Proceedings Publications

• Sutphin, G. L., Cassisi, D., & Crocker, A. M. (2004). 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. (2023, 8 Feb). The Purpose of Research – “Research - Why?” Panel Discussion. Discover BIO5 Open House. Tucson, AZ: BIO5 Institute, University of Arizona.
• Sutphin, G. L. (2022, 28 Oct). Precision sensitization of cancer cells to ferroptosis with 3-hydroxyanthanilic acid. University of Arizona Cancer Center 2022 Annual Scientific Retreat. Tucson, AZ: University of Arizona Cancer Center (UACC).
• Sutphin, G. L. (2022, 31 Jan). An automated C. elegans screening platform for molecular targets in aging and age-associated disease. Cancer Imaging and Engineering Working Group Meeting. Tucson, AZ: Cancer Imaging and Engineering Working Group, University of Arizona.
• Sutphin, G. L. (2022, 8 Nov). 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. (2022, 9 Nov). Targeting Kynurenine Metabolism in Aging and Age-Associated Disease. Invited Seminar, Augusta University. Augusta, GA: Augusta University.
• Sutphin, G. L. (2021, 20 Nov). Targeting kynurenine metabolism in cancer. University of Arizona Cancer Center Retreat 2021. Tucson, AZ: University of Arizona Cancer Center (UACC).
• Sutphin, G. L. (2021, 30 Aug). 3-hydroxyanthranilic acid (3HAA) – A new metabolite for healthy lifespan extension. Invited Seminar, The Jackson Laboratory Nathan Shock Center External Advisory Board Meeting. Bar Harbor, ME: The Jackson Laboratory.
• Sutphin, G. L. (2021, 6 Oct). Understanding the interplay between tryptophan and NAD metabolism during aging. 2021 AFAR Grantee Conference. Virtual: American Federation for Aging Research (AFAR).
• Sutphin, G. L. (2020, 15 Sep). A new platform for high-throughput longevity screening in C. elegans. 2nd Annual Drug Discovery & Development Summit. Tucson, AZ: University of Arizona.
• Sutphin, G. L. (2020, 17 Nov). Elevating systemic 3-hydroxyanthranilic acid (3HAA) to improve sepsis recovery in aged mice (and worms). 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. (2020, 4 Nov). GSA Career Development Panel Discussion. Gerontological Society of America 2020 Annual Scientific Meeting. Virtual: Gerontological Society of America (GSA).
• Sutphin, G. L. (2020, 6 May). Targeting tryptophan metabolism in aging and age-associated disease. Genetics Graduate Interdisciplinary Program (GIDP) Seminar Series. Tucson, AZ: University of Arizona.
• 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. (2020, May). The Science of Getting Older. College of Science Virtual Science Café. Tucson, AZ: College of Science, University of Arizona.
• Sutphin, G. L. (2019, 2 Feb). Targeting kynurenine metabolism in aging and Alzheimer's disease. Neuroscience Colloquium. Tucson, AZ: 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. (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. (2022, 17-20 May). Extending healthy lifespan with 3-hydroxyanthranilic acid. 50th Annual Meeting of the American Aging Association. San Antonio, TX: American Aging Association (AGE).
• Sutphin, G. L. (2022, 2-6 Nov). Extending a Healthy Lifespan with 3-Hydroxyanthranilic Acid. Gerontological Society of America 2022 Annual Scientific Meeting. Indianapolis, IN: Gerontological Society of America (GSA).
• Sutphin, G. L. (2021, 10-13 Nov). Targeting kynurenine metabolism to reduce inflammation and enhance stress response during aging. Gerontological Society of America 2021 Annual Scientific Meeting. Virtual: Gerontological Society of America (GSA).
  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. (2021, 20-23 Jul). Healthy lifespan extension through 3-hydroxyanthranilic acid. 49th Annual Meeting of the American Aging Association. Madison, WI: American Aging Association (AGE).
• Sutphin, G. L. (2020, 4-7 Nov). Defining the Response of Caenorhabditis elegans to Multiple Simultaneous Stressors. Gerontological Society of America 2020 Annual Scientific Meeting. Virtual: Gerontological Society of America (GSA).
  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. (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.