George Sutphin

Assistant Professor, Molecular and Cellular Biology
Assistant Professor, BIO5 Institute

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. In the Sutphin Lab, we use a combination of systems biology, comparative genetics, and molecular physiology to understand the molecular processes that underlie aging and drive age-associated disease.

Comparative Genetics of Aging

Virtually every cell and tissue type displays functional decline as we age. The aging process, in turn, is influenced by a wide range of molecular and physiological processes. Determining the range of genes and molecular processes that are capable of influencing aging and understanding how they interact in the context of an aging organism is an important step to identifying key intervention points to treat age-associated disease. To this end, a primary goal of our laboratory is to identify and characterize novel genetic determinants of longevity.

We use a combination of systems and comparative genetics to study evolutionarily conserved mechanisms of aging, leveraging the unique strengths of three model organisms: humans (Homo sapiens), mice (Mus musculus), and nematodes (Caenorhabditis elegans). We employ an experimental pipeline that (1) applies systems genetics to select candidate aging gene sets in humans and mice, (2) employs longevity screening in worms to select the subset of genes capable of directly affecting longevity or other age-associated phenotypes, and (3) uses molecular tools in worms and mice to characterize selected genes and build mechanistic models describing their interaction with aging. Ultimately, we will use these models to identify molecular targets to treat age-associated disease.

Targeting Kynurenine Metabolism in Age-Associated Disease

The first molecular process identified in our comparative genetics pipeline was the kynurenine pathway.  The kynurenine pathway is the primary metabolic destination for ingested tryptophan and has been linked to multiple age-related pathologies, including neurodegeneration, kidney disease, and cardiovascular disease. In C. elegans, inhibiting multiple kynurenine pathway enzymes extends lifespan and improves healthspan. In ongoing work, we are using C. elegans to determine which of several kynurenine-associated molecular processes—oxidative stress, proteostasis, neuroreceptors regulation, NAD synthesis—mediates the observed effect on lifespan. We are also validating our C. elegans observations in mice by manipulating kynurenine enzymes and measuring lifespan and other age-associated phenotypes. We are particularly interested in the efficacy of kynurenine-based interventions at specifically treating cardiovascular, renal, and neurodegenerative disease.

Environmental Influences on Aging

Our environment has a profound impact on how long we live and how healthy we are as we age. Our individual genetic make-up substantively effects how our bodies respond to different environmental factors, such as temperature, stress, or diet. These interactions are important when considering individual risk factors and in designing personalized clinical strategies to treat disease. We are interested in understanding this interaction between genes and environment.

In C. elegans, temperature is a primary environmental determinant of longevity. Worms maintained at 15°C live nearly twice as long on average as worms at maintained at 25°C. Manipulating specific molecular processes, including many of the most commonly studied processes in aging—mTOR signaling, insulin signaling, the hypoxic response, sirtuins—affects longevity and healthspan differently when worms are maintained at different temperatures. In the most severe cases, an intervention will extend lifespan at one temperature and shorten lifespan at another temperature. We are working to define the range of genes that display an interaction with environmental temperature and identify the key molecular processes that regulate the molecular and cellular response to temperature in the context of aging.



Castro-Portuguez, R., and G. L. Sutphin, "Kynurenine pathway, NAD synthesis, and mitochondrial function: Targeting tryptophan metabolism to promote longevity and healthspan.", Exp Gerontol, vol. 132, pp. 110841, 2020 04. PMCID: PMC7053056 PMID: 31954874


Bubier, J. A., G. L. Sutphin, T. J. Reynolds, R. Korstanje, A. Fuksman-Kumpa, E. J. Baker, M. A. Langston, and E. J. Chesler, "Integration of heterogeneous functional genomics data in gerontology research to find genes and pathway underlying aging across species.", PLoS One, vol. 14, issue 4, pp. e0214523, 2019. PMCID: PMC6461221 PMID: 30978202
Sutphin, G. L., "A new defense in the battle of the sexes.", Elife, vol. 8, 2019 08 16. PMCID: PMC6697443 PMID: 31418689


Sutphin, G. L., G. Backer, S. Sheehan, S. Bean, C. Corban, T. Liu, M. J. Peters, J. B. J. van Meurs, J. M. Murabito, A. D. Johnson, et al., "Caenorhabditis elegans orthologs of human genes differentially expressed with age are enriched for determinants of longevity.", Aging Cell, vol. 16, issue 4, pp. 672-682, 2017 08. PMCID: PMC5506438 PMID: 28401650
Mendenhall, A., M. M. Crane, S. Leiser, G. Sutphin, P. M. Tedesco, M. Kaeberlein, T. E. Johnson, and R. Brent, "Environmental Canalization of Life Span and Gene Expression in Caenorhabditis elegans.", J Gerontol A Biol Sci Med Sci, vol. 72, issue 8, pp. 1033-1037, 2017 Aug 01. PMCID: PMC5861850 PMID: 28369388
Miller, H., M. Fletcher, M. Primitivo, A. Leonard, G. L. Sutphin, N. Rintala, M. Kaeberlein, and S. F. Leiser, "Genetic interaction with temperature is an important determinant of nematode longevity.", Aging Cell, vol. 16, issue 6, pp. 1425-1429, 2017 12. PMCID: PMC5676069 PMID: 28940623


Sutphin, G. L., M. J Mahoney, K. Sheppard, D. O. Walton, and R. Korstanje, "WORMHOLE: Novel Least Diverged Ortholog Prediction through Machine Learning.", PLoS Comput Biol, vol. 12, issue 11, pp. e1005182, 2016 Nov. PMCID: PMC5094675 PMID: 27812085
Leiser, S. F., G. Jafari, M. Primitivo, G. L. Sutphin, J. Dong, A. Leonard, M. Fletcher, and M. Kaeberlein, "Age-associated vulval integrity is an important marker of nematode healthspan.", Age (Dordr), vol. 38, issue 5-6, pp. 419-431, 2016 Dec. PMCID: PMC5266215 PMID: 27566309


Vermulst, M., A. S. Denney, M. J. Lang, C-W. Hung, S. Moore, A. M Moseley, A. M. Mosely, W. J Thompson, W. J. Thompson, V. Madden, et al., "Transcription errors induce proteotoxic stress and shorten cellular lifespan.", Nat Commun, vol. 6, pp. 8065, 2015 Aug 25. PMCID: PMC4684168 PMID: 26304740
McCormick, M. A., J. R. Delaney, M. Tsuchiya, S. Tsuchiyama, A. Shemorry, S. Sim, A. Chia- Zong Chou, U. Ahmed, D. Carr, C. J. Murakami, et al., "A Comprehensive Analysis of Replicative Lifespan in 4,698 Single-Gene Deletion Strains Uncovers Conserved Mechanisms of Aging.", Cell Metab, vol. 22, issue 5, pp. 895-906, 2015 Nov 03. PMCID: PMC4862740 PMID: 26456335
Vermulst, M., A. S. Denney, M. J. Lang, C-W. Hung, S. Moore, A. M Moseley, W. J Thompson, V. Madden, J. Gauer, K. J. Wolfe, et al., "Corrigendum: Transcription errors induce proteotoxic stress and shorten cellular lifespan.", Nat Commun, vol. 6, pp. 8738, 2015 Oct 14. PMID: 26465398
Peters, M. J., R. Joehanes, L. C. Pilling, C. Schurmann, K. N. Conneely, J. Powell, E. Reinmaa, G. L. Sutphin, A. Zhernakova, K. Schramm, et al., "The transcriptional landscape of age in human peripheral blood.", Nat Commun, vol. 6, pp. 8570, 2015 Oct 22. PMCID: PMC4639797 PMID: 26490707
Chandler-Brown, D., H. Choi, S. Park, B. R. Ocampo, S. Chen, A. Le, G. L. Sutphin, L. S. Shamieh, E. D. Smith, and M. Kaeberlein, "Sorbitol treatment extends lifespan and induces the osmotic stress response in Caenorhabditis elegans.", Front Genet, vol. 6, pp. 316, 2015. PMCID: PMC4621483 PMID: 26579191


Sutphin, G. L., J. R. Delaney, and M. Kaeberlein, "Replicative life span analysis in budding yeast.", Methods Mol Biol, vol. 1205, pp. 341-57, 2014. PMID: 25213254
Dang, W., G. L. Sutphin, J. A. Dorsey, G. L. Otte, K. Cao, R. M. Perry, J. J. Wanat, D. Saviolaki, C. J. Murakami, S. Tsuchiyama, et al., "Inactivation of yeast Isw2 chromatin remodeling enzyme mimics longevity effect of calorie restriction via induction of genotoxic stress response.", Cell Metab, vol. 19, issue 6, pp. 952-66, 2014 Jun 03. PMCID: PMC4106248 PMID: 24814484


Schleit, J., S. C. Johnson, C. F. Bennett, M. Simko, N. Trongtham, A. Castanza, E. J. Hsieh, R. M. Moller, B. M. Wasko, J. R. Delaney, et al., "Molecular mechanisms underlying genotype-dependent responses to dietary restriction.", Aging Cell, vol. 12, issue 6, pp. 1050-61, 2013 Dec. PMCID: PMC3838465 PMID: 23837470
Delaney, J. R., U. Ahmed, A. Chou, S. Sim, D. Carr, C. J. Murakami, J. Schleit, G. L. Sutphin, E. H. An, A. Castanza, et al., "Stress profiling of longevity mutants identifies Afg3 as a mitochondrial determinant of cytoplasmic mRNA translation and aging.", Aging Cell, vol. 12, issue 1, pp. 156-66, 2013 Feb. PMCID: PMC3687586 PMID: 23167605
Delaney, J. R., A. Chou, B. Olsen, D. Carr, C. Murakami, U. Ahmed, S. Sim, E. H. An, A. S. Castanza, M. Fletcher, et al., "End-of-life cell cycle arrest contributes to stochasticity of yeast replicative aging.", FEMS Yeast Res, vol. 13, issue 3, pp. 267-76, 2013 May. PMCID: PMC3960949 PMID: 23336757
Delaney, J. R., C. Murakami, A. Chou, D. Carr, J. Schleit, G. L. Sutphin, E. H. An, A. S. Castanza, M. Fletcher, S. Goswami, et al., "Dietary restriction and mitochondrial function link replicative and chronological aging in Saccharomyces cerevisiae.", Exp Gerontol, vol. 48, issue 10, pp. 1006-13, 2013 Oct. PMCID: PMC3604125 PMID: 23235143


Sutphin, G. L., B. A. Olsen, B. K. Kennedy, and M. Kaeberlein, "Genome-wide analysis of yeast aging.", Subcell Biochem, vol. 57, pp. 251-89, 2012. PMID: 22094426
Murakami, C., J. R. Delaney, A. Chou, D. Carr, J. Schleit, G. L. Sutphin, E. H. An, A. S. Castanza, M. Fletcher, S. Goswami, et al., "pH neutralization protects against reduction in replicative lifespan following chronological aging in yeast.", Cell Cycle, vol. 11, issue 16, pp. 3087-96, 2012 Aug 15. PMCID: PMC3442919 PMID: 22871733
Sutphin, G. L., E. Bishop, M. E. Yanos, R. M. Moller, and M. Kaeberlein, "Caffeine extends life span, improves healthspan, and delays age-associated pathology in Caenorhabditis elegans.", Longev Healthspan, vol. 1, pp. 9, 2012. PMCID: PMC3922918 PMID: 24764514


Kruegel, U., B. Robison, T. Dange, G. Kahlert, J. R. Delaney, S. Kotireddy, M. Tsuchiya, S. Tsuchiyama, C. J. Murakami, J. Schleit, et al., "Elevated proteasome capacity extends replicative lifespan in Saccharomyces cerevisiae.", PLoS Genet, vol. 7, issue 9, pp. e1002253, 2011 Sep. PMCID: PMC3169524 PMID: 21931558
Burnett, C., S. Valentini, F. Cabreiro, M. Goss, M. Somogyvári, M. D. Piper, M. Hoddinott, G. L. Sutphin, V. Leko, J. J. McElwee, et al., "Absence of effects of Sir2 overexpression on lifespan in C. elegans and Drosophila.", Nature, vol. 477, issue 7365, pp. 482-5, 2011 Sep 21. PMCID: PMC3188402 PMID: 21938067
Delaney, J. R., G. L. Sutphin, B. Dulken, S. Sim, J. R. Kim, B. Robison, J. Schleit, C. J. Murakami, D. Carr, E. H. An, et al., "Sir2 deletion prevents lifespan extension in 32 long-lived mutants.", Aging Cell, vol. 10, issue 6, pp. 1089-91, 2011 Dec. PMCID: PMC3215821 PMID: 21902802