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Training Grant-
Biology of Aging

Dudley Lamming

Dudley W. Lamming

PhD, Harvard University
Assistant Professor, Dept. of Medicine- Endocrinology, Diabetes & Metabolism

The Regulation of Longevity and Age-related Diseases by Nutrient-responsive Protein Kinases

Age-related diseases - including type II diabetes, neurodegenerative disorders, cancer, and many others - are the major contributors to morbidity and mortality in modern society. The high prevalence of these diseases in the elderly limits the benefit that can be obtained by treating any one disease in isolation. Targeting the aging process directly may offer an alternative pathway by which we can delay or perhaps even prevent many age-related diseases simultaneously. It was recently discovered that rapamycin, a small molecule used as an immunosuppressant and for the treatment of specific cancers, can robustly extend the lifespan of mice.

The current focus of my work is to understand the regulation of lifespan and metabolism by the mechanistic Target Of Rapamycin (mTOR), a protein kinase that is inhibited by rapamycin. We have found that chronic, long-term treatment with rapamycin in vivo inhibits mTOR complex 2 (mTORC2), a protein complex that functions downstream of the insulin/IGF-1 receptor to regulate numerous physiological processes. Our work has highlighted a critical role for hepatic mTORC2 in the regulation of glucose homeostasis.

Our current work in cell culture and mouse models is focused on three major goals. First, we wish to understand the mechanism by which mTORC2 regulates metabolism and the response to different diets, and to translate our knowledge into developing novel therapeutic approaches for type 2 diabetes. A second goal is to understand the gender dimorphic effect of mTORC2 inhibition on longevity. Finally, our third goal is to identify small molecules that will allow us to specifically regulate different mTOR complexes, and test these compounds as potential therapies for age-related diseases such as Alzheimer's disease.

Representative Publications
Baar, E. L., Carbajal, K. A., Ong, I. M., & Lamming, D. W. (2016). Sex- and tissue-specific changes in mTOR signaling with age in C57BL/6J mice. Aging Cell, 15(1), 155-66.
View publication via DOI: DOI:10.1111/acel.12425

Arriola Apelo, S. I., Neuman, J. C., Baar, E. L., Syed, F. A., Cummings, N. E., Brar, H. K., Pumper, C. P., Kimple, M. E., & Lamming, D. W. (2016). Alternative rapamycin treatment regimens mitigate the impact of rapamycin on glucose homeostasis and the immune system. Aging Cell, 15(1), 28-38.
View publication via DOI: DOI:10.1111/acel.12405

Gregg, T., Poudel, C., Schmidt, B. A., Dhillon, R. S., Sdao, S. M., Truchan, N. A., Baar, E. L., Fernandez, L. A., Denu, J. M., Eliceiri, K. W., Rogers, J. D., Kimple, M. E., Lamming, D. W., & Merrins, M. J. (2016). Pancreatic beta-cells from mice offset age-associated mitochondrial deficiency with reduced KATP channel activity. Diabetes, 65(9), 2700-10.
View publication via DOI: DOI:10.2337/db16-0432

Fontana, L., Cummings, N. E., Arriola Apelo, S. I., Neuman, J. C., Kasza, I., Schmidt, B. A., ... Merrins, M. J., Alexander, C. M., Kimple, M. E., & Lamming, D. W. (2016). Decreased consumption of branched chain amino acids improves metabolic health. Cell Reports, 16(2), 520-30.
View publication via DOI: DOI:10.1016/j.celrep.2016.05.092

Cummings, N. E., & Lamming, D. W. (2016). Regulation of metabolic health and aging by nutrient-sensitive signaling pathways. Molecular and Cellular Endocrinology. Advance online publication.
View publication via DOI: DOI:10.1016/j.cmet.2016.05.009

Kennedy, B. K., & Lamming, D. W. (2016). The mechanistic target of rapamycin: The grand conducTOR of metabolism and aging. Cell Metabolism, 23(6), 990-1003.
View publication via DOI: DOI:10.1016/j.cmet.2016.05.009

Strong, R., Miller, R. A., Antebi, A., Astle, C. M., Bogue, M., Denzel, M. S., ... Lamming, D. W., ... Harrison, D. E. (2016). Longer lifespan in male mice treated with a weakly- estrogenic agonist, an antioxidant, an alpha -glucosidase inhibitor or a Nrf2-inducer. Aging Cell, 15(5), 872-884.
View publication via DOI: DOI:10.1111/acel.12496

Arriola Apelo, S. I., Pumper, C. P., Baar, E. L., Cummings, N. E., & Lamming, D. W. (2016). Intermittent administration of rapamycin extends the lifespan of female C57BL/6J mice. Journals of Gerontology. Series A, Biological Sciences and Medical Sciences, 71(7), 876-881.
View publication via DOI: DOI:10.1093/gerona/glw064

Arriola Apelo, S. I., & Lamming, D. W. (2016). Rapamycin: An InhibiTOR of aging emerges from the soil of Easter Island. Journals of Gerontology. Series A, Biological Sciences and Medical Sciences, 71(7), 841-849.
View publication via DOI: DOI:10.1093/gerona/glw090

Beyaz, S., Mana, M. D., Roper, J., Kedrin, D., Saadatpour, A., Hong, S. J., ... Lamming, D. W., ... Yilmaz, O. H. (2016). High-fat diet enhances stemness and tumorigenicity of intestinal progenitors. Nature, 531(7592), 53-8.
View publication via DOI: DOI:10.1038/nature17173

Covarrubias, A. J., Aksoylar, H. I., Yu, J., Snyder, N. W., Worth, A. J., Iyer, S. S., ... Lamming, D., ... Horng, T. (2016). Akt-mTORC1 signaling regulates Acly to integrate metabolic input to control of macrophage activation. eLife, 5, e11612.
View publication via DOI: DOI:10.7554/eLife.11612

Baar, E. L., Carbajal, K. A., Ong, I. O., & Lamming, D. W. (2016). Sex- and tissue-specific changes in mTOR signaling with age in C57BL/6J mice. Aging Cell, 15(1), 155-66.
View publication via DOI: DOI:10.1111/acel.12425

Tran, C. M., Mukherjee, S., Ye, L., Frederick, D. W., Kissig, M., Davis, J. G., Lamming, D. W., Seale, P., & Baur, J. A. (2016). Rapamycin blocks induction of the thermogenic program in white adipose tissue. Diabetes, 65(4), 927-41.
View publication via DOI: DOI:10.2337/db15-0502

Lamming, D. W., Cummings, N. E., Rastelli, A. L., Gao, F., Cava, E., Bertozzi, B., Spelta, F., Pili, R., & Fontana, L. (2015). Restriction of dietary protein decreases mTORC1 in tumors and somatic tissues of a tumor-bearing mouse xenograft model. Oncotarget, 6(31), 31233-31240.
View publication via DOI: DOI:10.18632/oncotarget.5180

Lamming, D. W., Demirkan, G., Boylan, J. M., Mihaylova, M. M., Peng, T., Ferreira, J., ... Gruppuso, P. A. (2014). Hepatic signaling by the mechanistic target of rapamycin complex 2 (mtorc2). FASEB, 28(1), 300-315.
View publication via DOI: DOI:10.1096/fj.13-237743

Lamming, D. W., & Anderson, R. M. (2014). Metabolic effects of caloric restriction. In eLS: Encyclopedia of Life Sciences. John Wiley & Sons, Ltd..
View publication via DOI: DOI:10.1002/9780470015902.a0021316.pub2

Lamming, D.W., Mihayalova, M.M., Katajisto, P., Baar, E.L., Yilmaz, O.H., Hutchins, A., Gultekin, Y., Gaither, R., & Sabatini, D.M. (2014). Depletion of Rictor, an essential protein component of mTORC2, decreases male lifespan. Aging Cell, 13(5), 911-917.
View publication via DOI: DOI:10.1111/acel.12256

Lamming, D.W. (2014). Diminished mTOR signaling: a common mode of action for endocrine longevity factors. SpringerPlus, 3, 735.
View publication via DOI: DOI:10.1186/2193-1801-3-735

Liu, Y., Diaz, V., Fernandez, E., Strong, R., Ye, L., Baur, J.A., Lamming, D.W., Richardson, A., & Salmon, A.B. (2014). Rapamycin-induced metabolic defects are reversible in both lean and obese mice. Aging, 6(9), 742-54.

Lamming, D.W. (2014). Hot topics at the intersection of aging and energetics: Diabetes/insulin resistance, Sirtuins, and the Microbiome. F1000Research, 3, 257.
View publication via DOI: DOI:10.12688/f1000research.5625.1

Lamming, D.W. (2014). MTORC2 takes the longevity stage. Oncotarget, 5(17), 7214-5.

Lamming, D.W., Ye, L., Astle, C.M., Baur, J.A., Sabatini, D.M., Harrison D. E. (2013). Young and old genetically heterogeneous HET3 mice on a rapamycin diet are glucose intolerant but insulin sensitive. Aging Cell, 12(4), 712-718.
View publication via DOI: DOI:10.1111/acel.1209

Lamming, D.W., Sabatini, D.M. (2013). A Central Role for mTOR in Lipid Homeostasis. Cell Metabolism, 18(4), 465-469.
View publication via DOI: DOI:10.1016/j.cmet.2013.08.002

Lamming, D.W., Ye, L., Sabatini, D.M., Baur, J.A. (2013). Rapalogs and mTOR inhibitors as anti-aging therapeutics. Journal of Clinical Investigation, 123(3), 980-989.
View publication via DOI: DOI:10.1172/JCI64099

Yilmaz, O.H., Katajisto, P., Lamming, D.W., Bakan, I., Sengupta, S., Birsoy, K., ... Sabatini, D.M. (2012). mTORC1 in the Paneth cell niche couples intestinal stem-cell function to calorie intake. Nature, 486(7404), 490-495.
View publication via DOI: DOI:10.1038/nature11163

Robida-Stubbs, S., Glover-Cutter K., Lamming, D.W., Mizunuma, M., Narasimhan, S.D., Neumann-Haefelin, E., Sabatini, D.M., Blackwell, T.K. (2012). TOR signaling and rapamycin influence longevity by regulating SKN-1/Nrf and DAF-16/FoxO. Cell Metabolism, 15(5), 713-724.
View publication via DOI: DOI:10.1016/j.cmet.2012.04.007

Lamming, D.W., Ye, L., Katajisto, P., Goncalves, M.D., Saitoh, M., Stevens, D.M., ... Baur, J.A. (2012). Rapamycin-induced insulin resistance is mediated by mTORC2 loss and uncoupled from longevity. Science, 335(6076), 1638-1643.
View publication via DOI: DOI:10.1126/science.1215135

Lamming, D.W. and Sabatini, D.M. (2011). A Radical Role for TOR in Longevity. Cell Metabolism, 13(6), 617-618.
View publication via DOI: DOI:10.1016/j.cmet.2011.05.006

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