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The major research interest of my laboratory is cancer and aging and the role played by the mechanistic target of rapamycin (mTOR) signaling system.
Our published work on the long-lived (in the vivarium) hypopituitary Ames dwarf mouse showed an inhibition of the mTOR complex 1 (mTORC1) effectors such as 4E-BP1 and S6K1 in liver and skeletal muscle. This is consistent with numerous lines of evidence in yeast, worms and flies that the TOR signaling system has an evolutionarily conserved role in the regulation of longevity.
These observations and those showing that diet restriction (DR) extended life and health span, prompted me to propose that chronic treatment of mice with an mTORC1 inhibitor, such as rapamycin, would mimic growth factor and/or diet restriction and would also extend life- and health-span in mice. This proposal was rigorously tested in three separate geographically located vivaria by the NIA funded Intervention Testing Program (ITP), whose site directors are Drs. Randy Strong at the UTHCSA, Rich Miller at the University of Michigan and David Harrison, Jackson Labs.
The trial was made possible by the development of a novel microencapsulated enterically-released formulation of rapamycin (called eRapa) by Dr. Randy Strong, which stabilized it in food and delivered rapamycin to the lower GI tract. The results of the first trial showed that mice starting encapsulated rapamycin when they are twenty months of age (equivalent to 60 in human years) live an additional 28% (males) to 38% (females) time. Importantly, and like the gold standard invention calorie restriction, both median and maximum life span was observed. These results were published in Nature.
The second rapamycin trial by the ITP was completed and published in Journal of Gerontology Biological Sciences, which showed that mice starting eRapa at nine months of age also showed similar extensions of median and maximum life spans for both males and females. These results also showed that chronic rapamycin treatment delayed the age-related decline in mobility of mice, and a reduction of cancer, which was the first strong indication of an improved health span.
Current efforts in our lab are directed toward determining if chronic rapamycin will prevent, delay, and/or reduce the severity of one of the most feared diseases of aging – cancer. Toward this end and in collaboration with Drs. Livi, Hasty and Christy, we are testing three mouse models. The first is mice deficient for the tumor suppressor p53, which is defective in most human cancers. DR was previously shown to extend the life span of this short-lived mouse (due to numerous types of cancers), and the prediction is that chronic rapamycin treatment will mimic CR. In a paper being prepared for publication, we show that the ability of chronic rapamycin treatment to extend life and health span is dependent on the number of good copies of p53 gene present in the mouse.
The second model is mice with tumors deficient for another famous suppressor of tumorigenesis, the retinoblastoma protein (pRb1). We published data showing that DR is minimally effective in delaying the development or growth of spontaneous neuroendocrine tumors (pituitary and thyroid) in Rb1+/- mice. Based on this, we predicted that eRapa treatment starting at 8-9 weeks of age would also be minimally effective in extending longevity and preventing tumor development and growth. We showed the exact opposite – eRapa is very effective in extending the life span of both male and female due to a reduction of thyroid tumors and a delay in the development and slower growth of pituitary tumors.
The third is a mouse model of intestinal adenomas called ApcMin/+. Since our formulation of rapamycin is delivered to the gut, we predicted it would be efficacious in this model. In a paper ready for submission, we show that eRapa starting at 8 weeks of age extends their life span to almost that of wild type mice (mid dose) or exceeds that of wild type (high dose).
In summary, eRapa is the first anticancer prophylactic drug, which could have a large impact on the amelioration of age-associated cancer and, at the same tiem, extend the healthy portion of our lives. The mTOR system like aging is woven into the very fabric of life. It is no wonder that its regulation has a profound effect on the length and quality of life. We are just beginning to understand this very deep connection and the exciting possibilities at hand.
- Christy B, Demaria M, Campisi J, Huang J, Jones D, Dodds SG, Williams C, Hubbard G, Livi CB, Gao X, Weintraub S, Curiel T, Sharp ZD, Hasty P. p53 and rapamycin are additive.
Oncotarget. 2015 Jun 30;6(18):15802-13.
- Dao V, Pandeswara S, Liu Y, Hurez V, Dodds S, Callaway D, Liu A, Hasty P, Sharp ZD, Curiel TJ.
Prevention of carcinogen and inflammation-induced dermal cancer by oral rapamycin includes reducing genetic damage. Cancer Prev Res (Phila). 2015 May;8(5):400-9. doi: 10.1158/1940-6207.CAPR-14-0313-T. Epub 2015 Mar 3.PMID: 25736275
- Calhoun C, Shivshankar P, Saker M, Sloane LB, Livi CB, Sharp ZD, Orihuela CJ, Adnot S, White ES, Richardson A, Jourdan Le Saux C. Senescent Cells Contribute to the Physiological Remodeling of Aged Lungs. J Gerontol A Biol Sci Med Sci. 2015 Jan 7. pii: glu241. [Epub ahead of print]
- Miller, RA, Harrison, DE, Astle, CM, Fernandez, E, Flurkey, K, Han, M, Javors, MA, Li, X, Nadon, NL, Nelson, JF, Pletcher, S, Salmon, AB, Sharp, ZD, Van Roekel, S, Winkleman, L, Strong, R. (2014) Rapamycin-Mediated Lifespan Increase in Mice is Dose and Sex-Dependent and Metabolically Distinct from Dietary Restriction. Aging Cell 13:468-77 PMID: 24341993
- Hasty P, Livi CB, Dodds SG, Jones D, Strong R, Javors M, Fischer KE, Sloane L, Murthy K, Hubbard G, Sun L, Hurez V, Curiel TJ, Sharp ZD. eRapa restores a normal life span in a FAP mouse model.
Cancer Prev Res (Phila). 2014 Jan;7(1):169-78. doi: 10.1158/1940-6207.CAPR-13-0299. Epub 2013 Nov 26.
- Livi CB, Hardman RL, Christy BA, Dodds SG, Jones D, Williams C, Strong R, Bokov A, Javors MA, Ikeno Y, Hubbard G, Hasty P, and Sharp ZD: (2013) Rapamycin extends life span of Rb1+/- mice by inhibiting neuroendocrine tumors. AGING (Albany NY). 5(2): 100-10. ePublished www.impactaging.com.
- Sharp ZD, Curiel TJ, and Livi CB: (2013) Chronic mechanistic target of rapamycin inhibition: Preventing cancer to delay aging, or vice versa? In Cancer and Aging: From Bench to the Clinics. Interdiscipl Top Gerontol, Extermann M (ed). Basel, Karger, Vol. 38, pp 1-16 (doi: 10.1159/000343625).
- Hasty P, Sharp ZD, Curiel TJ, and Campisi J: (2013) mTORC1 and p53: Clash of the gods? Cell Cycle 12(1): 20-5.
- Sharp ZD and Richardson AR.: (2011) Aging and cancer: can mTOR inhibitors kill two birds with one drug? Target Oncol. 6(1): 41-51.
- Miller RA, Harrison DE, Astle CM, Baur JA, Boyd AR, de Cabo R, Fernandez E, Flurkey K, Javors MA, Nelson JF, Orihuela CJ, Pletcher S, Sharp ZD, Sinclair D, Starnes JW, Wilkinson JE, Nadon NL, and Strong R.: (2011) Rapamycin, but not resveratrol or simvastatin, extends life span of genetically heterogeneous mice. J Gerontol A Biol Sci Med Sci. 66(2): 191-201.
- Sharp ZD: (2011) Aging and TOR: interwoven in the fabric of life. Cell Mol Life Sci. 68(4): 587-97.
- Sharp ZD and Strong R: (2010) The role of mTOR signaling in controlling mammalian life span: what a fungicide teaches us about longevity. J Gerontol A Biol Sci Med Sci. 65(6): 580-9.
- Harrison DE, Strong R, Sharp ZD, Nelson JF, Astle CM, Flurkey K, Nadon NL, Wilkinson JE, Frenkel K, Carter CS, Pahor M, Javors MA, Fernandez E, and Miller RA: (2009) Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. Nature. 460(7253): 392-5.