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Hsu, Ao Lin
  • Professor
  • Education:Ph.D., Med. Chem. and Pharmaceutics, University of Kentucky; Post-doc, Biochemistry and Biophysics, University of California San Francisco
  • Office:R613, 6F, Tradition Medicine Building
  • Phone:886-2-2826-7126 
Research--Genetic regulation of aging and longevity; The longevity response to dietary restriction; Development of anti-aging interventions.
Aging is a fundamental process characterized by progressive declines in physiological functions of multiple tissues and an increased likelihood of death. Accumulating evidence suggests that the rate of aging can be controlled by both hormonal and environmental cues. With its short lifespan, extensive genetics and well-described anatomy, the nematode C. elegans has been recognized as an excellent model system for aging studies. The main focus of our laboratory is to understand the biology of aging at the cellular and molecular level by investigating the genetic, environmental, and pharmacological factors that influence the rate of aging and longevity in model organisms. In particular, our current efforts are directed toward the following areas:
(1)Role of HSF-1 in longevity regulation: The importance of protein homeostasis and stress responses in the regulation of longevity and aging has been unveiled by recent studies. Heat-shock transcription factor (HSF-1) is the master regulator of the cellular defense mechanism against heat stress and has recently been directly linked to longevity. Our research has been focus on (i) the cross talks between HSF-1 and insulin/IGF-1 signaling, a well-studied longevity regulatory pathway, (ii) the upstream regulators of HSF-1, and (iii) the downstream targets of HSF-1 that plays important roles in aging regulation.
(2) Role of sirtuins in aging and stress response: Sirtuins are proteins that possess either deacetylase or mono-ribosyltransferase activity. They have been implicated in influencing aging, apoptosis, and stress resistance. We are interested in how SIR-2.4, a worm homolog of human SIRT6, controls stress resistance and aging by modulation the functions of FOXO transcription factor DAF-16.
(3)Genes involved in the longevity response to dietary restriction: Dietary restriction (DR) or caloric restriction (CR) is known to result in a robust increase in lifespan while maintaining the physiology of much younger animals in a wide range of species. However, the molecular mechanisms underlying the longevity response of DR remain largely unknown. One of the main focuses of our laboratory is to study genes that mediate this longevity effect of DR. In particular, our current research has been focusing on genes involved in the TOR and AMPK pathway, RNA translation, and SAM-dependent methylation.
(4)Pharmacological intervention that slows aging: The ultimate goal of our research is to develop new therapeutic strategies for combating aging and age-related diseases with the knowledge that we will obtain. We have been actively collaborating with several other groups to identify drugs or nature products that could slow the aging process or delay the onset of age-related neurodegenerative diseases, such as Huntington’s disease.
(5) Functional aging in the nervous system: As animals age, they exhibit a gradual loss in motor activity. We have previously identified the rate of motor activity decline as an excellent longevity predictor in C. elegans. We now aim to investigate the cellular and molecular origin of this age-associated motor activity decline by functionally characterizing the aging nervous system and muscles, in collaboration with a world leading worm electrophysiologist.
  • Zhang, B., Xiao, R., Ronan, E.A., He, Y., Hsu, A.L., Liu, J., Xu, X.Z. (2015): Environmental temperature differentially modulates C. elegans longevity through a thermosensitive channel.  Cell Reports, 11(9):1414-142.


  • Huang, C.H., Hsu, F.Y., Wu, Y.H., Zhong, L., Tseng, M.Y., Kuo, C.J., Hsu, A.L.*, Liang, S.S.*, Chiou, S.H.* (2015): Analysis of lifespan-promoting effect of garlic extract by integrated metabolo-proteomics approach.  J. Nutritional Biochem. 26(8) 808-817.     (*co-corresponding authors)


  • Vukoti, K., Yu, X., Sheng, Q., Saha, S., Feng, Z., Hsu, A.L.*, and Miyagi, M.* (2015): Monitoriing newly synthesized proteins over the adult life span of C. elegans. J. Proteome Res, 14(3): 1483-94.  [Epub: Feb 25, 2015]    (*co-corresponding authors)


  • Horikawa, M., Sural, S., Hsu, A.L., and Antebi, A. (2015): Co-chaperone p23 regulates C. elegans lifespan in response to temperature. PLoS Genetics, 11(4):e1005023.


  • Kumsta, C., Ching, T.T., Nichimura, M., Davis, A., Gelino, S., Catan, H.H., Panowski, S.H., Baird, N., Chu, C.C., Ong, B., Yu, X., Bodmer, R., Hsu, A.L., Hansen M. (2014): Integrin-linked kinase regulates longevity and thermo-tolerance via neuronal control of HSF-1 in C. elegans. Aging Cell. 13(3): 419-430.


  • Liu, J., Zhang, B., Lei, H., Feng, Z., Liu, J., Hsu, A.L., and Xu, X.Z. (2013): Functional aging in the nervous system contributes to age-dependent motor activity decline in C. elegans. Cell Metabolism. 18(3): 392-402.


  • Chiang, W.C., Tishkoff, D., Yang, B., Wilon-Grady, J., Yu, X., Mazer, T., Eckersdorff, M., Gygi, S., Lombard, D.B., and Hsu, A.L. (2012): C. elegans SIRT6/7 homolog SIR-2.4 promotes DAF-16 localization and function during stress. PLoS Genetics. 8(9): e1002948.


  • Yuan, Y., Kadiyala, C.S., Ching, T.T., Hakimi, P., Saha, S., Xu, H., Yuan, C., Mullangi, V., Wang, L., Fivenson E., Hanson, R.W., Ewing, R., Hsu, A.L.*, Miyagi, M.*, and Feng, Z.* (2012): Enhanced energy metabolism contributes to the extended lifespan of caloric restricted C. elegans. J Biol Chem. 287(37): 31414-31426. (*co-corresponding authors)


  • Chiang, W.C, Ching, T.T., Lee, H.C., Mousigian, C., and Hsu, A.L. (2012) HSF-1 regulators DDL-1/2 link insulin-like signaling to heat-shock response and modulation of longevity. Cell. 148(1-2): 322-334..


  • Ching, T.T., Chiang, W.C., Chen, C.S., and Hsu, A.L. (2011) Celecoxib extends C. elegans lifespan via inhibition of insulin-like signaling but not cyclooxygenase-2 activity. Aging Cell. 10(3): 506-519.


  • Ching, T.T. and Hsu, A.L. (2011)  Solid plate-based dietary restriction in Caenorhabditis elegans. J Vis Exp. (51): pii: 2701. [Epub: doi: 10.3791/2701].


  • Ching, T.T., Paal, A., Mehta, A., Zhong, L., and Hsu, A.L. (2010)  drr-2 encodes an eIF4H that acts downstream of TOR in diet-restriction-induced longevity of C. elegans.  Aging Cell. 9(4): 545-557.


  • Hsu, A.L.*, Feng, Z., Hsieh, M.Y., and Xu, X.Z.* (2009)  Identification by machine vision of the rate of motor activity decline as a lifespan predictor in C. elegans.  Neurobiology of Aging. 30(9): 1498-1503. (*co-corresponding authors)


  • Hansen M.*, Hsu, A.L.*, Dillin, A., and Kenyon, C. (2005) New genes tied to endocrine, metabolic and dietary regulation of lifespan from a Caenorhabditis elegans genomic RNAi screen.  PLoS Genetics. 1(1): 119-134. (*co-first authors)


  • Hsu, A.L., Murphy, C., and Kenyon, C. (2003)  Regulation of aging and age-related disease by DAF-16 and Heat-shock factor. Science. 300(5622): 1142-1145.


  • Dillin, A., Hsu, A.L., Arantes-Oliveira, N., Lehrer-Graiwer, J., Hsin, H., Fraser, A.G., Kamath, R.S., Ahringer, J., and Kenyon, C. (2002)  Rates of behavior and aging specified by mitochondrial function during development.  Science. 298(5602): 2398-401.


  • Garigan, D., Hsu, A.L., Fraser, A.G., Kamath, R.S., Ahringer, J., and Kenyon, C. (2002) Genetic analysis of tissue aging in C. elegans: Heat-shock factor prevents progeria and proliferating bacteria kill the animal. Genetics. 161(3): 1101-1112.


  • Johnson, A.J., Hsu, A.L., Song, X.Q., Lin, H.P., and Chen, C.S. (2002)  The cyclooxygenase-2 inhibitor celecoxib perturbs intracellular calcium by inhibiting endoplasmic reticulum Ca2+- ATPases. A plausible link with its anti-tumor effect and cardiovascular Risks.  Biochem J. 366(3): 831-837.


  • Ching, T.T., Hsu, A.L., Johnson, A.J., and Chen, C.S. (2001)  Phosphoinositide 3-kinase facilitate antigen-stimulated Ca2+ influx in RBL-2H3 mast cells via a phosphatidylinositol 3,4,5-triphosphate-sensitive Ca2+ entry mechanism.  J Biol Chem. 276(18): 14814-14820.


  • Johnson, A.J., Song, X.Q., Hsu, A.L., and Chen, C.S. (2001)  Apoptosis signaling pathway mediated by cyclooxygenase-2 inhibitors in prostate cancer cells. Adv Enzyme Regul. 41: 221-235.


  • Wang, D.S., Hsu, A.L., and Chen, C.S. (2001)  A phosphatidylinositol 3,4,5-triphosphate analogue with low serum-binding affinity. Bioorg Med Chem. 9(1): 133-139.


  • Hsu, A.L., Ching, T.T., Sen, G., Wang, D.S., Bondada, S., Authi, K.S., and Chen, C.S. (2000)  A novel function of phosphoinositide 3-kinase in T-cell calcium signaling: A phosphatidylinositol 3,4,5-triphosphate-mediated Ca2+ entry mechanism. J Biol Chem. 275(21): 16242-16250.


  • Hsu, A.L., Ching, T.T., Wang, D.S., Song, X.Q., Rangnekar, V.M., and Chen, C.S. (2000)  The cyclooxygenase-2 inhibitor celecoxib induces apoptosis by blocking Akt activation in human prostate cancer cells independently of Bcl-2. J Biol Chem. 275(15): 11397-11403.


  • Ching, T.T., Wang, D.S., Hsu, A.L., Lu, P.J., and Chen, C.S. (1999)  Identification of multiple phosphoinositide-specific phospholipases D as new regulatory enzymes for phosphatidylinositol 3,4,5-triphosphate. J Biol Chem. 274(13): 8611-8617.


  • Hsu, A.L., Lu, P.J., and Chen, C.S. (1998)  Regulation of nuclear calcium uptake by inositol phosphates and external calcium. Biochem Biophys Res Commun. 243(3): 653-656.


  • Lu, P.J., Hsu, A.L., Wang, D.S., and Chen, C.S. (1998)  Phosphatidylinositol 3,4,5-triphosphate triggers platelet aggregation by activating Ca2+ influx. Biochemistry. 37(27): 9776-9783.


  • Lu, P.J., Hsu, A.L., Wang, D.S., Yan, H.Y., Yin, H.L., and Chen, C.S. (1998) Phosphoinositide 3-Kinase signaling in rat liver nuclei. Biochemistry. 37(16): 5738-5745.


  • Wang, D.S., Hsu, A.L., Song, X.Q., Chiou, C.M., and Chen, C.S. (1998) Molecular recognition at the phosphatidylinositol 3,4,5-triphosphate-binding site. Studies using the permuted isomers of phosphatidylinositol triphosphate. J Org Chem. 63(16): 5430-5437.

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