Journal of Food and Nutrition Research
ISSN (Print): 2333-1119 ISSN (Online): 2333-1240 Website: Editor-in-chief: Prabhat Kumar Mandal
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Journal of Food and Nutrition Research. 2018, 6(10), 665-673
DOI: 10.12691/jfnr-6-10-8
Open AccessArticle

Leucine Exerts Lifespan Extension and Improvement in Three Types of Stress Resistance (Thermotolerance, Anti-Oxidation and Anti-UV Irradiation) in C. elegans

Hongyuan Wang1, 2, Jin Wang2 and Zhizhou Zhang1, 2,

1School of Chemistry and Chemical Engineering, Harbin Institute of Technology, Harbin 150001, China

2School of Marine Science and Technology, Harbin Institute of Technology, Weihai 264209, China

Pub. Date: November 18, 2018

Cite this paper:
Hongyuan Wang, Jin Wang and Zhizhou Zhang. Leucine Exerts Lifespan Extension and Improvement in Three Types of Stress Resistance (Thermotolerance, Anti-Oxidation and Anti-UV Irradiation) in C. elegans. Journal of Food and Nutrition Research. 2018; 6(10):665-673. doi: 10.12691/jfnr-6-10-8


Recent studies have found various compounds that can extend lifespan in different species. Amino acids as regulators in nutrition process and anti-aging have been investigated, but inconsistency existed in the literature in the context of lifespan-extending roles of some amino acids in C. elegans. In this paper, we measured the effects of individual branched-chain amino acids (BCAAs, leucine, valine and isoleucine) on lifespan in C. elegans. We found that 1000μM and 10000μM leucine could extend lifespan significantly coupled with increased stress resistance of thermotolerance, anti-oxidation and anti- UV irradiation. Furthermore, we used daf-2 and daf-16 mutants to explore the possible molecular mechanism of Leu-induced lifespan extension. Results suggested that the function of Leu on aging regulation is dependent on Insulin/IGF-1 (IIS) signaling. Our work confirmed that BCAAs play an important role in IIS signaling pathway to regulate aging and intake of such nutrients may also be good for healthspan in C. elegans.

C. elegans leucine aging stress resistance daf-16

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[1]  H. Gershon, D. Gershon, “Caenorhabditis elegans--a paradigm for aging research: advantages and limitations”, Mechanisms of Ageing and Development, 123 (4). 261-274. February 2002.
[2]  C.J. Kenyon, “The genetics of ageing”, Nature, 464 (7288). 504- 512. March 2010.
[3]  O. Altintas, S. Park, S.J. Lee, “The role of insulin/IGF-1 signaling in the longevity of model invertebrates, C. elegans and D. melanogaster”, BMB Reports, 49 (2). 81-92. February 2016.
[4]  H. Antikainen, M. Driscoll, G. Haspel, R. Dobrowolski, “TOR-mediated regulation of metabolism in aging”, Aging Cell, 16(6). 1219-1233. December 2017.
[5]  M. Kaeberlein, R.W. Powers, 3rd, K.K. Steffen, E.A. Westman, D. Hu, N. Dang, E.O. Kerr, K.T. Kirkland, S. Fields, B.K. Kennedy, “Regulation of yeast replicative life span by TOR and Sch9 in response to nutrients”, Science, 310 (5751). 1193-1196. November 2005.
[6]  P. Kapahi, B.M. Zid, T. Harper, D. Koslover, V. Sapin, S. Benzer, “Regulation of lifespan in Drosophila by modulation of genes in the TOR signaling pathway”, Current Biology, 14 (10). 885-890. May 2004.
[7]  L. Kappeler, C. De Magalhaes Filho, J. Dupont, P. Leneuve, P. Cervera, L. Perin, C. Loudes, A. Blaise, R. Klein, J. Epelbaum, Y. Le Bouc, M. Holzenberger, “Brain IGF-1 receptors control mammalian growth and lifespan through a neuroendocrine mechanism”, PLoS Biology, 6 (10). e254. October 2008.
[8]  R. Yuan, S.W. Tsaih, S.B. Petkova, C. Marin de Evsikova, S. Xing, M.A. Marion, M.A. Bogue, K.D. Mills, L.L. Peters, C.J. Bult, C.J. Rosen, J.P. Sundberg, D.E. Harrison, G.A. Churchill, B. Paigen, “Aging in inbred strains of mice: study design and interim report on median lifespans and circulating IGF1 levels”, Aging Cell, 8 (3). 277-287. June 2009.
[9]  C. Kenyon, “The plasticity of aging: insights from long-lived mutants”, Cell, 120 (4). 449-460. February 2005.
[10]  W.R. Swindell, “Rapamycin in mice”, Aging (Albany NY), 9 (9). 1941-1942. September 2017.
[11]  J. Apfeld, G. O'Connor, T. McDonagh, P.S. DiStefano, R. Curtis, “The AMP-activated protein kinase AAK-2 links energy levels and insulin-like signals to lifespan in C. elegans”, Genes & Development, 18 (24). 3004-3009. December 2004.
[12]  A. Berdichevsky, M. Viswanathan, H.R. Horvitz, L. Guarente, “C. elegans SIR-2.1 interacts with 14-3-3 proteins to activate DAF-16 and extend life span”, Cell, 125 (6). 1165-1177. June 2006.
[13]  F. Cabreiro, C. Au, K.Y. Leung, N. Vergara-Irigaray, H.M. Cocheme, T. Noori, D. Weinkove, E. Schuster, N.D. Greene, D. Gems, “Metformin retards aging in C. elegans by altering microbial folate and methionine metabolism”, Cell, 153 (1). 228-239. March 2013.
[14]  P.V. Castro, S. Khare, B.D. Young, S.G. Clarke, “Caenorhabditis elegans battling starvation stress: low levels of ethanol prolong lifespan in L1 larvae”, PLoS One, 7(1). e29984. January 2012.
[15]  T. Shintani, H. Sakoguchi, A. Yoshihara, K. Izumori, M. Sato, “D-Allulose, a stereoisomer of d-fructose, extends Caenorhabditis elegans lifespan through a dietary restriction mechanism: A new candidate dietary restriction mimetic”, Biochemical and Biophysical Research Communications, 493(4). 1528-1533. December 2017.
[16]  Lopez-Otin, M.A. Blasco, L. Partridge, M. Serrano, G. Kroemer, “The hallmarks of aging”, Cell, 153 (6). 1194-1217. June 2013.
[17]  C. Edwards, J. Canfield, N. Copes, A. Brito, M. Rehan, D. Lipps, J. Brunquell, S.D. Westerheide, P.C. Bradshaw, “Mechanisms of amino acid-mediated lifespan extension in Caenorhabditis elegans”, BMC Genetics, 16. 8. February 2015.
[18]  J. Gallinetti, E. Harputlugil, J.R. Mitchell, “Amino acid sensing in dietary-restriction-mediated longevity: roles of signal-transducing kinases GCN2 and TOR”, Biochemical Journal, 449 (1). 1-10. January 2013.
[19]  R.C. Grandison, M.D. Piper, L. Partridge, “Amino-acid imbalance explains extension of lifespan by dietary restriction in Drosophila”, Nature, 462 (7276). 1061-1064. December 2009.
[20]  K. Zarse, S. Jabin, M. Ristow, “L-Theanine extends lifespan of adult Caenorhabditis elegans”, European Journal of Nutrition, 51 (6). 765-768. September 2012.
[21]  G. D'Antona, M. Ragni, A. Cardile, L. Tedesco, M. Dossena, F. Bruttini, F. Caliaro, G. Corsetti, R. Bottinelli, M.O. Carruba, A. Valerio, E. Nisoli, “Branched-chain amino acid supplementation promotes survival and supports cardiac and skeletal muscle mitochondrial biogenesis in middle-aged mice”, Cell Metabolism, 12 (4). 362-372. October 2010.
[22]  A.L. Alvers, L.K. Fishwick, M.S. Wood, D. Hu, H.S. Chung, W.A. Dunn, Jr., J.P. Aris, “Autophagy and amino acid homeostasis are required for chronological longevity in Saccharomyces cerevisiae”, Aging Cell, 8 (4). 353-369. August 2009.
[23]  T. Stiernagle, “Maintenance of C. elegans”, WormBook, (2006) 1-11.
[24]  D. Gems, D.L. Riddle, “Defining wild-type life span in Caenorhabditis elegans”, The Journals of Gerontology. Series A, Biological Sciences and Medical Sciences, 55 (5). B215-219. May 2000.
[25]  E.M. Vayndorf, S.S. Lee, R.H. Liu, “Whole apple extracts increase lifespan, healthspan and resistance to stress in Caenorhabditis elegans”, Journal of Functional Foods, 5 (3). 1236-1243. July 2013.
[26]  M.A. McCormick, J.R. Delaney, M. Tsuchiya, et. al., “A Comprehensive Analysis of replicative lifespan in 4,698 single-gene deletion strains uncovers conserved mechanisms of aging”, Cell Metabolism, 22 (5). 895-906. November 2015.
[27]  A. Bruckbauer, J. Banerjee, Q. Cao, X. Cui, J. Jing, L. Zha, F. Li, B. Xue, H. Shi, M.B. Zemel, “Leucine-nicotinic acid synergy stimulates AMPK/Sirt1 signaling and regulates lipid metabolism and lifespan in Caenorhabditis elegans, and hyperlipidemia and atherosclerosis in mice”, American Journal of Cardiovascular Disease, 7 (2). 33-47. April 2017.
[28]  X. Dong, Z. Zhou, L. Wang, B. Saremi, A. Helmbrecht, Z. Wang, J.J. Loor, “Increasing the availability of threonine, isoleucine, valine, and leucine relative to lysine while maintaining an ideal ratio of lysine:methionine alters mammary cellular metabolites, mammalian target of rapamycin signaling, and gene transcription”, Journal of Dairy Science, 101(6). 5502-5514. June 2018.
[29]  K. Tajiri, Y. Shimizu, “Branched-chain amino acids in liver diseases”, World Journal of Gastroenterology, 19 (43). 7620-7629. November 2013.
[30]  Y. Macotela, B. Emanuelli, A.M. Bang, D.O. Espinoza, J. Boucher, K. Beebe, W. Gall, C.R. Kahn, “Dietary leucine--an environmental modifier of insulin resistance acting on multiple levels of metabolism”, PLoS One, 6 (6). e21187. June 2011.
[31]  F.J. Dijk, M. van Dijk, S. Walrand, L.J.C. van Loon, K. van Norren, Y.C. Luiking, “Differential effects of leucine and leucine-enriched whey protein on skeletal muscle protein synthesis in aged mice”, Clinical Nutrition ESPEN, 24. 127-133. April 2018.
[32]  J. Gao, H. Guo, Y. Sun, F. Ge, “Differential accumulation of leucine and methionine in red and green pea aphids leads to different fecundity in response to nitrogen fertilization”, Pest Management Science, 74(8). 1779-1789. August 2018.
[33]  D. Cristina, M. Cary, A. Lunceford, C. Clarke, C. Kenyon, “A regulated response to impaired respiration slows behavioral rates and increases lifespan in Caenorhabditis elegans”, PLoS Genetics, 5 (4). e1000450. April 2009.
[34]  C. Liang, B.J. Curry, P.L. Brown, M.B. Zemel, “Leucine modulates mitochondrial biogenesis and SIRT1-AMPK signaling in C2C12 myotubes”, Journal of Nutrition & Metabolism, 2014. 239750. October 2014.
[35]  L. Fu, A. Bruckbauer, F. Li, Q. Cao, X. Cui, R. Wu, H. Shi, M.B. Zemel, B. Xue, “Leucine amplifies the effects of metformin on insulin sensitivity and glycemic control in diet-induced obese mice”, Metabolism, 64 (7). 845-856. July 2015.
[36]  A. Longchamp, T. Mirabella, A. Arduini, M.R. MacArthur, A. Das, J.H. Trevino-Villarreal, C. Hine, I. Ben-Sahra, N.H. Knudsen, L.E. Brace, J. Reynolds, P. Mejia, M. Tao, G. Sharma, R. Wang, J.M. Corpataux, J.A. Haefliger, K.H. Ahn, C.H. Lee, B.D. Manning, D.A. Sinclair, C.S. Chen, C.K. Ozaki, J.R. Mitchell, “Amino acid restriction triggers angiogenesis via GCN2/ATF4 regulation of VEGF and H2S production”, Cell, 173 (1). 117-129. e14. March 2018.
[37]  V. Carraro, A.C. Maurin, S. Lambert-Langlais, J. Averous, C. Chaveroux, L. Parry, C. Jousse, D. Ord, T. Ord, P. Fafournoux, A. Bruhat, “Amino acid availability controls TRB3 transcription in liver through the GCN2/eIF2 alpha/ATF4 pathway”, Plos One, 5 (12). e15716. December 2010.
[38]  J.M. Kingsbury, N.D. Sen, M.E. Cardenas, “Branched-chain aminotransferases control TORC1 signaling in Saccharomyces cerevisiae”, PLoS Genetics, 11 (12). e1005714. December 2015.
[39]  T.P. Nguyen, A.R. Frank, J.L. Jewell, “Amino acid and small GTPase regulation of mTORC1”, Cellular Logistics, 7 (4). e1378794. September 2017.
[40]  C. Kurino, T. Furuhashi, K. Sudoh, K. Sakamoto, “Isoamyl alcohol odor promotes longevity and stress tolerance via DAF-16 in Caenorhabditis elegans”, Biochemical and Biophysical Research Communications, 485 (2). 395-399. April 2017.