Login | Register

Prolonging the Longevity of Budding Yeast: New Aging-Delaying Plant Extracts and the Identification of their Cellular Signaling Pathways


Prolonging the Longevity of Budding Yeast: New Aging-Delaying Plant Extracts and the Identification of their Cellular Signaling Pathways

Dakik, Pamela (2020) Prolonging the Longevity of Budding Yeast: New Aging-Delaying Plant Extracts and the Identification of their Cellular Signaling Pathways. PhD thesis, Concordia University.

[thumbnail of Dakik_PhD_F2020.pdf]
Text (application/pdf)
Dakik_PhD_F2020.pdf - Accepted Version


In studies presented in this thesis, we used a robust cell viability assay to conduct two screens of commercially available plant extract libraries in search of plant extracts that can delay chronological aging and prolong the longevity of the budding yeast S. cerevisiae. Many of the plant extracts in the library have been used for centuries in traditional Chinese and other herbal medicines or the Mediterranean and other customary diets. None of these plant extracts, however, were previously tested for their ability to slow aging and extend the longevity of any organism. Our screens have allowed us to discover twenty-one plant extracts that significantly prolong the longevity of chronologically aging yeast cells that are not limited in calorie supply. We provided evidence that each of these longevity-extending plant extracts is a geroprotector that lowers the rate of yeast chronological aging and elicits a hormetic stress response. Our findings demonstrated that the efficiencies of aging delay and longevity extension by many of these geroprotective plant extracts significantly exceed those for any of the chemical compounds previously known for their abilities to slow aging and prolong lifespan in yeasts, filamentous fungi, nematodes, fruit flies, daphnias, mosquitoes, honey bees, fish, mammals and cultured human cells. Our findings also revealed that each of the twenty-one geroprotective plant extracts mimics in limited in calorie supply yeast cells v
that are not the aging-delaying, longevity-extending, stress-protecting, metabolic and physiological effects of a caloric restriction diet. We also demonstrated that the discovered geroprotective plant extracts elicit partially overlapping effects on a distinct set of longevity-defining cellular processes. Such processes include the coupled mitochondrial respiration, maintenance of the electrochemical potential across the inner mitochondrial membrane, preservation of the cellular homeostasis of reactive oxygen species, protection of cellular macromolecules from reactive oxygen species- inflicted oxidative damage, maintenance of cell resistance to oxidative and thermal stresses, the efficiency of the lipolytic cleavage of neutral lipids deposited and stored in lipid droplets. We provided evidence that some of the discovered geroprotective plant extracts slow yeast chronological aging because they target different hubs, nodes and/or links of the longevity-defining network integrating specific evolutionarily conserved signaling pathways and protein kinases.

Divisions:Concordia University > Faculty of Arts and Science > Biology
Item Type:Thesis (PhD)
Authors:Dakik, Pamela
Institution:Concordia University
Degree Name:Ph. D.
Date:21 July 2020
Thesis Supervisor(s):Titorenko, Vladimir
Keywords:Longevity, Aging, Yeast, Age-delaying, Plant extracts
ID Code:987262
Deposited By: PAMELA DAKIK
Deposited On:25 Nov 2020 15:52
Last Modified:25 Nov 2020 15:52


1. Botstein D, Fink GR. Yeast: an experimental organism for 21st Century biology. Genetics. 2011; 189:695-704.

2. Duina AA, Miller ME, Keeney JB. Budding yeast for budding geneticists: a primer on the Saccharomyces cerevisiae model system. Genetics. 2014; 197:33-48.63.

3. Weissman J, Guthrie C, Fink GR. Guide to yeast genetics: Functional genomics, proteomics, and other systems analyses. Academic Press, Burlington, 2010.

4. Horst Feldmann H. (ed.). Yeast: Molecular and cell biology. Wiley-Blackwell, Weinheim, 2012.

5. Lee SS, Avalos Vizcarra I, Huberts DH, Lee LP, Heinemann M. Whole lifespan microscopic observation of budding yeast aging through a microfluidic dissection platform. Proc Natl Acad Sci USA. 2012; 109:4916-4920.

6. Sutphin GL, Olsen BA, Kennedy BK, Kaeberlein M. Genome-wide analysis of yeast aging. Subcell Biochem. 2012; 57:251-289.

7. Xie Z, Zhang Y, Zou K, Brandman O, Luo C, Ouyang Q, Li H. Molecular phenotyping of aging in single yeast cells using a novel microfluidic device. Aging Cell. 2012; 11:599-606.

8. Zhang Y, Luo C, Zou K, Xie Z, Brandman O, Ouyang Q, Li H. Single cell analysis of yeast replicative aging using a new generation of microfluidic device. PloS One. 2012; 7: e48275.

9. Richard VR, Bourque SD, Titorenko VI. Metabolomic and lipidomic analyses of chronologically aging yeast. Methods Mol Biol. 2014; 1205:359-373.

10. Strynatka KA, Gurrola-Gal MC, Berman JN, McMaster CR. How surrogate and chemical genetics in model organisms can suggest therapies for human genetic diseases. Genetics. 2018; 208:833-851.

11. Fontana L, Partridge L, Longo VD. Extending healthy life span - from yeast to humans. Science. 2010; 328:321-326.

12. Bilinski T, Bylak A, Zadrag-Tecza R. The budding yeast Saccharomyces cerevisiae as a model organism: possible implications for gerontological studies. Biogerontology. 2017; 18:631-640.

13. Zimmermann A, Hofer S, Pendl T, Kainz K, Madeo F, Carmona-Gutierrez D. Yeast as a tool to identify anti-aging compounds. FEMS Yeast Res. 2018; 18: foy020.

14. Kaeberlein M. Lessons on longevity from budding yeast. Nature. 2010; 464:513-519.

15. Longo VD, Shadel GS, Kaeberlein M, Kennedy B. Replicative and chronological aging in Saccharomyces cerevisiae. Cell Metab. 2012; 16:18-31.

16. Sutphin GL, Olsen BA, Kennedy BK, Kaeberlein M. Genome-wide analysis of yeast aging. Subcell Biochem. 2012; 57:251-289.

17. Arlia-Ciommo A, Leonov A, Piano A, Svistkova V, Titorenko VI. Cell-autonomous mechanisms of chronological aging in the yeast Saccharomyces cerevisiae. Microbial Cell. 2014; 1:164-178.

18. Denoth Lippuner A, Julou T, Barral Y. Budding yeast as a model organism to study the effects of age. FEMS Microbiol Rev. 2014; 38:300-325.

19. Garay E, Campos SE, Gonzalez de la Cruz J, AP Gaspar, Jinich A, Deluna A. High-resolution profiling of stationary-phase survival reveals yeast longevity factors and their genetic interactions. PLoS Genet. 2014; 10: e1004168.

20. He C, Zhou C, Kennedy BK. The yeast replicative aging model. Biochim Biophys Acta. 2018; 1864:2690-2696.

21. Alic N, Partridge L. Death and dessert: nutrient signalling pathways and ageing. Curr Opin Cell Biol. 2011; 23:738-743.

22. Johnson SC, Rabinovitch PS, Kaeberlein M. mTOR is a key modulator of ageing
and age-related disease. Nature. 2013 Jan 17;493(7432):338-45.

23. Fontana L, Partridge L. Promoting health and longevity through diet: from
model organisms to humans. Cell. 2015; 161:106-118.

24. Ruetenik A, Barrientos A. Dietary restriction, mitochondrial function and aging: from yeast to humans. Biochim Biophys Acta. 2015; 1847:1434-1447.

25. Janssens GE, Veenhoff LM. Evidence for the hallmarks of human aging in replicatively aging yeast. Microb Cell. 2016; 3:263-274.

26. Kaeberlein M. The biology of aging: Citizen scientists and their pets as a bridge between research on model organisms and human subjects. Vet Pathol. 2016; 53:291-298.

27. Kapahi P, Kaeberlein M, Hansen M. Dietary restriction and lifespan: Lessons from invertebrate models. Ageing Res Rev. 2017; 39:3-14.

28. Akbari M, Kirkwood TBL, Bohr VA. Mitochondria in the signaling pathways that control longevity and health span. Ageing Res Rev. 2019; 54:100940.

29. Andréasson C, Ott M, Büttner S. Mitochondria orchestrate proteostatic and metabolic stress responses. EMBO Rep. 2019; 20: e47865.

30. Sampaio-Marques B, Burhans WC, Ludovico P. Yeast at the forefront of research on ageing and age-related diseases. Prog Mol Subcell Biol. 2019; 58:217-242.

31. Banerjee R, Joshi N, Nagotu S. Cell organelles and yeast longevity: an intertwined regulation. Curr Genet. 2020; 66:15-41.

32. Goldberg AA, Bourque SD, Kyryakov P, Gregg C, Boukh-Viner T, Beach A, Burstein MT, Machkalyan G, Richard V, Rampersad S, Cyr D, Milijevic S, Titorenko VI. Effect of calorie restriction on the metabolic history of chronologically aging yeast. Exp Gerontol. 2009; 44:555-571.

33. Steffen KK, Kennedy BK, Kaeberlein M. Measuring replicative life span in the budding yeast. J Vis Exp. 2009; 28: 1209.

34. Hu J, Wei M, Mirisola MG, Longo VD. Assessing chronological aging in Saccharomyces cerevisiae. Methods Mol Biol. 2013; 965:463-472.

35. Sinclair DA. Studying the replicative life span of yeast cells. Methods Mol Biol. 2013; 1048:49-63.

36. Steinkraus KA, Kaeberlein M, Kennedy BK. Replicative aging in yeast: the means to the end. Annu Rev Cell Dev Biol. 2008; 24:29-54.

37. McCormick MA, Delaney JR, Tsuchiya M, Tsuchiyama S, Shemorry A, Sim S, Chou AC, Ahmed U, Carr D, Murakami CJ, Schleit J, Sutphin GL, Wasko BM, Bennett CF, Wang AM, Olsen B, Beyer RP, Bammler TK, Prunkard D, Johnson SC, Pennypacker JK, An E, Anies A, Castanza AS, Choi E, Dang N, Enerio S, Fletcher M, Fox L, Goswami S, Higgins SA, Holmberg MA, Hu D, Hui J, Jelic M, Jeong KS, Johnston E, Kerr EO, Kim J, Kim D, Kirkland K, Klum S, Kotireddy S, Liao E, Lim M, Lin MS, Lo WC, Lockshon D, Miller HA, Moller RM, Muller B, Oakes J, Pak DN, Peng ZJ, Pham KM, Pollard TG, Pradeep P, Pruett D, Rai D, Robison B, Rodriguez AA, Ros B, Sage M, Singh MK, Smith ED, Snead K, Solanky A, Spector BL, Steffen KK, Tchao BN, Ting MK, Vander Wende H, Wang D, Welton KL, Westman EA, Brem RB, Liu XG, Suh Y, Zhou Z, Kaeberlein M, Kennedy BK. A comprehensive analysis of replicative lifespan in 4,698 single-gene deletion strains uncovers conserved mechanisms of aging. Cell Metab. 2015 Nov 3;22(5):895-906.

38. Ghavidel A, Baxi K, Ignatchenko V, Prusinkiewicz M, Arnason TG, Kislinger T, Carvalho CE, Harkness TA. A genome scale screen for mutants with delayed exit from mitosis: Ire1-independent induction of autophagy integrates ER homeostasis into mitotic lifespan. PLoS Genet. 2015; 11: e1005429.

39. Janssens GE, Veenhoff LM. Evidence for the hallmarks of human aging in replicatively aging yeast. Microb Cell. 2016; 3:263-274.

40. Fabrizio P, Longo VD. The chronological life span of Saccharomyces cerevisiae. Methods Mol Biol. 2007; 371: 89-95.

41. Piper PW. Maximising the yeast chronological lifespan. Subcell Biochem. 2012; 57:145-159.

42. Burtner CR, Murakami CJ, Kennedy BK, Kaeberlein M. A molecular mechanism of chronological aging in yeast. Cell Cycle. 2009; 8:1256-1270.

43. Burtner CR, Murakami CJ, Olsen B, Kennedy BK, Kaeberlein M. A genomic analysis of chronological longevity factors in budding yeast. Cell Cycle. 2011; 10:1385-1396.

44. Mirisola MG, Longo VD. Acetic acid and acidification accelerate chronological and replicative aging in yeast. Cell Cycle. 2012; 11:3532-3533.

45. Murakami C, Delaney JR, Chou A, Carr D, Schleit J, Sutphin GL, An EH, Castanza AS, Fletcher M, Goswami S, Higgins S, Holmberg M, Hui J, Jelic M, Jeong KS, Kim JR, Klum S, Liao E, Lin MS, Lo W, Miller H, Moller R, Peng ZJ, Pollard T, Pradeep P, Pruett D, Rai D, Ros V, Schuster A, Singh M, Spector BL, Vander Wende H, Wang AM, Wasko BM, Olsen B, Kaeberlein M. pH neutralization protects against reduction in replicative lifespan following chronological aging in yeast. Cell Cycle. 2012; 11:3087-3096.

46. Polymenis M, Kennedy BK. Chronological and replicative lifespan in yeast: do they meet in the middle? Cell Cycle. 2012; 11:3531-3532.

47. Delaney JR, Murakami C, Chou A, Carr D, Schleit J, Sutphin GL, An EH, Castanza AS, Fletcher M, Goswami S, Higgins S, Holmberg M, Hui J, Jelic M, Jeong KS, Kim JR, Klum S, Liao E, Lin MS, Lo W, Miller H, Moller R, Peng ZJ, Pollard T, Pradeep P, Pruett D, Rai D, Ros V, Schuster A, Singh M, Spector BL, Wende HV, Wang AM, Wasko BM, Olsen B, Kaeberlein M. Dietary restriction and mitochondrial function link replicative and chronological aging in Saccharomyces cerevisiae. Exp Gerontol. 2013; 48:1006-1013.

48. Arlia-Ciommo A, Piano A, Leonov A, Svistkova V, Titorenko VI. Quasi-programmed aging of budding yeast: a trade-off between programmed processes of cell proliferation, differentiation, stress response, survival and death defines yeast lifespan. Cell Cycle. 2014; 13:3336-3349.

49. Molon M, Zadrag-Tecza R, Bilinski T. The longevity in the yeast Saccharomyces cerevisiae: A comparison of two approaches for assessment the lifespan. Biochem Biophys Res Commun. 2015; 460:651-656.

50. Blagosklonny MV, and Hall MN. Growth and aging: a common molecular mechanism.
Aging (Albany NY). 2009; 1: 357-362.

51. Kapahi P, Chen D, Rogers AN, Katewa SD, Li PW, Thomas EL and Kockel L. With TOR, less is more: a key role for the conserved nutrient-sensing TOR pathway in aging. Cell Metab. 2010; 11: 453-465.

52. Evans DS, Kapahi P, Hsueh WC, and Kockel L. TOR signaling never gets old: aging, longevity and TORC1 activity. Ageing Res Rev. 2011; 10: 225-227.

53. Jazwinski SM. The retrograde response and other pathways of interorganelle communication in yeast replicative aging. Subcell Biochem. 2012; 57: 79-100.

54. Jazwinski SM. The retrograde response: when mitochondrial quality control is not enough. Biochim Biophys Acta. 2013; 1833: 400-409.

55. Leonov A, and Titorenko VI. A network of interorganellar communications underlies cellular aging. IUBMB Life. 2013; 65: 665-674.

56. López-Otín C, Blasco MA, Partridge L, Serrano M, and Kroemer G. The hallmarks of aging. Cell. 2013; 153: 1194-1217.

57. Bitto A, Wang AM, Bennett CF, and Kaeberlein M. Biochemical genetic pathways that modulate aging in multiple species. Cold Spring Harb Perspect Med. 2015; 5: a025114.

58. Chantranupong L, Wolfson RL, and Sabatini DM. Nutrient-sensing mechanisms across evolution. Cell. 2015; 161: 67-83.

59. Titorenko VI, and Terlecky SR. Peroxisome metabolism and cellular aging. Traffic. 2011; 12: 252-259.

60. Kaeberlein M, Powers RW 3rd, Steffen KK, Westman EA, Hu D, Dang N, Kerr EO, Kirkland KT, Fields S, and Kennedy BK. Regulation of yeast replicative life span by TOR and Sch9 in response to nutrients. Science. 2005; 310: 1193-1196.

61. Powers RW 3rd, Kaeberlein M, Caldwell SD, Kennedy BK, and Fields S. Extension of chronological life span in yeast by decreased TOR pathway signaling. Genes Dev. 2006; 20: 174-184.

62. Bonawitz ND, Chatenay-Lapointe M, Pan Y, and Shadel GS. Reduced TOR signaling extends chronological life span via increased respiration and upregulation of mitochondrial gene expression. Cell Metab. 2007; 5: 265-277.

63. Medvedik O, Lamming DW, Kim KD, and Sinclair DA. MSN2 and MSN4 link calorie restriction and TOR to sirtuin-mediated lifespan extension in Saccharomyces cerevisiae. PLoS Biol. 2007; 5: e261.

64. Longo VD. Mutations in signal transduction proteins increase stress resistance and longevity in yeast, nematodes, fruit flies, and mammalian neuronal cells. Neurobiol Aging. 1999; 20: 479-486.

65. Lin SJ, Defossez PA, and Guarente L. Requirement of NAD and SIR2 for life-span extension by calorie restriction in Saccharomyces cerevisiae. Science. 2000; 289: 2126-2128.

66. Fabrizio P, Pozza F, Pletcher SD, Gendron CM, and Longo VD. Regulation of longevity and stress resistance by Sch9 in yeast. Science. 2001; 292: 288-290.

67. Fabrizio P, Liou LL, Moy VN, Diaspro A, Valentine JS, Gralla EB, and Longo VD. SOD2 functions downstream of Sch9 to extend longevity in yeast. Genetics. 2003; 163: 35-46.

68. Wei M, Fabrizio P, Hu J, Ge H, Cheng C, Li L, and Longo VD. Life span extension by calorie restriction depends on Rim15 and transcription factors downstream of Ras/PKA, Tor, and Sch9. PLoS Genet. 2008; 4: e13.

69. Burtner CR, Murakami CJ, Olsen B, Kennedy BK, and Kaeberlein M. A genomic analysis of chronological longevity factors in budding yeast. Cell Cycle. 2011; 10: 1385-1396.

70. Huang X, Liu J, and Dickson RC. Down-regulating sphingolipid synthesis increases yeast lifespan. PLoS Genet. 2012; 8: e1002493.

71. Liu J, Huang X, Withers BR, Blalock E, Liu K, and Dickson RC. Reducing sphingolipid synthesis orchestrates global changes to extend yeast lifespan. Aging Cell. 2013; 12: 833-841.

72. Huang X, Withers BR, and Dickson RC. Sphingolipids and lifespan regulation. Biochim Biophys Acta. 2014; 1841: 657-664.

73. Teixeira V, and Costa V. Unraveling the role of the Target of Rapamycin signaling in sphingolipid metabolism. Prog Lipid Res. 2016; 61: 109-133.

74. Thompson-Jaeger S, François J, Gaughran JP, and Tatchell K. Deletion of SNF1 affects the nutrient response of yeast and resembles mutations which activate the adenylate cyclase pathway. Genetics. 1991; 129: 697-706.

75. Ashrafi K, Lin SS, Manchester JK, and Gordon JI. Sip2p and its partner snf1p kinase affect aging in S. cerevisiae. Genes Dev. 2000; 14: 1872-1885.

76. Lin SS, Manchester JK, and Gordon JI. Sip2, an N-myristoylated beta subunit of Snf1 kinase, regulates aging in Saccharomyces cerevisiae by affecting cellular histone kinase activity, recombination at rDNA loci, and silencing. J Biol Chem. 2003; 278: 13390-13397.

77. Lu JY, Lin YY, Sheu JC, Wu JT, Lee FJ, Chen Y, Lin MI, Chiang FT, Tai TY, Berger SL, Zhao Y, Tsai KS, Zhu H, Chuang LM, and Boeke JD. Acetylation of yeast AMPK controls intrinsic aging independently of caloric restriction. Cell. 2011; 146: 969-979.

78. Friis RM, Glaves JP, Huan T, Li L, Sykes BD, and Schultz MC. Rewiring AMPK and mitochondrial retrograde signaling for metabolic control of aging and histone acetylation in respiratory-defective cells. Cell Rep. 2014; 7: 565-574.

79. Jiao R, Postnikoff S, Harkness TA, and Arnason TG. The SNF1 kinase ubiquitin-associated domain restrains its activation, activity, and the yeast life span. J Biol Chem. 2015; 290: 15393-15404.

80. Tang F, Watkins JW, Bermudez M, Gray R, Gaban A, Portie K, Grace S, Kleve M, Craciun G. A lifespan extending form of autophagy employs the vacuole-vacuole fusion machinery. Autophagy. 2008; 4:874-886.

81. Alvers AL, Fishwick LK, Wood MS, Hu D, Chung HS, Dunn WA Jr, and Aris JP. Autophagy and amino acid homeostasis are required for chronological longevity in Saccharomyces cerevisiae. Aging Cell. 2009; 8:353-369.

82. Alvers AL, Wood MS, Hu D, Kaywell AC, Dunn WA Jr, and Aris JP. Autophagy is required for extension of yeast chronological life span by rapamycin. Autophagy. 2009; 5:847-849.

83. Eisenberg T, Knauer H, Schauer A, Büttner S, Ruckenstuhl C, Carmona-Gutierrez D, Ring J, Schroeder S, Magnes C, Antonacci L, Fussi H, Deszcz L, Hartl R, Schraml E, Criollo A, Megalou E, Weiskopf D, Laun P, Heeren G, Breitenbach M, Grubeck-Loebenstein B, Herker E, Fahrenkrog B, Fröhlich KU, Sinner F, Tavernarakis N, Minois N, Kroemer G, and Madeo F. Induction of autophagy by spermidine promotes longevity. Nat Cell Biol. 2009; 11:1305-1314.

84. Morselli E, Galluzzi L, Kepp O, Criollo A, Maiuri MC, Tavernarakis N, Madeo F, and Kroemer G. Autophagy mediates pharmacological lifespan extension by spermidine and resveratrol. Aging (Albany NY). 2009; 1:961-970.

85. Matecic M, Smith DL, Pan X, Maqani N, Bekiranov S, Boeke JD, and Smith JS. A microarray-based genetic screen for yeast chronological aging factors. PLoS Genet. 2010; 6: e1000921.

86. Aris JP, Alvers AL, Ferraiuolo RA, Fishwick LK, Hanvivatpong A, Hu D, Kirlew C, Leonard MT, Losin KJ, Marraffini M, Seo AY, Swanberg V, Westcott JL, Wood MS, Leeuwenburgh C, and Dunn WA Jr. Autophagy and leucine promote chronological longevity and respiration proficiency during calorie restriction in yeast. Exp Gerontol. 2013; 48:1107-1119.

87. Richard VR, Leonov A, Beach A, Burstein MT, Koupaki O, Gomez-Perez A, Levy S, Pluska L, Mattie S, Rafesh R, Iouk T, Sheibani S, Greenwood M, Vali H, Titorenko VI. Macromitophagy is a longevity assurance process that in chronologically aging yeast limited in calorie supply sustains functional mitochondria and maintains cellular lipid homeostasis. Aging (Albany NY). 2013; 5:234-269.

88. Klionsky DJ et al. (several hundred co-authors). Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition). Autophagy. 2016; 12:1-222.

89. Urban J, Soulard A, Huber A, Lippman S, Mukhopadhyay D, Deloche O, Wanke V, Anrather D, Ammerer G, Riezman H, Broach JR, De Virgilio C, Hall MN, and Loewith R. Sch9 is a major target of TORC1 in Saccharomyces cerevisiae. Mol Cell. 2007; 26: 663-674.

90. Wei M, Fabrizio P, Hu J, Ge H, Cheng C, Li L, and Longo VD. Life span extension by calorie restriction depends on Rim15 and transcription factors downstream of Ras/PKA, Tor, and Sch9. PLoS Genet. 2008; 4: e13.

91. Huang X, Liu J, and Dickson RC. Down-regulating sphingolipid synthesis increases yeast lifespan. PLoS Genet. 2012; 8: e1002493.

92. Liu J, Huang X, Withers BR, Blalock E, Liu K, and Dickson RC. Reducing sphingolipid synthesis orchestrates global changes to extend yeast lifespan. Aging Cell. 2013; 12: 833-841.

93. Huang X, Withers BR, and Dickson RC. Sphingolipids and lifespan regulation. Biochim Biophys Acta. 2014; 1841: 657-664.

94. Swinnen E, Ghillebert R, Wilms T, and Winderickx J. Molecular mechanisms linking the evolutionary conserved TORC1-Sch9 nutrient signalling branch to lifespan regulation in Saccharomyces cerevisiae. FEMS Yeast Res. 2014; 14: 17-32.

95. De Virgilio C. The essence of yeast quiescence. FEMS Microbiol Rev. 2012; 36:306-339.

96. Conrad M, Schothorst J, Kankipati HN, Van Zeebroeck G, Rubio-Texeira M, and Thevelein JM. Nutrient sensing and signaling in the yeast Saccharomyces cerevisiae. FEMS Microbiol Rev. 2014; 38:254-299.

97. Smets B, Ghillebert R, De Snijder P, Binda M, Swinnen E, De Virgilio C, and Winderickx J. Life in the midst of scarcity: adaptations to nutrient availability in Saccharomyces cerevisiae. Curr Genet. 2010; 56:1-32.

98. Beach A, and Titorenko, V.I. In search of housekeeping pathways that regulate longevity. Cell Cycle. 2011; 10:3042-3044.

99. Broach JR. Nutritional control of growth and development in yeast. Genetics. 2012; 192:73-105.

100. Burstein MT, Kyryakov P, Beach A, Richard VR, Koupaki O, Gomez-Perez A, Leonov A, Levy S, Noohi F, Titorenko VI. Lithocholic acid extends longevity of chronologically aging yeast only if added at certain critical periods of their lifespan. Cell Cycle. 2012; 11:3443-3462.

101. Kyryakov P, Beach A, Richard VR, Burstein MT, Leonov A, Levy S, and Titorenko VI. Caloric restriction extends yeast chronological lifespan by altering a pattern of age-related changes in trehalose concentration. Front Physiol. 2012; 3:256.

102. Beach A, Richard VR, Leonov A, Burstein MT, Bourque SD, Koupaki O, Juneau M, Feldman R, Iouk T, and Titorenko VI. Mitochondrial membrane lipidome defines yeast longevity. Aging (Albany NY). 2013; 5:551-574.

103. Burstein MT, and Titorenko VI. A mitochondrially targeted compound delays aging in yeast through a mechanism linking mitochondrial membrane lipid metabolism to mitochondrial redox biology. Redox Biol. 2014; 2:305-307.

104. Engelberg D, Perlman R, and Levitzki A. Transmembrane signaling in Saccharomyces cerevisiae as a model for signaling in metazoans: state of the art after 25 years. Cell Signal. 2014; 26:2865-2878.

105. Rødkaer SV, and Faergeman NJ. Glucose- and nitrogen sensing and regulatory mechanisms in Saccharomyces cerevisiae. FEMS Yeast Res. 2014; 14:683-696.

106. Beach A, Richard VR, Bourque S, Boukh-Viner T, Kyryakov P, Gomez-Perez A, Arlia-Ciommo A, Feldman R, Leonov A, Piano A, Svistkova V, and Titorenko VI. Lithocholic bile acid accumulated in yeast mitochondria orchestrates a development of an anti-aging cellular pattern by causing age-related changes in cellular proteome. Cell Cycle. 2015; 14:1643-1656.

107. Medkour Y, Titorenko VI. Mitochondria operate as signaling platforms in yeast
aging. Aging (Albany NY). 2016; 8:212-213.

108. Eisenberg T, Knauer H, Schauer A, Büttner S, Ruckenstuhl C, Carmona-Gutierrez D, Ring J, Schroeder S, Magnes C, Antonacci L, Fussi H, Deszcz L, Hartl R, Schraml E, Criollo A, Megalou E, Weiskopf D, Laun P, Heeren G, Breitenbach M, Grubeck-Loebenstein B, Herker E, Fahrenkrog B, Fröhlich KU, Sinner F, Tavernarakis N, Minois N, Kroemer G, and Madeo F. Induction of autophagy by spermidine promotes longevity. Nat Cell Biol. 2009; 11:1305-1314.

109. Goldberg AA, Kyryakov P, Bourque SD, and Titorenko VI. Xenohormetic, hormetic and cytostatic selective forces driving longevity at the ecosystemic level. Aging (Albany NY). 2010; 2:361-370.

110. Goldberg AA, Richard VR, Kyryakov P, Bourque SD, Beach A, Burstein MT, Glebov A, Koupaki O, Boukh-Viner T, Gregg C, Juneau M, English AM, Thomas DY, and Titorenko VI. Chemical genetic screen identifies lithocholic acid as an anti-aging compound that extends yeast chronological life span in a TOR-independent manner, by modulating housekeeping longevity assurance processes. Aging (Albany NY). 2010; 2:393-414.

111. Minois N, Carmona-Gutierrez D, and Madeo F. Polyamines in aging and disease. Aging (Albany NY). 2011; 3:716-732.

112. Burstein MT, Beach A, Richard VR, Koupaki O, Gomez-Perez A, Goldberg AA, Kyryakov P, Bourque SD, Glebov A, and Titorenko VI. Interspecies chemical signals released into the environment may create xenohormetic, hormetic and cytostatic selective forces that drive the ecosystemic evolution of longevity regulation mechanisms. Dose-Response. 2012; 10:75-82.

113. Arlia-Ciommo A, Piano A, Svistkova V, Mohtashami S, and Titorenko VI. Mechanisms underlying the anti-aging and anti-tumor effects of lithocholic bile acid. Int J Mol Sci. 2014; 15:16522-16543.

114. de Cabo R, Carmona-Gutierrez D, Bernier M, Hall MN, and Madeo F. The search for antiaging interventions: from elixirs to fasting regimens. Cell. 2014; 157:1515-1526.

115. Hubbard BP, and Sinclair DA. Small molecule SIRT1 activators for the treatment of aging and age-related diseases. Trends Pharmacol Sci. 2014; 35:146-154.

116. Leonov A, Arlia-Ciommo A, Piano A, Svistkova V, Lutchman V, Medkour Y, and Titorenko VI. Longevity extension by phytochemicals. Molecules. 2015; 20:6544-6572.

117. Bonawitz ND, Shadel GS. Rethinking the mitochondrial theory of aging: the role of mitochondrial gene expression in lifespan determination. Cell Cycle. 2007; 6:1574-1578.

118. Pan Y, Shadel GS. Extension of chronological life span by reduced TOR signaling requires down-regulation of Sch9p and involves increased mitochondrial OXPHOS complex density. Aging (Albany NY). 2009; 1:131-145.

119. Wei M, Fabrizio P, Madia F, Hu J, Ge H, Li LM, Longo VD. Tor1/Sch9-regulated carbon source substitution is as effective as calorie restriction in life span extension. PLoS Genet. 2009; 5: e1000467.

120. Mesquita A, Weinberger M, Silva A, Sampaio-Marques B, Almeida B, Leão C, Costa V, Rodrigues F, Burhans WC, Ludovico P. Caloric restriction or catalase inactivation extends yeast chronological lifespan by inducing H2O2 and superoxide dismutase activity. Proc Natl Acad Sci USA. 2010; 107:15123-81512.

121. Pan Y. Mitochondria, reactive oxygen species, and chronological aging: a message from yeast. Exp Gerontol. 2011; 46:847-852.

122. Pan Y, Schroeder EA, Ocampo A, Barrientos A, Shadel GS. Regulation of yeast chronological life span by TORC1 via adaptive mitochondrial ROS signaling. Cell Metab. 2011; 13:668-678.

123. Beach A, Burstein MT, Richard VR, Leonov A, Levy S, Titorenko VI. Integration of peroxisomes into an endomembrane system that governs cellular aging. Front Physiol. 2012; 3: 4.

124. Cai L, Tu BP. Driving the cell cycle through metabolism. Annu Rev Cell Dev Biol. 2012; 28:59-87.

125. Ocampo A, Liu J, Schroeder EA, Shadel GS, Barrientos A. Mitochondrial respiratory thresholds regulate yeast chronological life span and its extension by caloric restriction. Cell Metab. 2012; 16:55-67.

126. Barral Y. A new answer to old questions. Elife. 2013; 2: e00515.

127. Beach A, Titorenko VI. Essential roles of peroxisomally produced and metabolized biomolecules in regulating yeast longevity. Subcell Biochem. 2013; 69:050--167.

128. Brandes N, Tienson H, Lindemann A, Vitvitsky V, Reichmann D, Banerjee R, Jakob U. Timeline of redox events in aging postmitotic cells. Elife. 2013; 2: e00306.

129. Hachinohe M, Yamane M, Akazawa D, Ohsawa K, Ohno M, Terashita Y, Masumoto H. A reduction in age-enhanced gluconeogenesis extends lifespan. PLoS One. 2013; 8: e54011.

130. Mirisola MG, Longo VD. A radical signal activates the epigenetic regulation of longevity. Cell Metab. 2013; 17:812-813.

131. Orlandi I, Ronzulli R, Casatta N, Vai M. Ethanol and acetate acting as carbon/energy sources negatively affect yeast chronological aging. Oxid Med Cell Longev. 2013; 2013: 802870.

132. Schroeder EA, Raimundo N, Shadel GS. Epigenetic silencing mediates mitochondria stress-induced longevity. Cell Metab. 2013; 17:954-964.

133. Tahara EB, Cunha FM, Basso TO, Della Bianca BE, Gombert AK, Kowaltowski AJ. Calorie restriction hysteretically primes aging Saccharomyces cerevisiae toward more effective oxidative metabolism. PLoS One. 2013; 8: e56388.

134. Martins D, Titorenko VI, English AM. Cells with impaired mitochondrial H2O2 sensing generate less •OH radicals and live longer. Antioxid Redox Signal. 2014; 21:1490-1503.

135. Fabrizio P, Gattazzo C, Battistella L, Wei M, Cheng C, McGrew K, Longo VD. Sir2 blocks extreme life-span extension. Cell. 2005 Nov 18;123(4):655-67.

136. Goldberg AA, Bourque SD, Kyryakov P, Boukh-Viner T, Gregg C, Beach A, Burstein MT, Machkalyan G, Richard V, Rampersad S, Titorenko VI. A novel function of lipid droplets in regulating longevity. Biochem Soc Trans. 2009; 37:1050-1055.

137. Wei M, Fabrizio P, Madia F, Hu J, Ge H, Li LM, Longo VD. Tor1/Sch9-regulated carbon source substitution is as effective as calorie restriction in life span extension. PLoS Genet. 2009; 5: e1000467.

138. Longo VD, Fabrizio P. Chronological aging in Saccharomyces cerevisiae. Subcell Biochem. 2012; 57:101-121.

139. Eisenberg T, Schroeder S, Andryushkova A, Pendl T, Küttner V, Bhukel A, Mariño G, Pietrocola F, Harger A, Zimmermann A, Moustafa T, Sprenger A, Jany E, Büttner S, Carmona-Gutierrez D, Ruckenstuhl C, Ring J, Reichelt W, Schimmel K, Leeb T, Moser C, Schatz S, Kamolz LP, Magnes C, Sinner F, Sedej S, Fröhlich KU, Juhasz G, Pieber TR, Dengjel J, Sigrist SJ, Kroemer G, Madeo F. Nucleocytosolic depletion of the energy metabolite acetyl-coenzyme a stimulates autophagy and prolongs lifespan. Cell Metab. 2014 Mar 4;19(3):431-44.

140. Hu J, Wei M, Mirzaei H, Madia F, Mirisola M, Amparo C, Chagoury S, Kennedy B, Longo VD. Tor-Sch9 deficiency activates catabolism of the ketone body-like acetic acid to promote trehalose accumulation and longevity. Aging Cell. 2014; 13:457-467.

141. Burtner CR, Murakami CJ, Kaeberlein M. A genomic approach to yeast chronological aging. Methods Mol Biol. 2009; 548:101-114.

142. Longo VD, Fabrizio P. Chronological aging in Saccharomyces cerevisiae. Subcell Biochem. 2012; 57:101-121.

143. Fraenkel DG (2011). Yeast intermediary metabolism. Cold Spring Harbor Laboratory Press, Cold Spring Harbor.

144. Crespo JL, Powers T, Fowler B, Hall MN. The TOR-controlled transcription activators GLN3, RTG1, and RTG3 are regulated in response to intracellular levels of glutamine. Proc Natl Acad Sci USA. 2002; 99:6784-6789.

145. Jewell JL, Russell RC, Guan KL. Amino acid signalling upstream of mTOR. Nat Rev Mol Cell Biol. 2013; 14:133-139.

146. Shimobayashi M, Hall MN. Making new contacts: the mTOR network in metabolism and signalling crosstalk. Nat Rev Mol Cell Biol. 2014; 15:155-162.

147. Singer MA, Lindquist S. Multiple effects of trehalose on protein folding in vitro and in vivo. Mol Cell. 1998; 1:639-648.

148. Singer MA, Lindquist S. Thermotolerance in Saccharomyces cerevisiae: the Yin and Yang of trehalose. Trends Biotechnol. 1998; 16:460-468.

149. Benaroudj N, Lee DH, Goldberg AL. Trehalose accumulation during cellular stress protects cells and cellular proteins from damage by oxygen radicals. J Biol Chem. 2001; 276:24261-24267.

150. Elbein AD, Pan YT, Pastuszak I, Carroll D. New insights on trehalose: a multifunctional molecule. Glycobiology. 2003; 13:17R-27R.

151. Jain NK, Roy I. Effect of trehalose on protein structure. Protein Sci. 2009; 18:24-36.

152. Chen B, Retzlaff M, Roos T, Frydman J. Cellular strategies of protein quality control. Cold Spring Harb Perspect Biol. 2011; 3: a004374.

153. Lindquist SL, Kelly JW. Chemical and biological approaches for adapting proteostasis to ameliorate protein misfolding and aggregation diseases: progress and prognosis. Cold Spring Harb Perspect Biol. 2011; 3: a004507.

154. Taylor RC, Dillin A. Aging as an event of proteostasis collapse. Cold Spring Harb Perspect Biol. 2011; 3: a004440.

155. Kim YE, Hipp MS, Bracher A, Hayer-Hartl M, Hartl FU. Molecular chaperone functions in protein folding and proteostasis. Annu Rev Biochem. 2013; 82:323-355.

156. Piper PW, Harris NL, MacLean M. Preadaptation to efficient respiratory maintenance is essential both for maximal longevity and the retention of replicative potential in chronologically ageing yeast. Mech Ageing Dev. 2006; 127:733-740.

157. Lavoie H, Whiteway M. Increased respiration in the sch9Delta mutant is required for increasing chronological life span but not replicative life span. Eukaryot Cell. 2008; 7:1127-1135.

158. Schroeder EA, Shadel GS. Crosstalk between mitochondrial stress signals regulates yeast chronological lifespan. Mech Ageing Dev. 2014; 135:41-49.

159 Kawałek A, Lefevre SD, Veenhuis M, van der Klei IJ. Peroxisomal catalase deficiency modulates yeast lifespan depending on growth conditions. Aging (Albany NY). 2013; 5:67-83.

160. Lefevre SD, van Roermund CW, Wanders RJ, Veenhuis M, van der Klei IJ. The significance of peroxisome function in chronological aging of Saccharomyces cerevisiae. Aging Cell. 2013; 12:784-793.

161. Sheibani S, Richard VR, Beach A, Leonov A, Feldman R, Mattie S, Khelghatybana L, Piano A, Greenwood M, Vali H, Titorenko VI. Macromitophagy, neutral lipids synthesis, and peroxisomal fatty acid oxidation protect yeast from "liponecrosis", a previously unknown form of programmed cell death. Cell Cycle. 2014; 13:138-147.

162. Orzechowski Westholm J, Tronnersjö S, Nordberg N, Olsson I, Komorowski J, Ronne H. Gis1 and Rph1 regulate glycerol and acetate metabolism in glucose depleted yeast cells. PLoS One. 2012; 7: e31577.

163. Ma C, Agrawal G, Subramani S. Peroxisome assembly: matrix and membrane protein biogenesis. J Cell Biol. 2011; 193:7-16.

164. Liu X, Ma C, Subramani S. Recent advances in peroxisomal matrix protein import. Curr Opin Cell Biol. 2012; 24:484-489.

165. Hasan S, Platta HW, Erdmann R. Import of proteins into the peroxisomal matrix. Front Physiol. 2013; 4: 261.

166. Legakis JE, Koepke JI, Jedeszko C, Barlaskar F, Terlecky LJ, Edwards HJ, Walton PA, Terlecky SR. Peroxisome senescence in human fibroblasts. Mol Biol Cell. 2002; 13:4243-4255.

167. Terlecky SR, Koepke JI, Walton PA. Peroxisomes and aging. Biochim Biophys Acta. 2006; 1763:1749-1754.

168. Ivashchenko O, Van Veldhoven PP, Brees C, Ho YS, Terlecky SR, Fransen M. Intraperoxisomal redox balance in mammalian cells: oxidative stress and interorganellar cross-talk. Mol Biol Cell. 2011; 22:1440-1451.

169. Islinger M, Grille S, Fahimi HD, Schrader M. The peroxisome: an update on mysteries. Histochem Cell Biol. 2012; 137:547-574.

170. Walton PA, Pizzitelli M. Effects of peroxisomal catalase inhibition on mitochondrial function. Front Physiol. 2012; 3: 108.

171. Wang B, Van Veldhoven PP, Brees C, Rubio N, Nordgren M, Apanasets O, Kunze M, Baes M, Agostinis P, Fransen M. Mitochondria are targets for peroxisome-derived oxidative stress in cultured mammalian cells. Free Radic Biol Med. 2013; 65:882-894.

172. Nordgren M, Fransen M. Peroxisomal metabolism and oxidative stress. Biochimie. 2014; 98:56-62.

173. Titorenko VI, Rachubinski RA. The peroxisome: orchestrating important developmental decisions from inside the cell. J Cell Biol. 2004; 164:641-645.

174. Hiltunen JK, Mursula AM, Rottensteiner H, Wierenga RK, Kastaniotis AJ, Gurvitz A. The biochemistry of peroxisomal beta-oxidation in the yeast Saccharomyces cerevisiae. FEMS Microbiol Rev. 2003; 27:35-64.

175. Minois N. Molecular basis of the 'anti-aging' effect of spermidine and other natural polyamines - a mini-review. Gerontology. 2014; 60:319-326.

176. Morselli E, Mariño G, Bennetzen MV, Eisenberg T, Megalou E, Schroeder S, Cabrera S, Bénit P, Rustin P, Criollo A, Kepp O, Galluzzi L, Shen S, Malik SA, Maiuri MC, Horio Y, López-Otín C, Andersen JS, Tavernarakis N, Madeo F, Kroemer G. Spermidine and resveratrol induce autophagy by distinct pathways converging on the acetylproteome. J Cell Biol. 2011; 192:615-629.

177. Binns D, Januszewski T, Chen Y, Hill J, Markin VS, Zhao Y, Gilpin C, Chapman KD, Anderson RG, Goodman JM. An intimate collaboration between peroxisomes and lipid bodies. J Cell Biol. 2006; 173:719-731.

178. D'Autréaux B, Toledano MB. ROS as signalling molecules: mechanisms that generate specificity in ROS homeostasis. Nat Rev Mol Cell Biol. 2007; 8:813-824.

179. Giorgio M, Trinei M, Migliaccio E, Pelicci PG. Hydrogen peroxide: a metabolic by-product or a common mediator of ageing signals? Nat Rev Mol Cell Biol. 2007; 8:722-728.

180. Veal EA, Day AM, Morgan BA. Hydrogen peroxide sensing and signaling. Mol Cell. 2007; 26:1-14.

181. Goodman JM. The gregarious lipid droplet. J Biol Chem. 2008; 283:28005-28009.

182. Adeyo O, Horn PJ, Lee S, Binns DD, Chandrahas A, Chapman KD, Goodman JM. The yeast lipin orthologue Pah1p is important for biogenesis of lipid droplets. J Cell Biol. 2011; 192:1043-1055.

183. Kohlwein SD, Veenhuis M, van der Klei IJ. Lipid droplets and peroxisomes: key players in cellular lipid homeostasis or a matter of fat - store 'em up or burn 'em down. Genetics. 2013; 193:1-50.

184. van der Klei IJ, Yurimoto H, Sakai Y, Veenhuis M. The significance of peroxisomes in methanol metabolism in methylotrophic yeast. Biochim Biophys Acta. 2006; 1763:1453-1462.

185. Beach A, Leonov A, Arlia-Ciommo A, Svistkova V, Lutchman V, Titorenko VI. Mechanisms by which different functional states of mitochondria define yeast longevity. Int J Mol Sci. 2015; 16:5528-5554.

186. Epstein CB, Waddle JA, Hale W 4th, Davé V, Thornton J, Macatee TL, Garner HR, Butow RA. Genome-wide responses to mitochondrial dysfunction. Mol Biol Cell. 2001; 12:297-308.

187. Traven A, Wong JM, Xu D, Sopta M, Ingles CJ. Interorganellar communication. Altered nuclear gene expression profiles in a yeast mitochondrial DNA mutant. J Biol Chem. 2001; 276:4020-4027.

188. Martínez-Pastor MT, Marchler G, Schüller C, Marchler-Bauer A, Ruis H, Estruch F. The Saccharomyces cerevisiae zinc finger proteins Msn2p and Msn4p are required for transcriptional induction through the stress response element (STRE). EMBO J. 1996; 15:2227-2235.

189. Schmitt AP, McEntee K. Msn2p, a zinc finger DNA-binding protein, is the transcriptional activator of the multistress response in Saccharomyces cerevisiae. Proc Natl Acad Sci USA. 1996; 93:5777-5782.

190. Boy-Marcotte E, Perrot M, Bussereau F, Boucherie H, Jacquet M. Msn2p and Msn4p control a large number of genes induced at the diauxic transition which are repressed by cyclic AMP in Saccharomyces cerevisiae. J Bacteriol. 1998; 180:1044-1052.

191. Causton HC, Ren B, Koh SS, Harbison CT, Kanin E, Jennings EG, Lee TI, True HL, Lander ES, Young RA. Remodeling of yeast genome expression in response to environmental changes. Mol Biol Cell. 2001; 12:323-337.

192. Hinnebusch AG. Translational regulation of GCN4 and the general amino acid control of yeast. Annu Rev Microbiol. 2005; 59:407-450.

193. Huber A, Bodenmiller B, Uotila A, Stahl M, Wanka S, Gerrits B, Aebersold R, Loewith R. Characterization of the rapamycin-sensitive phosphoproteome reveals that Sch9 is a central coordinator of protein synthesis. Genes Dev. 2009; 23:1929-1943.

194. Eltschinger S, Loewith R. TOR complexes and the maintenance of cellular homeostasis. Trends Cell Biol. 2016; 26:148-159.

195. Roelants FM, Torrance PD, Thorner J. Differential roles of PDK1- and PDK2-phosphorylation sites in the yeast AGC kinases Ypk1, Pkc1 and Sch9. Microbiology. 2004; 150: 3289-3304.

196. Liu K, Zhang X, Lester RL, Dickson RC. The sphingoid long chain base phytosphingosine activates AGC-type protein kinases in Saccharomyces cerevisiae including Ypk1, Ypk2, and Sch9. J Biol Chem. 2005; 280:22679-22687.

197. Wanke V, Cameroni E, Uotila A, Piccolis M, Urban J, Loewith R, De Virgilio C. Caffeine extends yeast lifespan by targeting TORC1. Mol Microbiol. 2008; 69:277-285.

198. Swinnen E, Ghillebert R, Wilms T, Winderickx J. Molecular mechanisms linking the evolutionary conserved TORC1-Sch9 nutrient signalling branch to lifespan regulation in Saccharomyces cerevisiae. FEMS Yeast Res. 2014; 14:17-32.

199. Lee P, Cho BR, Joo HS, Hahn JS. Yeast Yak1 kinase, a bridge between PKA and stress-responsive transcription factors, Hsf1 and Msn2/Msn4. Mol Microbiol. 2008; 70:882-895.

200. Johnson JE, Johnson FB. Methionine restriction activates the retrograde response and confers both stress tolerance and lifespan extension to yeast, mouse and human cells. PLoS One. 2014; 9: e97729.

201. Laplante M, Sabatini DM. mTOR signaling in growth control and disease. Cell. 2012; 149:274-293.

202. Yorimitsu T, Zaman S, Broach JR, Klionsky DJ. Protein kinase A and Sch9 cooperatively regulate induction of autophagy in Saccharomyces cerevisiae. Mol Biol Cell. 2007; 18:4180-4189.

203. Stephan JS, Yeh YY, Ramachandran V, Deminoff SJ, Herman PK. The Tor and PKA signaling pathways independently target the Atg1/Atg13 protein kinase complex to control autophagy. Proc Natl Acad Sci USA. 2009; 106:17049-1054.

204. Stephan, J. S., Yeh, Y. Y., Ramachandran, V., Deminoff, S. J., and Herman, P. K. (2010). The Tor and cAMP-dependent protein kinase signaling pathways coordinately control autophagy in Saccharomyces cerevisiae. Autophagy 6, 294–295.

205. Ruckenstuhl C, Netzberger C, Entfellner I, Carmona-Gutierrez D, Kickenweiz T, Stekovic S, Gleixner C, Schmid C, Klug L, Sorgo AG, Eisenberg T, Büttner S, Mariño G, Koziel R, Jansen-Dürr P, Fröhlich KU, Kroemer G, Madeo F. Lifespan extension by methionine restriction requires autophagy-dependent vacuolar acidification. PLoS Genet. 2014; 10: e1004347.

206. Wu Z, Song L, Liu SQ, Huang D. Independent and additive effects of glutamic acid and methionine on yeast longevity. PLoS One. 2013; 8: e79319.

207. Madeo F, Tavernarakis N, Kroemer G. Can autophagy promote longevity? Nat Cell Biol. 2010; 12:842-846.

208. Schroeder S, Pendl T, Zimmermann A, Eisenberg T, Carmona-Gutierrez D, Ruckenstuhl C, Mariño G, Pietrocola F, Harger A, Magnes C, Sinner F, Pieber TR, Dengjel J, Sigrist SJ, Kroemer G, Madeo F. Acetyl-coenzyme A: a metabolic master regulator of autophagy and longevity. Autophagy. 2014; 10:1335-1337.

209. Arlia-Ciommo A, Svistkova V, Mohtashami S, Titorenko VI. A novel approach to the discovery of anti-tumor pharmaceuticals: searching for activators of liponecrosis. Oncotarget. 2016; 7:5204-5225.

210. Richard VR, Beach A, Piano A, Leonov A, Feldman R, Burstein MT, Kyryakov P, Gomez-Perez A, Arlia-Ciommo A, Baptista S, Campbell C, Goncharov D, Pannu S, Patrinos D, Sadri B, Svistkova V, Victor A, Titorenko VI. Mechanism of liponecrosis, a distinct mode of programmed cell death. Cell Cycle. 2014; 13:3707-3726.

211. Harborne JR. Introduction to ecological biochemistry, 4th edition. Elsevier Inc., London, 1993.

212. Gershenzon J. The cost of plant chemical defense against herbivory: a biochemical perspective. In: Insect-plant interactions. Bernays EA (ed.). CRC Press, Boca Raton, 1994; pp. 105-173.

213. Reymond P, Weber H, Damond M, Farmer EE. Differential gene expression in response to mechanical wounding and insect feeding in Arabidopsis. Plant Cell. 2000; 12:707-720.

214. Hermsmeier D, Schittko U, Baldwin IT. Molecular interactions between the specialist herbivore Manduca sexta (Lepidoptera, Sphingidae) and its natural host Nicotiana attenuata. I. Large-scale changes in the accumulation of growth- and defense-related plant mRNAs. Plant Physiol. 2001; 125:683-700.

215. Strobel G, Daisy B, Castillo U, Harper J. Natural products from endophytic microorganisms. J Nat Prod. 2004; 67:257-268.

216. Verma VC, Kharwar RN, Strobel GA. Chemical and functional diversity of natural products from plant associated endophytic fungi. Nat Prod Commun. 2009; 4:1511-1532.

217. Yu H, Zhang L, Li L, Zheng C, Guo L, Li W, Sun P, Qin L. Recent developments and future prospects of antimicrobial metabolites produced by endophytes. Microbiol Res. 2010; 165:437-449.

218. Kennedy DO, Wightman EL. Herbal extracts and phytochemicals: plant secondary metabolites and the enhancement of human brain function. Adv Nutr. 2011; 2:32-50.

219. Bascom-Slack CA, Arnold AE, Strobel SA. IBI series winner. Student-directed discovery of the plant microbiome and its products. Science. 2012; 338:485-486.

220. Aly AH, Debbab A, Proksch P. Fungal endophytes - secret producers of bioactive plant metabolites. Pharmazie. 2013; 68:499-505.

221. Mousa WK, Raizada MN. The diversity of anti-microbial secondary metabolites produced by fungal endophytes: an interdisciplinary perspective. Front Microbiol. 2013; 4: 65.

222. Hansen BG, Halkier BA. New insight into the biosynthesis and regulation of indole compounds in Arabidopsis thaliana. Planta. 2005; 221:603-606.

223. Hooper PL, Hooper PL, Tytell M, Vígh L. Xenohormesis: health benefits from an eon of plant stress response evolution. Cell Stress Chaperones. 2010; 15:761-770.

224. Higdon J, Drake VJ. An evidence-based approach to phytochemicals and other dietary factors, 2nd ed. Thieme, New York, 2012.

225. Menendez JA, Joven J, Aragonès G, Barrajón-Catalán E, Beltrán-Debón R, Borrás-Linares I, Camps J, Corominas-Faja B, Cufí S, Fernández-Arroyo S, Garcia-Heredia A, Hernández-Aguilera A, Herranz-López M, Jiménez-Sánchez C, López-Bonet E, Lozano-Sánchez J, Luciano-Mateo F, Martin-Castillo B, Martin-Paredero V, Pérez-Sánchez A, Oliveras-Ferraros C, Riera-Borrull M, Rodríguez-Gallego E, Quirantes-Piné R, Rull A, Tomás-Menor L, Vazquez-Martin A, Alonso-Villaverde C, Micol V, Segura-Carretero A. Xenohormetic and anti-aging activity of secoiridoid polyphenols present in extra virgin olive oil: a new family of gerosuppressant agents. Cell Cycle. 2013; 12:555-578.

226. Si H, Liu D. Dietary antiaging phytochemicals and mechanisms associated with prolonged survival. J Nutr Biochem. 2014; 25:581-591.

227. Wu Z, Song L, Liu SQ, Huang D. Tanshinones extend chronological lifespan in budding yeast Saccharomyces cerevisiae. Appl Microbiol Biotechnol. 2014; 98:8617-8628.

228. Somani SJ, Modi KP, Majumdar AS, Sadarani BN. Phytochemicals and their potential usefulness in inflammatory bowel disease. Phytother Res. 2015; 29:339-350.

229. Wink M. Evolution of secondary metabolites from an ecological and molecular phylogenetic perspective. Phytochemistry. 2003; 64:3-19.

230. Tahara S. A journey of twenty-five years through the ecological biochemistry of flavonoids. Biosci Biotechnol Biochem. 2007; 71:1387-1404.

231. Murakami A. Modulation of protein quality control systems by food phytochemicals. J Clin Biochem Nutr. 2013; 52:215-227.

232. Adrian M, Jeandet P, Veneau J, Weston LA, Bessis R. Biological activity of resveratrol, a stilbenic compound from grapevines, against Botrytis cinerea, the causal agent for gray mold. J Chem Ecol. 1997; 23:1689-1702.

233. Heath MC. Hypersensitive response-related death. Plant Mol Biol. 2000; 44:321-334.

234. Trewavas A, Stewart D. Paradoxical effects of chemicals in the diet on health. Curr Opin Plant Biol. 2003; 6:185-190.

235. Arimura G, Kost C, Boland W. Herbivore-induced, indirect plant defences. Biochim Biophys Acta. 2005; 1734:91-111.

236. Brencic A, Winans SC. Detection of and response to signals involved in host-microbe interactions by plant-associated bacteria. Microbiol Mol Biol Rev. 2005; 69:155-194.

237. Mattson MP, Son TG, Camandola S. Viewpoint: mechanisms of action and therapeutic potential of neurohormetic phytochemicals. Dose Response. 2007; 5:174-186.

238. Santiago R, Malvar RA. Role of dehydrodiferulates in maize resistance to pests and diseases. Int J Mol Sci. 2010; 11:691-703.

239. Tang K, Zhan JC, Yang HR, Huang WD. Changes of resveratrol and antioxidant enzymes during UV-induced plant defense response in peanut seedlings. J Plant Physiol. 2010; 167:95-102.

240. Arimura G, Ozawa R, Maffei ME. Recent advances in plant early signaling in response to herbivory. Int J Mol Sci. 2011; 12:3723-3739.

241. Barros-Rios J, Malvar RA, Jung HJ, Santiago R. Cell wall composition as a maize defense mechanism against corn borers. Phytochemistry. 2011; 72:365-371.

242. Bednarek P. Sulfur-containing secondary metabolites from Arabidopsis thaliana and other Brassicaceae with function in plant immunity. Chembiochem. 2012; 13:1846-1859.

243. Nwachukwu ID, Slusarenko AJ, Gruhlke MC. Sulfur and sulfur compounds in plant defence. Nat Prod Commun. 2012; 7:395-400.

244. Huot OB, Nachappa P, Tamborindeguy C. The evolutionary strategies of plant defenses have a dynamic impact on the adaptations and interactions of vectors and pathogens. Insect Sci. 2013; 20:297-306.

245. Kazan K, Lyons R. Intervention of Phytohormone Pathways by Pathogen Effectors. Plant Cell. 2014; 26:2285-2309.

246. Porras-Alfaro A, Bayman P. Hidden fungi, emergent properties: endophytes and microbiomes. Annu Rev Phytopathol. 2011; 49:291-315.

247. Zhao J, Shan T, Mou Y, Zhou L. Plant-derived bioactive compounds produced by endophytic fungi. Mini Rev Med Chem. 2011; 11:159-168.

248. Kusari S, Hertweck C, Spiteller M. Chemical ecology of endophytic fungi: origins of secondary metabolites. Chem Biol. 2012; 19:792-798.

249. Nath A, Raghunatha P, Joshi SR. Diversity and Biological Activities of Endophytic Fungi of Emblica officinalis, an Ethnomedicinal Plant of India. Mycobiology. 2012; 40:8-13.

250. Zhang Y, Han T, Ming Q, Wu L, Rahman K, Qin L. Alkaloids produced by endophytic fungi: a review. Nat Prod Commun. 2012; 7:963-968.

251. Lebeis SL. The potential for give and take in plant-microbiome relationships. Front Plant Sci. 2014; 5: 287.

252. Harikumar KB, Aggarwal BB. Resveratrol: a multitargeted agent for age-associated chronic diseases. Cell Cycle. 2008; 7:1020-1035.

253. Son TG, Camandola S, Mattson MP. Hormetic dietary phytochemicals. Neuromolecular Med. 2008; 10:236-246.

254. Calabrese V, Cornelius C, Dinkova-Kostova AT, Iavicoli I, Di Paola R, Koverech A, Cuzzocrea S, Rizzarelli E, Calabrese EJ. Cellular stress responses, hormetic phytochemicals and vitagenes in aging and longevity. Biochim Biophys Acta. 2012; 1822:753-783.

255. Dong Y, Guha S, Sun X, Cao M, Wang X, Zou S. Nutraceutical interventions for promoting healthy aging in invertebrate models. Oxid Med Cell Longev. 2012; 2012: 718491.

256. Lamming DW, Sabatini DM, Baur JA. Pharmacologic Means of Extending Lifespan. J Clin Exp Pathol. 2012; Suppl 4: 7327.

257. Vauzour D. Dietary polyphenols as modulators of brain functions: biological actions and molecular mechanisms underpinning their beneficial effects. Oxid Med Cell Longev. 2012; 2012: 914273.

258. Argyropoulou A, Aligiannis N, Trougakos IP, Skaltsounis AL. Natural compounds with anti-ageing activity. Nat Prod Rep. 2013; 30:1412-1437.

259. Lee JH, Khor TO, Shu L, Su ZY, Fuentes F, Kong AN. Dietary phytochemicals and cancer prevention: Nrf2 signaling, epigenetics, and cell death mechanisms in blocking cancer initiation and progression. Pharmacol Ther. 2013; 137:153-171.

260. Lucanic M, Lithgow GJ, Alavez S. Pharmacological lifespan extension of invertebrates. Ageing Res Rev. 2013; 12:445-458.

261. Monroy A, Lithgow GJ, Alavez S. Curcumin and neurodegenerative diseases. Biofactors. 2013; 39:122-132.

262. de Cabo R, Carmona-Gutierrez D, Bernier M, Hall MN, Madeo F. The search for antiaging interventions: from elixirs to fasting regimens. Cell. 2014; 157:1515-1526.

263. Grabacka MM, Gawin M, Pierzchalska M. Phytochemical modulators of mitochondria: the search for chemopreventive agents and supportive therapeutics. Pharmaceuticals (Basel). 2014; 7:913-942.

264. Hubbard BP, Sinclair DA. Small molecule SIRT1 activators for the treatment of aging and age-related diseases. Trends Pharmacol Sci. 2014; 35:146-154.

265. Kennedy DO. Polyphenols and the human brain: plant “secondary metabolite” ecologic roles and endogenous signaling functions drive benefits. Adv Nutr. 2014; 5:515-533.

266. Koch K, Havermann S, Büchter C, Wätjen W. Caenorhabditis elegans as model system in pharmacology and toxicology: effects of flavonoids on redox-sensitive signalling pathways and ageing. ScientificWorldJournal. 2014; 2014: 920398.

267. Lee J, Jo DG, Park D, Chung HY, Mattson MP. Adaptive cellular stress pathways as therapeutic targets of dietary phytochemicals: focus on the nervous system. Pharmacol Rev. 2014; 66:815-868.

268. Mansuri ML, Parihar P, Solanki I, Parihar MS. Flavonoids in modulation of cell survival signalling pathways. Genes Nutr. 2014; 9: 400.

269. Rege SD, Geetha T, Griffin GD, Broderick TL, Babu JR. Neuroprotective effects of resveratrol in Alzheimer disease pathology. Front Aging Neurosci. 2014; 6: 218.

270. Hubbard BP, Sinclair DA. Small molecule SIRT1 activators for the treatment of aging and age-related diseases. Trends Pharmacol Sci. 2014; 35:146-154.

271. Howitz KT, Bitterman KJ, Cohen HY, Lamming DW, Lavu S, Wood JG, Zipkin RE, Chung P, Kisielewski A, Zhang LL, Scherer B, Sinclair DA. Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan. Nature. 2003; 425:191-196.

272. Xiang L, Sun K, Lu J, Weng Y, Taoka A, Sakagami Y, Qi J. Anti-aging effects of phloridzin, an apple polyphenol, on yeast via the SOD and Sir2 genes. Biosci Biotechnol Biochem. 2011; 75:854-858.

273. Belinha I, Amorim MA, Rodrigues P, de Freitas V, Moradas-Ferreira P, Mateus N, Costa V. Quercetin increases oxidative stress resistance and longevity in Saccharomyces cerevisiae. J Agric Food Chem. 2007; 55:2446-2451.

274. Yuan R, Lin Y. Traditional Chinese medicine: an approach to scientific proof and clinical validation. Pharmacol Ther. 2000; 86:191-198.

275. Tang JL, Liu BY, Ma KW. Traditional Chinese medicine. Lancet. 2008; 372:1938-1940.

276. Xu Z. Modernization: one step at a time. Nature. 2011; 480: S90-S92.

277. Hao C, Xiao PG. Network pharmacology: a Rosetta Stone for traditional Chinese medicine. Drug Dev Res. 2014; 75:299-312.

278. Buriani A, Garcia-Bermejo ML, Bosisio E, Xu Q, Li H, Dong X, Simmonds MS, Carrara M, Tejedor N, Lucio-Cazana J, Hylands PJ. Omic techniques in systems biology approaches to traditional Chinese medicine research: present and future. J Ethnopharmacol. 2012; 140:535-544.

279. Uzuner H, Bauer R, Fan TP, Guo DA, Dias A, El-Nezami H, Efferth T, Williamson EM, Heinrich M, Robinson N, Hylands PJ, Hendry BM, Cheng YC, Xu Q. Traditional Chinese medicine research in the post-genomic era: good practice, priorities, challenges and opportunities. J Ethnopharmacol. 2012; 140:458-468.

280. Xue R, Fang Z, Zhang M, Yi Z, Wen C, Shi T. TCMID: traditional Chinese Medicine integrative database for herb molecular mechanism analysis. Nucleic Acids Res. 2013; 41: D1089-D1095.

281. Sánchez-Vidaña DI, Rajwani R, Wong MS. The use of omic technologies applied to traditional Chinese medicine research. Evid Based Complement Alternat Med. 2017; 2017: 6359730.

282. Hopkins AL. Network pharmacology. Nat Biotechnol. 2007; 25:1110-1111.

283. Li S, Zhang ZQ, Wu LJ, Zhang XG, Li YD, Wang YY. Understanding ZHENG in traditional Chinese medicine in the context of neuro-endocrine-immune network. IET Syst Biol. 2007; 1:51-60.

284. Li S, Zhang B. Traditional Chinese medicine network pharmacology: theory, methodology and application. Chin J Nat Med. 2013; 11:110-120.

285. Tao W, Xu X, Wang X, Li B, Wang Y, Li Y, Yang L. Network pharmacology-based prediction of the active ingredients and potential targets of Chinese herbal Radix Curcumae formula for application to cardiovascular disease. J Ethnopharmacol. 2013; 145:1-10.

286. Liang X, Li H, Li S. A novel network pharmacology approach to analyse traditional herbal formulae: the Liu-Wei-Di-Huang pill as a case study. Mol Biosyst. 2014; 10:1014-1022.

287. Tang F, Tang Q, Tian Y, Fan Q, Huang Y, Tan X. Network pharmacology-based prediction of the active ingredients and potential targets of Mahuang Fuzi Xixin decoction for application to allergic rhinitis. J Ethnopharmacol. 2015; 176:402-412.

288. Li S. Exploring traditional Chinese medicine by a novel therapeutic concept of network target. Chin J Integr Med. 2016; 22:647-552.

289. Fang J, Wang L, Wu T, Yang C, Gao L, Cai H, Liu J, Fang S, Chen Y, Tan W, Wang Q. Network pharmacology-based study on the mechanism of action for herbal medicines in Alzheimer treatment. J Ethnopharmacol. 2017; 196:281-292.

290. Zeng L, Yang K. Exploring the pharmacological mechanism of Yanghe Decoction on HER2-positive breast cancer by a network pharmacology approach. J Ethnopharmacol. 2017; 199:68-85.

291. Chen L, Cao Y, Zhang H, Lv D, Zhao Y, Liu Y, Ye G, Chai Y. Network pharmacology-based strategy for predicting active ingredients and potential targets of Yangxinshi tablet for treating heart failure. J Ethnopharmacol. 2018; 219:359-368.

292. Zuo H, Zhang Q, Su S, Chen Q, Yang F, Hu Y. A network pharmacology-based approach to analyse potential targets of traditional herbal formulas: an example of Yu Ping Feng decoction. Sci Rep. 2018; 8: 11418.

293. Ding F, Zhang Q, Ung CO, Wang Y, Han Y, Hu Y, Qi J. An analysis of chemical ingredients network of Chinese herbal formulae for the treatment of coronary heart disease. PLoS One. 2015; 10: e0116441.

294. Liang H, Ruan H, Ouyang Q, Lai L. Herb-target interaction network analysis helps to disclose molecular mechanism of traditional Chinese medicine. Sci Rep. 2016; 6: 36767.

295. Zhang Y, Mao X, Su J, Geng Y, Guo R, Tang S, Li J, Xiao X, Xu H, Yang H. A network pharmacology-based strategy deciphers the underlying molecular mechanisms of Qixuehe Capsule in the treatment of menstrual disorders. Chin Med. 2017; 12: 23.

296. Borisy AA, Elliott PJ, Hurst NW, Lee MS, Lehar J, Price ER, Serbedzija G, Zimmermann GR, Foley MA, Stockwell BR, Keith CT. Systematic discovery of multicomponent therapeutics. Proc Natl Acad Sci U S A. 2003; 100:7977-7982.

297. Csermely P, Agoston V, Pongor S. The efficiency of multi-target drugs: the network approach might help drug design. Trends Pharmacol Sci. 2005; 26:178-182.

298. Keith CT, Borisy AA, Stockwell BR. Multicomponent therapeutics for networked systems. Nat Rev Drug Discov. 2005; 4:71-78.

299. Smalley KS, Haass NK, Brafford PA, Lioni M, Flaherty KT, Herlyn M. Multiple signaling pathways must be targeted to overcome drug resistance in cell lines derived from melanoma metastases. Mol Cancer Ther. 2006; 5:1136-1144.

300. Kitano H. A robustness-based approach to systems-oriented drug design. Nat Rev Drug Discov. 2007; 6:202-210.

301. Zimmermann GR, Lehár J, Keith CT. Multi-target therapeutics: when the whole is greater than the sum of the parts. Drug Discov Today. 2007; 12:34-42.

302. Lehár J, Stockwell BR, Giaever G, Nislow C. Combination chemical genetics. Nat Chem Biol. 2008; 4:674-681.

303. Podolsky SH, Greene JA. Combination drugs—hype, harm, and hope. N Engl J Med. 2011; 365:488-491.

304. Csermely P, Korcsmáros T, Kiss HJ, London G, Nussinov R. Structure and dynamics of molecular networks: a novel paradigm of drug discovery: a comprehensive review. Pharmacol Ther. 2013; 138:333-408.

305. Baym M, Stone LK, Kishony R. Multidrug evolutionary strategies to reverse antibiotic resistance. Science. 2016; 351: aad3292.

306. He B, Lu C, Zheng G, He X, Wang M, Chen G, Zhang G, Lu A. Combination therapeutics in complex diseases. J Cell Mol Med. 2016; 20:2231-2240.

307. Lopez JS, Banerji U. Combine and conquer: challenges for targeted therapy combinations in early phase trials. Nat Rev Clin Oncol. 2017; 14:57-66.

308. Singh N, Yeh PJ. Suppressive drug combinations and their potential to combat antibiotic resistance. J Antibiot (Tokyo). 2017; 70:1033-1042.

309. Hao T, Wang Q, Zhao L, Wu D, Wang E, Sun J. Analyzing of molecular networks for human diseases and drug discovery. Curr Top Med Chem. 2018; 18:1007-1014.

310. Weiss A, Nowak-Sliwinska P. Current trends in multidrug optimization: an alley of future successful treatment of complex disorders. SLAS Technol. 2017; 22:254-275.

311. Nelson HS. Advair: combination treatment with fluticasone propionate/salmeterol in the treatment of asthma. J Allergy Clin Immunol. 2001; 107:398-416.

312. Glass G. Cardiovascular combinations. Nat Rev Drug Discov. 2004; 3:731-732.

313. Herrick TM, Million RP. Tapping the potential of fixed-dose combinations. Nat Rev Drug Discov. 2007; 6:513-514.

314. Pangalos MN, Schechter LE, Hurko O. Drug development for CNS disorders: strategies for balancing risk and reducing attrition. Nat Rev Drug Discov. 2007; 6:521-532.

315. Kummar S, Chen HX, Wright J, Holbeck S, Millin MD, Tomaszewski J, Zweibel J, Collins J, Doroshow JH. Utilizing targeted cancer therapeutic agents in combination: novel approaches and urgent requirements. Nat Rev Drug Discov. 2010; 9:843-856.

316. Humphrey RW, Brockway-Lunardi LM, Bonk DT, Dohoney KM, Doroshow JH, Meech SJ, Ratain MJ, Topalian SL, Pardoll DM. Opportunities and challenges in the development of experimental drug combinations for cancer. J Natl Cancer Inst. 2011; 103:1222-1226.

317. Casado JL, Bañón S. Dutrebis (lamivudine and raltegravir) for use in combination with other antiretroviral products for the treatment of HIV-1 infection. Expert Rev Clin Pharmacol. 2015; 8:709-718.

318. Horita N, Kaneko T. Role of combined indacaterol and glycopyrronium bromide (QVA149) for the treatment of COPD in Japan. Int J Chron Obstruct Pulmon Dis. 2015; 10:813-822.

319. Yang J, Tang H, Li Y, Zhong R, Wang T, Wong S, Xiao G, Xie Y. DIGRE: drug-induced genomic residual effect model for successful prediction of multidrug effects. CPT Pharmacometrics Syst Pharmacol. 2015; 4: e1.

320. Patel SJ, Kuten SA, Musick WL, Gaber AO, Monsour HP, Knight RJ. Combination drug products for HIV-A word of caution for the transplant clinician. Am J Transplant. 2016; 16:2479-2482.

321. Spitzer M, Robbins N, Wright GD. Combinatorial strategies for combating invasive fungal infections. Virulence. 2017; 8:169-185.

322. Yin Z, Deng Z, Zhao W, Cao Z. Searching synergistic dose combinations for anticancer drugs. Front Pharmacol. 2018; 9: 535.

323. Lehár J, Zimmermann GR, Krueger AS, Molnar RA, Ledell JT, Heilbut AM, Short GF 3rd, Giusti LC, Nolan GP, Magid OA, Lee MS, Borisy AA, Stockwell BR, Keith CT. Chemical combination effects predict connectivity in biological systems. Mol Syst Biol. 2007; 3: 80.

324. Yeh P, Kishony R. Networks from drug-drug surfaces. Mol Syst Biol. 2007; 3: 85.

325. Chou TC. Drug combination studies and their synergy quantification using the Chou-Talalay method. Cancer Res. 2010; 70:440-446.

326. Tallarida RJ. Quantitative methods for assessing drug synergism. Genes Cancer. 2011; 2:1003-1008.

327. Zou J, Ji P, Zhao YL, Li LL, Wei YQ, Chen YZ, Yang SY. Neighbor communities in drug combination networks characterize synergistic effect. Mol Biosyst. 2012; 8:3185-3196.

328. Bansal M, Yang J, Karan C, Menden MP, Costello JC, Tang H, Xiao G, Li Y, Allen J, Zhong R, Chen B, Kim M, Wang T, et al, and NCI-DREAM Community. A community computational challenge to predict the activity of pairs of compounds. Nat Biotechnol. 2014; 32:1213-1222.

329. Foucquier J, Guedj M. Analysis of drug combinations: current methodological landscape. Pharmacol Res Perspect. 2015; 3: e00149.

330. Yadav B, Wennerberg K, Aittokallio T, Tang J. Searching for drug synergy in complex dose-response landscapes using an interaction potency Model. Comput Struct Biotechnol J. 2015; 13:504-513.

331. Li X, Qin G, Yang Q, Chen L, Xie L. Biomolecular network-based synergistic drug combination discovery. Biomed Res Int. 2016; 2016: 8518945.

332. Harman D. The aging process: major risk factor for disease and death. Proc Natl Acad Sci USA. 1991; 88:5360-5363.

333. Blagosklonny MV. Validation of anti-aging drugs by treating age-related diseases. Aging (Albany NY). 2009; 1:281-288.

334. Niccoli T, Partridge L. Ageing as a risk factor for disease. Curr Biol. 2012; 22: R741–R52.

335. Kaeberlein M. Longevity and aging. F1000Prime Rep. 2013; 5: 5.

336. Kaeberlein M. The biology of aging: citizen scientists and their pets as a bridge between research on model organisms and human subjects. Vet Pathol. 2016; 53:291-298.

337. de Cabo R, Carmona-Gutierrez D, Bernier M, Hall MN, Madeo F. The search for antiaging interventions: from elixirs to fasting regimens. Cell. 2014; 157:1515-1526.

338. Kennedy BK, Berger SL, Brunet A, Campisi J, Cuervo AM, Epel ES, Franceschi C, Lithgow GJ, Morimoto RI, Pessin JE, Rando TA, Richardson A, Schadt EE, et al. Geroscience: linking aging to chronic disease. Cell. 2014; 159:709-713.

339. Longo VD, Antebi A, Bartke A, Barzilai N, Brown-Borg HM, Caruso C, Curiel TJ, de Cabo R, Franceschi C, Gems D, Ingram DK, Johnson TE, Kennedy BK, et al. Interventions to slow aging in humans: are we ready? Aging Cell. 2015; 14:497-510.

340. Fontana L, Partridge L, Longo VD. Extending healthy life span—from yeast to humans. Science. 2010; 328:321-326.

341. López-Otín C, Blasco MA, Partridge L, Serrano M, Kroemer G. The hallmarks of aging. Cell. 2013; 153:1194-1217.

342. Carvalhal Marques F, Volovik Y, Cohen E. The roles of cellular and organismal aging in the development of late-onset maladies. Annu Rev Pathol. 2015; 10:1-23.

343. Fontana L, Partridge L. Promoting health and longevity through diet: from model organisms to humans. Cell. 2015; 161:106-118.

344. Mazucanti CH, Cabral-Costa JV, Vasconcelos AR, Andreotti DZ, Scavone C, Kawamoto EM. Longevity pathways (mTOR, SIRT, Insulin/IGF-1) as key modulatory targets on aging and neurodegeneration. Curr Top Med Chem. 2015; 15:2116-2138.

345. Burkewitz K, Weir HJ, Mair WB. AMPK as a Pro-longevity Target. Exp Suppl. 2016; 107:227-256.

346. Pan H, Finkel T. Key proteins and pathways that regulate lifespan. J Biol Chem. 2017; 292:6452-6460.

347. Aliper A, Belikov AV, Garazha A, Jellen L, Artemov A, Suntsova M, Ivanova A, Venkova L, Borisov N, Buzdin A, Mamoshina P, Putin E, Swick AG, et al. In search for geroprotectors: in silico screening and in vitro validation of signalome-level mimetics of young healthy state. Aging (Albany NY). 2016; 8:2127-2152.

348. Moskalev A, Chernyagina E, Tsvetkov V, Fedintsev A, Shaposhnikov M, Krut’ko V, Zhavoronkov A, Kennedy BK. Developing criteria for evaluation of geroprotectors as a key stage toward translation to the clinic. Aging Cell. 2016; 15:407-415.

349. Blagosklonny MV. From rapalogs to anti-aging formula. Oncotarget. 2017; 8:35492-35507.

350. Ladiges W, Liggitt D. Testing drug combinations to slow aging. Pathobiol Aging Age Relat Dis. 2017; 8: 1407203.

351. Blagosklonny MV. Koschei the immortal and anti-aging drugs. Cell Death Dis. 2014; 5: e1552.

352. Strong R, Miller RA, Antebi A, Astle CM, Bogue M, Denzel MS, Fernandez E, Flurkey K, Hamilton KL, Lamming DW, Javors MA, de Magalhães JP, Martinez PA, et al. Longer lifespan in male mice treated with a weakly estrogenic agonist, an antioxidant, an α-glucosidase inhibitor or a Nrf2-inducer. Aging Cell. 2016; 15:872-884.

353. Weiss R, Fernandez E, Liu Y, Strong R, Salmon AB. Metformin reduces glucose intolerance caused by rapamycin treatment in genetically heterogeneous female mice. Aging (Albany NY). 2018; 10:386-401.

354. Danilov A, Shaposhnikov M, Plyusnina E, Kogan V, Fedichev P, Moskalev A. Selective anticancer agents suppress aging in Drosophila. Oncotarget. 2013; 4:1507-1526.

355. Snell TW, Johnston RK, Rabeneck B, Zipperer C, Teat S. Joint inhibition of TOR and JNK pathways interacts to extend the lifespan of Brachionus manjavacas (Rotifera). Exp Gerontol. 2014; 52:55-69.

356. Admasu TD, Chaithanya Batchu K, Barardo D, Ng LF, Lam VY, Xiao L, Cazenave-Gassiot A, Wenk MR, Tolwinski NS, Gruber J. Drug synergy slows aging and improves healthspan through IGF and SREBP lipid signaling. Dev Cell. 2018; 47:67-79.

357. Huang X, Liu J, Withers BR, Samide AJ, Leggas M, Dickson RC. Reducing signs of aging and increasing lifespan by drug synergy. Aging Cell. 2013; 12:652-660.

358. Huang X, Leggas M, Dickson RC. Drug synergy drives conserved pathways to increase fission yeast lifespan. PLoS One. 2015; 10: e0121877.

359. McDonald RB. Biology of aging. Garland Science, Taylor & Francis Group, LLC. 2014; Chapters 1 and 2, Pages 1-54.

360. de Magalhães JP, Cabral JA, Magalhães D. The influence of genes on the aging process of mice: a statistical assessment of the genetics of aging. Genetics. 2005; 169: 265-274.

361. Finch CE. Longevity, senescence, and the genome. University of Chicago Press, Chicago, 1990.

362. Abrams PA. Evolutionary biology: mortality and lifespan. Nature. 2004; 431:1048–1049.

363. Kirkwood TB. Understanding the odd science of aging. Cell. 2005; 120:437–447.

364. Medkour Y, Svistkova V, Titorenko VI. Cell-non-autonomous mechanisms underlying cellular and organismal aging. Int Rev Cell Mol Biol. 2016; 321:259-297.

365. Blagosklonny MV. Answering the ultimate question “what is the proximal cause of aging?” Aging (Albany NY). 2012; 4:861-877.

366. Fries JF, Bruce B, Chakravarty E. Compression of morbidity 1980–2011: a focused review of paradigms and progress. J Aging Res. 2011; 2011: 261702.

367. Gavrilov LA, Gavrilova NS. The biology of life span: a quantitative approach. New York, New York/Chur, Switzerland, Harwood Academic, 1991.

368. Lashmanova E, Proshkina E, Zhikrivetskaya S, Shevchenko O, Marusich E, Leonov S, Melerzanov A, Zhavoronkov A, Moskalev A. Fucoxanthin increases lifespan of Drosophila melanogaster and Caenorhabditis elegans. Pharmacol Res. 2015; 100:228-241.

369. Burstein MT, Beach A, Richard VR, Koupaki O, Gomez-Perez A, Goldberg AA, Kyryakov P, Bourque SD, Glebov A, Titorenko VI. Interspecies chemical signals released into the environment may create xenohormetic, hormetic and cytostatic selective forces that drive the ecosystemic evolution of longevity regulation mechanisms. Dose Response. 2012a; 10:75–82.

370. Calabrese EJ, Mattson MP. Hormesis provides a generalized quantitative estimate of biological plasticity. J Cell Commun Signal. 2011; 5:25–38.

371. Goldberg AA, Kyryakov P, Bourque SD, Titorenko VI. Xenohormetic, hormetic and cytostatic selective forces driving longevity at the ecosystemic level. Aging (Albany NY). 2010b; 2:461–470.

372. Cui H, Kong Y, Zhang H. Oxidative stress, mitochondrial dysfunction, and aging. J Signal Transduct. 2012; 2012: 646354.

373. Ray PD, Huang BW, Tsuji Y. Reactive oxygen species (ROS) homeostasis and redox regulation in cellular signaling. Cell Signal. 2012; 24:981-990.

374. Gladyshev VN. The origin of aging: imperfectness-driven non-random damage defines the aging process and control of lifespan. Trends Genet. 2013; 29:506-512.

375. Gladyshev VN. The free radical theory of aging is dead. Long live the damage theory! Antioxid Redox Signal. 2014; 20:727-731.

376. Ristow M, Schmeisser K. Mitohormesis: Promoting health and lifespan by increased levels of reactive oxygen species (ROS). Dose Response. 2014; 12:288-341.

377. Schieber M, Chandel NS. ROS function in redox signaling and oxidative stress. Curr Biol. 2014; 24: R453-R462.

378. Shadel GS, Horvath TL. Mitochondrial ROS signaling in organismal homeostasis. Cell. 2015; 163:560-569.

379. Wang Y, Hekimi S. Mitochondrial dysfunction and longevity in animals: Untangling the knot. 2015; 350:1204-1207.

380. Gems D, Partridge L. Stress-response hormesis and aging: “that which does not kill us makes us stronger”. Cell Metab. 2008; 7:200-203.

381. Calabrese V, Cornelius C, Cuzzocrea S, Iavicoli I, Rizzarelli E, Calabrese EJ. Hormesis, cellular stress response and vitagenes as critical determinants in aging and longevity. Mol Aspects Med. 2011; 32:279-304.

382. Veal E, Day A. Hydrogen peroxide as a signaling molecule. Antioxid Redox Signal. 2011; 15:147-151.

383. Walther TC, Farese RV Jr. Lipid droplets and cellular lipid metabolism. Annu Rev Biochem. 2012; 81:687–714.

384. Koch B, Schmidt C, Daum G. Storage lipids of yeasts: a survey of nonpolar lipid metabolism in Saccharomyces cerevisiae, Pichia pastoris, and Yarrowia lipolytica. FEMS Microbiol Rev. 2014; 38:892–915.

385. Klug L, Daum G. Yeast lipid metabolism at a glance. FEMS Yeast Res. 2014; 14:369–388.

386. Ohsaki Y, Suzuki M, Fujimoto T. Open questions in lipid droplet biology. Chem Biol. 2014; 21:86–96.

387. Pol A, Gross SP, Parton RG. Review: biogenesis of the multifunctional lipid droplet: lipids, proteins, and sites. J Cell Biol. 2014; 204:635–646.

388. Wang CW. Lipid droplet dynamics in budding yeast. Cell Mol Life Sci. 2015; 72:2677–2695.

389. Blüher M, Kahn BB, Kahn CR. Extended longevity in mice lacking the insulin receptor in adipose tissue. Science. 2003; 299:572–574.

390. Chiu CH, Lin WD, Huang SY, Lee YH. Effect of a C/EBP gene replacement on mitochondrial biogenesis in fat cells. Genes Dev. 2004; 18:1970–1975.

391. Picard F, Kurtev M, Chung N, Topark-Ngarm A, Senawong T, Machado De Oliveira R, Leid M, McBurney MW, Guarente L. Sirt1 promotes fat mobilization in white adipocytes by repressing PPAR-γ. Nature. 2004; 429:771–776.

392. Grönke S, Mildner A, Fellert S, Tennagels N, Petry S, Müller G, Jäckle H, Kühnlein RP. Brummer lipase is an evolutionary conserved fat storage regulator in Drosophila. Cell Metab. 2005; 1:323–330.

393. Haemmerle G, Lass A, Zimmermann R, Gorkiewicz G, Meyer C, Rozman J, Heldmaier G, Maier R, Theussl C, Eder S, Kratky D, Wagner EF, Klingenspor M, et al. Defective lipolysis and altered energy metabolism in mice lacking adipose triglyceride lipase. Science. 2006; 312:734–737.

394. Russell SJ, Kahn CR. Endocrine regulation of ageing. Nat Rev Mol Cell Biol. 2007; 8:681–691.

395. Blüher M. Fat tissue and long life. Obes Facts. 2008; 1:176–182.

396. Wang MC, O’Rourke EJ, Ruvkun G. Fat metabolism links germline stem cells and longevity in C. elegans. Science. 2008; 322:957–960.

397. Narbonne P, Roy R. Caenorhabditis elegans dauers need LKB1/AMPK to ration lipid reserves and ensure long-term survival. Nature. 2009; 457:210–214.

398. Greenberg AS, Coleman RA, Kraemer FB, McManaman JL, Obin MS, Puri V, Yan QW, Miyoshi H, Mashek DG. The role of lipid droplets in metabolic disease in rodents and humans. J Clin Invest. 2011; 121:2102–2110.

399. Zechner R, Zimmermann R, Eichmann TO, Kohlwein SD, Haemmerle G, Lass A, Madeo F. FAT SIGNALS - lipases and lipolysis in lipid metabolism and signaling. Cell Metab. 2012; 15:279–291.

400. Krahmer N, Farese RV Jr, Walther TC. Balancing the fat: lipid droplets and human disease. EMBO Mol Med. 2013; 5:905–915.

401. Rambold AS, Cohen S, Lippincott-Schwartz J. Fatty acid trafficking in starved cells: regulation by lipid droplet lipolysis, autophagy, and mitochondrial fusion dynamics. Dev Cell. 2015; 32:678–692.

402. Welte MA. Expanding roles for lipid droplets. Curr Biol. 2015; 25: R470–R481.

403. Miquel J, Fleming J and Economos AC. Antioxidants, metabolic rate and aging in Drosophila. Arch Gerontol Geriatr. 1982; 1:159-165.

404. Richie JP Jr, Mills BJ and Lang CA. Dietary nordihydroguaiaretic acid increases the life span of the mosquito. Proc Soc Exp Biol Med. 1986; 183:81-85.

405. Wang P, Zhang Z, Ma X, Huang Y, Liu X, Tu P and Tong T. HDTIC-1 and HDTIC-2, two compounds extracted from Astragali Radix, delay replicative senescence of human diploid fibroblasts. Mech Ageing Dev. 2003; 124:1025-1034.

406. Bauer JH, Goupil S, Garber GB and Helfand SL. An accelerated assay for the identification of lifespan-extending interventions in Drosophila melanogaster. Proc Natl Acad Sci USA. 2004; 101:12980-12985.

407. West M, Mhatre M, Ceballos A, Floyd RA, Grammas P, Gabbita SP, Hamdheydari L, Mai T, Mou S, Pye QN, Stewart C, West S, Williamson KS, Zemlan F and Hensley K. The arachidonic acid 5-lipoxygenase inhibitor nordihydroguaiaretic acid inhibits tumor necrosis factor alpha activation of microglia and extends survival of G93A-SOD1 transgenic mice. J Neurochem. 2004; 91:133-143.

408. Wood JG, Rogina B, Lavu S, Howitz K, Helfand SL, Tatar M and Sinclair D. Sirtuin activators mimic caloric restriction and delay ageing in metazoans. Nature. 2004; 430:686-689.

409. Kiaei M, Kipiani K, Petri S, Chen J, Calingasan NY and Beal MF. Celastrol blocks neuronal cell death and extends life in transgenic mouse model of amyotrophic lateral sclerosis. Neurodegener Dis. 2005; 2:246-254.

410. Valenzano DR, Terzibasi E, Genade T, Cattaneo A, Domenici L and Cellerino A. Resveratrol prolongs lifespan and retards the onset of age-related markers in a short-lived vertebrate. Curr Biol. 2006; 16:296-300.

411. Kampkötter A, Gombitang Nkwonkam C, Zurawski RF, Timpel C, Chovolou Y, Wätjen W and Kahl R. Effects of the flavonoids kaempferol and fisetin on thermotolerance, oxidative stress and FoxO transcription factor DAF-16 in the model organism Caenorhabditis elegans. Arch Toxicol. 2007; 81:849-858.

412. Katsiki M, Chondrogianni N, Chinou I, Rivett AJ and Gonos ES. The olive constituent oleuropein exhibits proteasome stimulatory properties in vitro and confers life span extension of human embryonic fibroblasts. Rejuvenation Res. 2007; 10:157-172.

413. Petrascheck M, Ye X and Buck LB. An antidepressant that extends lifespan in adult Caenorhabditis elegans. Nature. 2007; 450:553-556.

414. Anisimov VN, Berstein LM, Egormin PA, Piskunova TS, Popovich IG, Zabezhinski MA, Tyndyk ML, Yurova MV, Kovalenko IG, Poroshina TE and Semenchenko AV. Metformin slows down aging and extends life span of female SHR mice. Cell Cycle. 2008; 7:2769-2773.

415. Benedetti MG, Foster AL, Vantipalli MC, White MP, Sampayo JN, Gill MS, Olsen A and Lithgow GJ. Compounds that confer thermal stress resistance and extended lifespan. Exp Gerontol. 2008; 43:882-891.

416. Engel N and Mahlknecht U. Aging and anti-aging: unexpected side effects of everyday medication through sirtuin1 modulation. Int J Mol Med. 2008; 21:223-232.

417. Evason K, Collins JJ, Huang C, Hughes S and Kornfeld K. Valproic acid extends Caenorhabditis elegans lifespan. Aging Cell. 2008; 7:305-317.

418. Kampkötter A, Timpel C, Zurawski RF, Ruhl S, Chovolou Y, Proksch P and Wätjen W. Increase of stress resistance and lifespan of Caenorhabditis elegans by quercetin. Comp Biochem Physiol B Biochem Mol Biol. 2008; 149:314-323.

419. Pan W, Jiang S, Luo P, Wu J and Gao P. Isolation, purification and structure identification of antioxidant compound from the roots of Incarvillea younghusbandii Sprague and its life span prolonging effect in Drosophila melanogaster. Nat Prod Res. 2008; 22:719-725.

420. Pearson KJ, Baur JA, Lewis KN, Peshkin L, Price NL, Labinskyy N, Swindell WR, Kamara D, Minor RK, Perez E, Jamieson HA, Zhang Y, Dunn SR, Sharma K, Pleshko N, Woollett LA, Csiszar A, Ikeno Y, Le Couteur D, Elliott PJ, Becker KG, Navas P, Ingram DK, Wolf NS, Ungvari Z, Sinclair DA and de Cabo R. Resveratrol delays age-related deterioration and mimics transcriptional aspects of dietary restriction without extending life span. Cell Metab. 2008; 8:157-168.

421. Srivastava D, Arya U, SoundaraRajan T, Dwivedi H, Kumar S and Subramaniam JR. Reserpine can confer stress tolerance and lifespan extension in the nematode C. elegans. Biogerontology. 2008; 9:309-316.

422. Strong R, Miller RA, Astle CM, Floyd RA, Flurkey K, Hensley KL, Javors MA, Leeuwenburgh C, Nelson JF, Ongini E, Nadon NL, Warner HR and Harrison DE. Nordihydroguaiaretic acid and aspirin increase lifespan of genetically heterogeneous male mice. Aging Cell. 2008; 7:641-650.

423. Abbas S and Wink M. Epigallocatechin gallate from green tea (Camellia sinensis) increases lifespan and stress resistance in Caenorhabditis elegans. Planta Med. 2009; 75:216-221.

424. Arya U, Dwivedi H and Subramaniam JR. Reserpine ameliorates Abeta toxicity in the Alzheimer's disease model in Caenorhabditis elegans. Exp Gerontol. 2009; 44:462-466.

425. Bakshi HA, Sam S, Feroz A, Ravesh Z, Shah GA and Sharma M. Crocin from Kashmiri saffron (Crocus sativus) induces in vitro and in vivo xenograft growth inhibition of Dalton's lymphoma (DLA) in mice. Asian Pac J Cancer Prev. 2009; 10:887-890.

426. Pietsch K, Saul N, Menzel R, Stürzenbaum SR and Steinberg CE. Quercetin mediated lifespan extension in Caenorhabditis elegans is modulated by age-1, daf-2, sek-1 and unc-43. Biogerontology. 2009; 10:565-578.

427. Saul N, Pietsch K, Menzel R, Stürzenbaum SR and Steinberg CE. Catechin induced longevity in C. elegans: from key regulator genes to disposable soma. Mech Ageing Dev. 2009; 130:477-486.

428. 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. Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. Nature. 2009; 460:392-395.

429. Skulachev VP, Anisimov VN, Antonenko YN, Bakeeva LE, Chernyak BV, Erichev VP, Filenko OF, Kalinina NI, Kapelko VI, Kolosova NG, Kopnin BP, Korshunova GA, Lichinitser MR, Obukhova LA, Pasyukova EG, Pisarenko OI, Roginsky VA, Ruuge EK, Senin II, Severina II, Skulachev MV, Spivak IM, Tashlitsky VN, Tkachuk VA, Vyssokikh MY, Yaguzhinsky LS, Zorov DB. An attempt to prevent senescence: a mitochondrial approach. Biochim Biophys Acta. 2009; 1787:437-461.

430. Bjedov I, Toivonen JM, Kerr F, Slack C, Jacobson J, Foley A and Partridge L. Mechanisms of life span extension by rapamycin in the fruit fly Drosophila melanogaster. Cell Metab. 2010; 11:35-46.

431. Choi MJ, Kim BK, Park KY, Yokozawa T and Song YO and Cho EJ. Anti-aging effects of cyanidin under a stress-induced premature senescence cellular system. Biol Pharm Bull. 2010; 33:421-426.

432. Chondrogianni N, Kapeta S, Chinou I, Vassilatou K, Papassideri I and Gonos ES. Anti-ageing and rejuvenating effects of quercetin. Exp Gerontol. 2010; 45:763-771.

433. Lee KS, Lee BS, Semnani S, Avanesian A, Um CY, Jeon HJ, Seong KM, Yu K, Min KJ and Jafari M. Curcumin extends life span, improves health span, and modulates the expression of age-associated aging genes in Drosophila melanogaster. Rejuvenation Res. 2010; 13:561-570.

434. Onken B and Driscoll M. Metformin induces a dietary restriction-like state and the oxidative stress response to extend C. elegans healthspan via AMPK, LKB1, and SKN-1. PLoS One. 2010; 5: e8758.

435. Saul N, Pietsch K, Menzel R, Stürzenbaum SR and Steinberg CE. The longevity effect of tannic acid in Caenorhabditis elegans: Disposable Soma meets hormesis. J Gerontol A Biol Sci Med Sci. 2010; 65:626-635.

436. Cai WJ, Huang JH, Zhang SQ, Wu B, Kapahi P, Zhang XM and Shen ZY. Icariin and its derivative icariside II extend healthspan via insulin/IGF-1 pathway in C. elegans. PLoS One. 2011; 6: e28835.

437. Liao VH, Yu CW, Chu YJ, Li WH, Hsieh YC and Wang TT. Curcumin-mediated lifespan extension in Caenorhabditis elegans. Mech Ageing Dev. 2011; 132:480-487.

438. Lublin A, Isoda F, Patel H, Yen K, Nguyen L, Hajje D, Schwartz M and Mobbs C. FDA-approved drugs that protect mammalian neurons from glucose toxicity slow aging dependent on cbp and protect against proteotoxicity. PLoS One. 2011; 6: e27762.

439. Powolny AA, Singh SV, Melov S, Hubbard A and Fisher AL. The garlic constituent diallyl trisulfide increases the lifespan of C. elegans via skn-1 activation. Exp Gerontol. 2011; 46:441-452.

440. Pietsch K, Saul N, Chakrabarti S, Stürzenbaum SR, Menzel R and Steinberg CE. Hormetins, antioxidants and prooxidants: defining quercetin-, caffeic acid- and rosmarinic acid-mediated life extension in C. elegans. Biogerontology. 2011; 12:329-347.

441. Sayed AA. Ferulsinaic acid attenuation of advanced glycation end products extends the lifespan of Caenorhabditis elegans. J Pharm Pharmacol. 2011; 63:423-428.

442. Saul N, Pietsch K, Stürzenbaum SR, Menzel R and Steinberg CE. Diversity of polyphenol action in Caenorhabditis elegans: between toxicity and longevity. J Nat Prod. 2011; 74:1713-1720.

443. Xue YL, Ahiko T, Miyakawa T, Amino H, Hu F, Furihata K, Kita K, Shirasawa T, Sawano Y and Tanokura M. Isolation and Caenorhabditis elegans lifespan assay of flavonoids from onion. J Agric Food Chem. 2011; 59:5927-5934.

444. Caesar I, Jonson M, Nilsson KP, Thor S and Hammarström P. Curcumin promotes A-beta fibrillation and reduces neurotoxicity in transgenic Drosophila. PLoS One. 2012; 7: e31424.

445. Cañuelo A, Gilbert-López B, Pacheco-Liñán P, Martínez-Lara E, Siles E and Miranda-Vizuete A. Tyrosol, a main phenol present in extra virgin olive oil, increases lifespan and stress resistance in Caenorhabditis elegans. Mech Ageing Dev. 2012; 133:563-574.

446 Grünz G, Haas K, Soukup S, Klingenspor M, Kulling SE, Daniel H and Spanier B. Structural features and bioavailability of four flavonoids and their implications for lifespan-extending and antioxidant actions in C. elegans. Mech Ageing Dev. 2012; 133:1-10.

447. Rascón B, Hubbard BP, Sinclair DA and Amdam GV. The lifespan extension effects of resveratrol are conserved in the honey bee and may be driven by a mechanism related to caloric restriction. Aging (Albany NY). 2012; 4:499-508.

448. Sutphin GL, Bishop E, Yanos ME, Moller RM and Kaeberlein M. Caffeine extends life span, improves healthspan, and delays age-associated pathology in Caenorhabditis elegans. Longev Healthspan. 2012; 1: 9.

449. Rallis C, Codlin S and Bähler J. TORC1 signaling inhibition by rapamycin and caffeine affect lifespan, global gene expression, and cell proliferation of fission yeast. Aging Cell. 2013; 12:563-573.

450. Si H, Fu Z, Babu PV, Zhen W, Leroith T, Meaney MP, Voelker KA, Jia Z, Grange RW and Liu D. Dietary epicatechin promotes survival of obese diabetic mice and Drosophila melanogaster. J Nutr. 2011; 141:1095-1100.

451. Shen LR, Xiao F, Yuan P, Chen Y, Gao QK, Parnell LD, Meydani M, Ordovas JM, Li D and Lai CQ. Curcumin-supplemented diets increase superoxide dismutase activity and mean lifespan in Drosophila. Age (Dordr). 2013; 35:1133-1142.

452. Blagosklonny MV. Aging and immortality: quasi-programmed senescence and its pharmacologic inhibition. Cell Cycle. 2006; 5:2087–2102.

453. Blagosklonny MV, Hall MN. Growth and aging: a common molecular mechanism. Aging (Albany NY). 2009; 1:357–362.

454. Goldberg AA, Beach A, Davies GF, Harkness TA, Leblanc A, Titorenko VI. Lithocholic bile acid selectively kills neuroblastoma cells, while sparing normal neuronal cells. Oncotarget. 2011; 2:761–782.

455. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011; 144:646–674.

456. Rodier F, Campisi J. Four faces of cellular senescence. J Cell Biol. 2011; 192:547–556.

457. Campisi J. Aging, cellular senescence, and cancer. Annu Rev Physiol. 2013; 75:685–705.

458. Goldberg AA, Titorenko VI, Beach A, Sanderson JT. Bile acids induce apoptosis selectively in androgen-dependent and -independent prostate cancer cells. PeerJ. 2013; 1: e122.

459. Partridge L. Intervening in ageing to prevent the diseases of ageing. Trends Endocrinol Metab. 2014; 25:555–557.

460. Piano A, Titorenko VI. The Intricate interplay between mechanisms underlying aging and cancer. Aging Dis. 2014; 6:56–75.

461. Lutchman V, Medkour Y, Samson E, Arlia-Ciommo A, Dakik P, Cortes B, Feldman R, Mohtashami S, McAuley M, Chancharoen M, Rukundo B, Simard E, and Titorenko VI. Discovery of plant extracts that greatly delay yeast chronological aging and have different effects on longevity-defining cellular processes. Oncotarget. 2016; 7: 16542-16566.

462. Demidenko ZN. Chronological lifespan in stationary culture: from yeast to human cells. Aging (Albany NY). 2011; 3:1041-1042.

463. Fabrizio P, and Wei M. Conserved role of medium acidification in chronological senescence of yeast and mammalian cells. Aging (Albany NY). 2011; 3:1127-1129.

464. Leontieva OV, and Blagosklonny MV. Yeast-like chronological senescence in mammalian cells: phenomenon, mechanism and pharmacological suppression. Aging (Albany NY). 2011; 3:1078-1091.

465. Blagosklonny MV. Cell cycle arrest is not yet senescence, which is not just cell cycle arrest: terminology for TOR-driven aging. Aging (Albany NY). 2012; 4:159-165.

466. McCubrey JA, Steelman LS, Chappell WH, Sun L, Davis NM, Abrams SL, Franklin RA, Cocco L, Evangelisti C, Chiarini F, Martelli AM, Libra M, Candido S, et al. Advances in targeting signal transduction pathways. Oncotarget. 2012; 3:1505-1521.

467. Leontieva OV, Demidenko ZN, and Blagosklonny MV. S6K in geroconversion. Cell Cycle. 2013; 12:3249-3252.

468. Blagosklonny MV. Geroconversion: irreversible step to cellular senescence. Cell Cycle. 2014; 13:3628-3635.

469. Colman RJ, Anderson RM, Johnson SC, Kastman EK, Kosmatka KJ, Beasley TM, Allison DB, Cruzen C, Simmons HA, Kemnitz JW, and Weindruch R. Caloric restriction delays disease onset and mortality in rhesus monkeys. Science. 2009; 325:201-204.

470. Colman RJ, Beasley TM, Kemnitz JW, Johnson SC, Weindruch R, and Anderson RM. Caloric restriction reduces age-related and all-cause mortality in rhesus monkeys. Nat Commun. 2014; 5: 3557.

471. Gems D. What is an anti-aging treatment? Exp Gerontol. 2014; 58:14-18.

472. Kennedy BK, and Pennypacker JK. Drugs that modulate aging: the promising yet difficult path ahead. Transl Res. 2014; 163:456-465.

473. Sinclair DA, and Guarente L. Small-molecule allosteric activators of sirtuins. Annu Rev Pharmacol Toxicol. 2014; 54:363-380.

474. Moskalev A, Chernyagina E, de Magalhães JP, Barardo D, Thoppil H, Shaposhnikov M, Budovsky A, Fraifeld VE, Garazha A, Tsvetkov V, Bronovitsky E, Bogomolov V, Scerbacov A, Kuryan O, Gurinovich R, Jellen LC, Kennedy B, Mamoshina P, Dobrovolskaya E, Aliper A, Kaminsky D, Zhavoronkov A. Geroprotectors.org: a new, structured and curated database of current therapeutic interventions in aging and age-related disease. Aging (Albany NY). 2015; 7:616-628.

475. Pitt JN, and Kaeberlein M. Why is aging conserved and what can we do about it? PLoS Biol. 2015; 13: e1002131.

476. Health Canada. http://www.hc-sc.gc.ca/index-eng.php.

477. Lutchman V, Dakik P, McAuley M, Cortes B, Ferraye G, Gontmacher L, Graziano D, Moukhariq FZ, Simard É, Titorenko VI. Six plant extracts delay yeast chronological aging through different signaling pathways. Oncotarget. 2016; 7:50845-50863.

478. Lee D, Hwang W, Artan M, Jeong DE, Lee SJ. Effects of nutritional components on aging. Aging Cell. 2015; 14:8-16.

479. Madeo F, Eisenberg T, Pietrocola F, Kroemer G. Spermidine in health and
disease. Science. 2018; 359: eaan2788.

480. Park SJ, Ahmad F, Philp A, Baar K, Williams T, Luo H, Ke H, Rehmann H, Taussig R, Brown AL, Kim MK, Beaven MA, Burgin AB, et al. Resveratrol ameliorates aging-related metabolic phenotypes by inhibiting cAMP phosphodiesterases. Cell. 2012; 148:421–433.

481. Sajish M, Schimmel P. A human tRNA synthetase is a potent PARP1-activating effector target for resveratrol. Nature. 2015; 519:370–373.

482. Berenbaum MC. What is synergy? Pharmacol Rev. 1989; 41:93–141.

483. Slinker BK. The statistics of synergism. J Mol Cell Cardiol. 1998; 30:723–731.

484. Nieuwenhuis S, Forstmann BU, Wagenmakers EJ. Erroneous analyses of interactions in neuroscience: a problem of significance. Nat Neurosci. 2011; 14:1105–1107.

485. Geary N. Understanding synergy. Am J Physiol Endocrinol Metab. 2013; 304: E237–E253.

486. Madeo F, Carmona-Gutierrez D, Kepp O, Kroemer G. Spermidine delays aging in humans. Aging (Albany NY). 2018; 10:2209-2211.

487. Strynatka KA, Gurrola-Gal MC, Berman JN, McMaster CR. How surrogate and chemical genetics in model organisms can suggest therapies for human genetic diseases. Genetics. 2018; 208:833-851.

488. Masoro EJ. Overview of caloric restriction and ageing. Mech Ageing Dev. 2005; 126:913-922.

489. Mair W, Dillin A. Aging and survival: the genetics of life span extension by
dietary restriction. Annu Rev Biochem. 2008; 77:727-754.

490. Mattison JA, Colman RJ, Beasley TM, Allison DB, Kemnitz JW, Roth GS, Ingram DK, Weindruch R, de Cabo R, Anderson RM. Caloric restriction improves health and survival of rhesus monkeys. Nat Commun. 2017; 8: 14063.

491. Sinclair DA. Toward a unified theory of caloric restriction and longevity
regulation. Mech Ageing Dev. 2005; 126:987-1002.

492. Ingram DK, Zhu M, Mamczarz J, Zou S, Lane MA, Roth GS, deCabo R. Calorie
restriction mimetics: an emerging research field. Aging Cell. 2006; 5:97-108.

493. de Magalhães JP, Wuttke D, Wood SH, Plank M, Vora C. Genome-environment
interactions that modulate aging: powerful targets for drug discovery. Pharmacol
Rev. 2012; 64:88-101.

494. Lee SH, Min KJ. Caloric restriction and its mimetics. BMB Rep. 2013; 46:181-187.

495. Ingram DK, Roth GS. Calorie restriction mimetics: can you have your cake and
eat it, too? Ageing Res Rev. 2015; 20:46-62.

496. Lee C, Longo V. Dietary restriction with and without caloric restriction for healthy aging. F1000Res. 2016; 5: F1000 Faculty Rev-117.

497. Kirkwood TB. Deciphering death: a commentary on Gompertz (1825) 'On the nature of the function expressive of the law of human mortality, and on a new mode of determining the value of life contingencies.' Philos Trans R Soc Lond B Biol Sci. 2015; 370: 20140379.

498. Creevy KE, Austad SN, Hoffman JM, O’Neill DG, Promislow DEL, 2016. The Companion Dog as a Model for the Longevity Dividend, pp. 107-120. In Olshansky SJ, Martin GM, Kirkland JL. (eds.), Aging: The Longevity Dividend. Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY.

499. Promislow DE, Tatar M, Khazaeli AA, Curtsinger JW. Age-specific patterns of genetic variance in Drosophila melanogaster. I. Mortality. Genetics. 1996; 143:839-848.

500. Burger O, Baudisch A, Vaupel JW. Human mortality improvement in evolutionary context. Proc Natl Acad Sci USA. 2012; 109:18210-18214.

501. Chen J, Senturk D, Wang JL, Müller HG, Carey JR, Caswell H, Caswell-Chen EP. A demographic analysis of the fitness cost of extended longevity in Caenorhabditis elegans. J Gerontol A Biol Sci Med Sci. 2007; 62:126-135.

502. Goldberg AA, Kyryakov P, Bourque SD, Titorenko VI. Xenohormetic, hormetic and cytostatic selective forces driving longevity at the ecosystemic level. Aging (Albany NY). 2010; 2:461-470.

503. Calabrese EJ, Mattson MP. Hormesis provides a generalized quantitative estimate of biological plasticity. J Cell Commun Signal. 2011; 5:25-38.

504. Sampaio-Marques B, Burhans WC, Ludovico P. Longevity pathways and maintenance of the proteome: the role of autophagy and mitophagy during yeast ageing. Microb Cell. 2014; 1:118-127.

505. Medkour Y, Dakik P, McAuley M, Mohammad K, Mitrofanova D, Titorenko VI. Mechanisms underlying the essential role of mitochondrial membrane lipids in yeast chronological aging. Oxid Med Cell Longev. 2017; 2017: 2916985.

506. Mitrofanova D, Dakik P, McAuley M, Medkour Y, Mohammad K, Titorenko VI. Lipid metabolism and transport define longevity of the yeast Saccharomyces cerevisiae. Front Biosci (Landmark Ed). 2018; 23:1166-1194.

507. Zorov DB, Juhaszova M, Sollott SJ. Mitochondrial reactive oxygen species (ROS) and ROS-induced ROS release. Physiol Rev. 2014; 94:909-950.

508. Yang W, Hekimi S. A mitochondrial superoxide signal triggers increased longevity in Caenorhabditis elegans. PLoS Biol. 2010; 8: e1000556.

509. Yee C, Yang W, Hekimi S. The intrinsic apoptosis pathway mediates the pro-longevity response to mitochondrial ROS in C. elegans. Cell. 2014; 157:897-909.

510. Hekimi S, Wang Y, Noë A. Mitochondrial ROS and the effectors of the intrinsic apoptotic pathway in aging cells: The discerning killers! Front Genet. 2016; 7: 161.

511. Rottenberg H, Hoek JB. The path from mitochondrial ROS to aging runs through the mitochondrial permeability transition pore. Aging Cell. 2017; 16:943-955.

512. Bárcena C, Mayoral P, Quirós PM. Mitohormesis, an antiaging paradigm. Int Rev Cell Mol Biol. 2018; 340:35-77.

513. Giorgi C, Marchi S, Simoes ICM, Ren Z, Morciano G, Perrone M, Patalas-Krawczyk P, Borchard S, Jędrak P, Pierzynowska K, Szymański J, Wang DQ, Portincasa P, Węgrzyn G, Zischka H, Dobrzyn P, Bonora M, Duszynski J, Rimessi A, Karkucinska-Wieckowska A, Dobrzyn A, Szabadkai G, Zavan B, Oliveira PJ, Sardao VA, Pinton P, Wieckowski MR. Mitochondria and reactive oxygen species in aging and age-related diseases. Int Rev Cell Mol Biol. 2018; 340:209-344.

514. Blasiak J, Glowacki S, Kauppinen A, Kaarniranta K. Mitochondrial and nuclear DNA damage and repair in age-related macular degeneration. Int J Mol Sci. 2013; 14:2996-3010.

515. Santos RX, Correia SC, Zhu X, Smith MA, Moreira PI, Castellani RJ, Nunomura A, Perry G. Mitochondrial DNA oxidative damage and repair in aging and Alzheimer's disease. Antioxid Redox Signal. 2013; 18:2444-2457.

516. Szczepanowska K, Trifunovic A. Different faces of mitochondrial DNA mutators. Biochim Biophys Acta. 2015; 1847:1362-1372.

517. Nissanka N, Moraes CT. Mitochondrial DNA damage and reactive oxygen species in neurodegenerative disease. FEBS Lett. 2018; 592:728-742.

518. Kaarniranta K, Pawlowska E, Szczepanska J, Jablkowska A, Blasiak J. Role of mitochondrial DNA damage in ROS-Mediated pathogenesis of age-related macular degeneration (AMD). Int J Mol Sci. 2019; 20: E2374.

519. Medkour Y, Mohammad K, Arlia-Ciommo A, Svistkova V, Dakik P, Mitrofanova D, Rodriguez MEL, Junio JAB, Taifour T, Escudero P, Goltsios FF, Soodbakhsh S, Maalaoui H, Simard É, Titorenko VI. Mechanisms by which PE21, an extract from the white willow Salix alba, delays chronological aging in budding yeast. Oncotarget. 2019; 10:5780-5816.

520. Dakik P, McAuley M, Chancharoen M, Mitrofanova D, Lozano Rodriguez ME, Baratang Junio JA, Lutchman V, Cortes B, Simard É, Titorenko VI. Pairwise combinations of chemical compounds that delay yeast chronological aging through different signaling pathways display synergistic effects on the extent of the aging delay. Oncotarget. 2019; 10:313-338.

521. Niccoli T, Partridge L. Ageing as a risk factor for disease. Curr Biol. 2012; 22: R741-R752.
All items in Spectrum are protected by copyright, with all rights reserved. The use of items is governed by Spectrum's terms of access.

Repository Staff Only: item control page

Downloads per month over past year

Research related to the current document (at the CORE website)
- Research related to the current document (at the CORE website)
Back to top Back to top