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Health Benefits of Anti-aging Drugs

  • Veronika Piskovatska
  • Olha Strilbytska
  • Alexander Koliada
  • Alexander Vaiserman
  • Oleh LushchakEmail author
Chapter
Part of the Subcellular Biochemistry book series (SCBI, volume 91)

Abstract

Aging, as a physiological process mediated by numerous regulatory pathways and transcription factors, is manifested by continuous progressive functional decline and increasing risk of chronic diseases. There is an increasing interest to identify pharmacological agents for treatment and prevention of age-related disease in humans. Animal models play an important role in identification and testing of anti-aging compounds; this step is crucial before the drug will enter human clinical trial or will be introduced to human medicine. One of the main goals of animal studies is better understanding of mechanistic targets, therapeutic implications and side-effects of the drug, which may be later translated into humans. In this chapter, we summarized the effects of different drugs reported to extend the lifespan in model organisms from round worms to rodents. Resveratrol, rapamycin, metformin and aspirin, showing effectiveness in model organism life- and healthspan extension mainly target the master regulators of aging such as mTOR, FOXO and PGC1α, affecting autophagy, inflammation and oxidative stress. In humans, these drugs were demonstrated to reduce inflammation, prevent CVD, and slow down the functional decline in certain organs. Additionally, potential anti-aging pharmacologic agents inhibit cancerogenesis, interfering with certain aspects of cell metabolism, proliferation, angioneogenesis and apoptosis.

Keywords

Aging Lifespan Healthspan Model organisms Anti-aging drugs 

References

  1. Ait Ouakrim D, Dashti SG, Chau R, Buchanan DD, Clendenning M, Rosty C, Winship IM, Young JP, Giles GG, Leggett B, Macrae FA, Ahnen DJ, Casey G, Gallinger S, Haile RW, Le Marchand L, Thibodeau SN, Lindor NM, Newcomb PA, Potter JD, Baron JA, Hopper JL, Jenkins MA, Win AK (2015) Aspirin, ibuprofen, and the risk of colorectal cancer in Lynch syndrome. J Natl Cancer Inst 107(9). pii: djv170Google Scholar
  2. Alfonso L, Ai G, Spitale RC, Bhat GJ (2014) Molecular targets of aspirin and cancer prevention. Br J Cancer 111(1):61–67PubMedPubMedCentralCrossRefGoogle Scholar
  3. American Diabetes Association (2002). Implications of the United Kingdom prospective diabetes study. Diabetes Care 25(suppl 1):s28–s32. https://www.clinicaltrials.gov/ct2/show/NCT02432287?term=metformin&cond=Ageing&rank=2, https://www.afar.org/natgeo/, https://www.clinicaltrials.gov/ct2/show/NCT02099123
  4. An J, Shi F, Liu S, Ma J, Ma Q (2017) Preoperative statins as modifiers of cardiac and inflammatory outcomes following coronary artery bypass graft surgery: a meta-analysis. Interact Cardiovasc Thorac Surg 25:958–965PubMedCrossRefGoogle Scholar
  5. Anisimov VN, Berstein LM, Egormin PA, Piskunova TS, Popovich IG, Zabezhinski MA, Tyndyk ML, Yurova MV, Kovalenko IG, Poroshina TE, Semenchenko AV (2008) Metformin slows down ageing and extends life span of female SHR mice. Cell Cycle 7(17):2769–2773PubMedCrossRefGoogle Scholar
  6. Araki K, Ellebedy AH, Ahmed R (2011) TOR in the immune system. Curr Opin Cell Biol 23(6):707–715PubMedPubMedCentralCrossRefGoogle Scholar
  7. Ayyadevara S, Bharill P, Dandapat A, Hu C, Khaidakov M, Mitra S, Shmookler Reis RJ, Mehta JL (2013) Aspirin inhibits oxidant stress, reduces age-associated functional declines, and extends lifespan of Caenorhabditis elegans. Antioxid Redox Signal 18(5):481–490PubMedCrossRefGoogle Scholar
  8. Bahadorani S, Hilliker AJ (2008) Cocoa confers life span extension in Drosophila melanogaster. Nutr Res 28(6):377–382PubMedCrossRefGoogle Scholar
  9. Bahadorani S, Bahadorani P, Phillips JP, Hilliker AJ (2008) The effects of vitamin supplementation on Drosophila life span under normoxia and under oxidative stress. J Gerontol A Biol Sci Med Sci 63(1):35–42PubMedCrossRefGoogle Scholar
  10. Bass TM, Weinkove D, Houthoofd K, Gems D, Partridge L (2007) Effects of resveratrol on lifespan in Drosophila melanogaster and Caenorhabditis elegans. Mech Ageing Dev 128(10):546–552PubMedCrossRefGoogle Scholar
  11. Baur JA, Sinclair DA (2006) Therapeutic potential of resveratrol: the in vivo evidence. Nat Rev Drug Discov 5(6):493–506PubMedCrossRefGoogle Scholar
  12. Baur JA, Pearson KJ, Price NL, Jamieson HA, Lerin C, Kalra A, Prabhu VV, Allard JS, Lopez-Lluch G, Lewis K, Pistell PJ, Poosala S, Becker KG, Boss O, Gwinn D, Wang M, Ramaswamy S, Fishbein KW, Spencer RG, Lakatta EG, Le Couteur D, Shaw RJ, Navas P, Puigserver P, Ingram DK, de Cabo R, Sinclair DA (2006) Resveratrol improves health and survival of mice on a high-calorie diet. Nature 444(7117):337–342PubMedPubMedCentralCrossRefGoogle Scholar
  13. Benedetti MG, Foster AL, Vantipalli MC, White MP, Sampayo JN, Gill MS, Olsen A, Lithgow GJ (2008) Compounds that confer thermal stress resistance and extended lifespan. Exp Gerontol 43(10):882–891PubMedPubMedCentralCrossRefGoogle Scholar
  14. Bhullar KS, Hubbard BP (2015) Lifespan and healthspan extension by resveratrol. Biochim Biophys Acta 1852(6):1209–1218PubMedCrossRefGoogle Scholar
  15. Biswas SK (2016) Does the interdependence between oxidative stress and inflammation explain the antioxidant paradox? Oxidative Med Cell Longev 2016:5698931CrossRefGoogle Scholar
  16. Bitto A, Wang AM, Bennett CF, Kaeberlein M (2015) Biochemical genetic pathways that modulate ageing in multiple species. Cold Spring Harb Perspect Med 5(11). pii: a025114Google Scholar
  17. Bjedov I, Toivonen JM, Kerr F, Slack C, Jacobson J, Foley A, Partridge L (2010) Mechanisms of life span extension by rapamycin in the fruit fly Drosophila melanogaster. Cell Metab 11(1):35–46PubMedPubMedCentralCrossRefGoogle Scholar
  18. Björkhem-Bergman L, Asplund AB, Lindh JD (2011) Metformin for weight reduction in non-diabetic patients on antipsychotic drugs: a systematic review and meta-analysis. J Psychopharmacol 25(3):299–305PubMedCrossRefGoogle Scholar
  19. Blagosklonny MV (2009) Validation of anti-ageing drugs by treating age-related diseases. Ageing (Albany NY) 1:281–288Google Scholar
  20. Blagosklonny MV (2012a) Rapalogs in cancer prevention: anti-ageing or anticancer? Cancer Biol Ther 13(14):1349–1354PubMedPubMedCentralCrossRefGoogle Scholar
  21. Blagosklonny MV (2012b) Once again on rapamycin-induced insulin resistance and longevity: despite of or owing to. Ageing (Albany NY) 4(5):350–358Google Scholar
  22. Blagosklonny MV (2017) From rapalogs to anti-ageing formula. Oncotarget 8(22):35492–35507PubMedPubMedCentralCrossRefGoogle Scholar
  23. Bonilla E, Medina-Leendertz S, Díaz S (2002) Extension of life span and stress resistance of Drosophila melanogaster by long-term supplementation with melatonin. Exp Gerontol 37(5):629–638PubMedCrossRefGoogle Scholar
  24. Bouza C, López-Cuadrado T, Gutierrez-Torres LF, Amate JM (2012) Efficacy and safety of metformin for treatment of overweight and obesity in adolescents: an updated systematic review and meta-analysis. Obes Facts 5:753–765PubMedCrossRefGoogle Scholar
  25. Brack C, Bechter-Thüring E, Labuhn M (1997) N-acetylcysteine slows down ageing and increases the life span of Drosophila melanogaster. Cell Mol Life Sci 53(11–12):960–966PubMedGoogle Scholar
  26. Brotons C, Benamouzig R, Filipiak KJ, Limmroth V, Borghi CA (2015) Systematic review of aspirin in primary prevention: is it time for a new approach? Am J Cardiovasc Drugs 15(2):113–133PubMedCrossRefGoogle Scholar
  27. Brouet I, Ohshima H (1995) Curcumin, an anti-tumour promoter and anti-inflammatory agent, inhibits induction of nitric oxide synthase in activated macrophages. Biochem Biophys Res Commun 206(2):533–540PubMedCrossRefGoogle Scholar
  28. Buommino E, Pasquali D, Sinisi AA, Bellastella A, Morelli F, Metafora S (2000) Sodium butyrate/retinoic acid costimulation induces apoptosis-independent growth arrest and cell differentiation in normal and ras-transformed seminal vesicle epithelial cells unresponsive to retinoic acid. J Mol Endocrinol 24(1):83–94PubMedCrossRefGoogle Scholar
  29. Burd CE, Gill MS, Niedernhofer LJ, Robbins PD, Austad SN, Barzilai N, Kirkland JL (2016) Barriers to the preclinical development of therapeutics that target ageing mechanisms. J Gerontol A Biol Sci Med Sci 71(11):1388–1394PubMedPubMedCentralCrossRefGoogle Scholar
  30. Burn J, Gerdes AM, Macrae F, Mecklin JP, Moeslein G, Olschwang S, Eccles D, Evans DG, Maher ER, Bertario L, Bisgaard ML, Dunlop MG, Ho JW, Hodgson SV, Lindblom A, Lubinski J, Morrison PJ, Murday V, Ramesar R, Side L, Scott RJ, Thomas HJ, Vasen HF, Barker G, Crawford G, Elliott F, Movahedi M, Pylvanainen K, Wijnen JT, Fodde R, Lynch HT, Mathers JC, Bishop DT, CAPP2 Investigators (2011) Long-term effect of aspirin on cancer risk in carriers of hereditary colorectal cancer: an analysis from the CAPP2 randomised controlled trial. Lancet 378(9809):2081–2087PubMedPubMedCentralCrossRefGoogle Scholar
  31. Buu-Hoi NP, Ratsimamanga AR (1959) Retarding action of nordihydroguiaiaretic acid on ageing in the rat. C R Seances Soc Biol Fil 153:1180–1182. (in French)PubMedGoogle Scholar
  32. Cai H, Zhang G, Wang Z, Luo Z, Zhou X (2015) Relationship between the use of statins and patient survival in colorectal cancer: a systematic review and meta-analysis. PLoS One 10(6):e0126944PubMedPubMedCentralCrossRefGoogle Scholar
  33. Cameron AR, Morrison VL, Levin D, Mohan M, Forteath C, Beall C, McNeilly AD, Balfour DJ, Savinko T, Wong AK, Viollet B, Sakamoto K, Fagerholm SC, Foretz M, Lang CC, Rena G (2016) Anti-inflammatory effects of metformin irrespective of diabetes status. Circ Res 119(5):652–665PubMedPubMedCentralCrossRefGoogle Scholar
  34. Cash H, Shah S, Moore E, Caruso A, Uppaluri R, Van Waes C, Allen C (2015) mTOR and MEK1/2 inhibition differentially modulate tumor growth and the immune microenvironment in syngeneic models of oral cavity cancer. Oncotarget 6(34):36400–36417PubMedPubMedCentralCrossRefGoogle Scholar
  35. Castillo-Quan JI, Li L, Kinghorn KJ, Ivanov DK, Tain LS, Slack C, Kerr F, Nespital T, Thornton J, Hardy J, Bjedov I, Partridge L (2016) Lithium promotes longevity through GSK3/NRF2-dependent hormesis. Cell Rep 15(3):638–650PubMedPubMedCentralCrossRefGoogle Scholar
  36. Chamberlain JJ, Herman WH, Leal S, Rhinehart AS, Shubrook JH, Skolnik N, Kalyani RR (2017) Pharmacologic therapy for type 2 diabetes: synopsis of the 2017 American Diabetes Association Standards of Medical Care in Diabetes. Ann Intern Med 166:572–578PubMedCrossRefGoogle Scholar
  37. Chang CI, Kuo CC, Chang JY, Kuo YH (2004) Three new oleanane-type triterpenes from Ludwigia octovalvis with cytotoxic activity against two human cancer cell lines. J Nat Prod 67(1):91–93PubMedCrossRefGoogle Scholar
  38. Chen W, Rezaizadehnajafi L, Wink M (2013) Influence of resveratrol on oxidative stress resistance and life span in Caenorhabditis elegans. J Pharm Pharmacol 65(5):682–688PubMedCrossRefGoogle Scholar
  39. Chen Y, Du J, Zhao YT, Zhang L, Lv G, Zhuang S, Qin G, Zhao TC (2015) Histone deacetylase (HDAC) inhibition improves myocardial function and prevents cardiac remodeling in diabetic mice. Cardiovasc Diabetol 14:99PubMedPubMedCentralCrossRefGoogle Scholar
  40. Chen W, Liu X, Ye S (2016) Effects of metformin on blood and urine pro-inflammatory mediators in patients with type 2 diabetes. J Inflamm (London, England) 13:34CrossRefGoogle Scholar
  41. Chin RM, Fu X, Pai MY, Vergnes L, Hwang H, Deng G, Diep S, Lomenick B, Meli VS, Monsalve GC, Hu E, Whelan SA, Wang JX, Jung G, Solis GM, Fazlollahi F, Kaweeteerawat C, Quach A, Nili M, Krall AS, Godwin HA, Chang HR, Faull KF, Guo F, Jiang M, Trauger SA, Saghatelian A, Braas D, Christofk HR, Clarke CF, Teitell MA, Petrascheck M, Reue K, Jung ME, Frand AR, Huang J (2014) The metabolite α-ketoglutarate extends lifespan by inhibiting ATP synthase and TOR. Nature 510(7505):397–401PubMedPubMedCentralCrossRefGoogle Scholar
  42. Ching TT, Chiang WC, Chen CS, Hsu AL (2011) Celecoxib extends C. elegans lifespan via inhibition of insulin-like signaling but not cyclooxygenase-2 activity. Ageing. Cell 10(3):506–519Google Scholar
  43. Chinnakotla S, Davis GL, Vasani S, Kim P, Tomiyama K, Sanchez E, Onaca N, Goldstein R, Levy M, Klintmalm GB (2009) Impact of sirolimus on the recurrence of hepatocellular carcinoma after liver transplantation. Liver Transpl 15(12):1834–1842PubMedCrossRefGoogle Scholar
  44. Chou R, Dana T, Blazina I, Daeges M, Jeanne TL (2016) Statins for prevention of cardiovascular disease in adults: evidence report and systematic review for the US Preventive Services Task Force. JAMA 316(19):2008–2024PubMedCrossRefGoogle Scholar
  45. Chubak J, Kamineni A, Buist DSM, Anderson ML, Whitlock EP (2015) Aspirin use for the prevention of colorectal cancer. Agency for Healthcare Research and Quality (US), RockvilleGoogle Scholar
  46. Chubak J, Whitlock EP, Williams SB, Kamineni A, Burda BU, Buist DS et al (2016) Aspirin for the prevention of cancer incidence and mortality: systematic evidence reviews for the U.S. Preventive Services Task Force. Ann Intern Med 164:814–825PubMedCrossRefGoogle Scholar
  47. Col NF, Ochs L, Springmann V, Aragaki AK, Chlebowski RT (2012) Metformin and breast cancer risk: a meta-analysis and critical literature review. Breast Cancer Res Treat 135:639–646PubMedCrossRefGoogle Scholar
  48. Collins R, Reith C, Emberson J, Armitage J, Baigent C, Blackwell L, Blumenthal R, Danesh J, Smith GD, DeMets D, Evans S, Law M, MacMahon S, Martin S, Neal B, Poulter N, Preiss D, Ridker P, Roberts I, Rodgers A, Sandercock P, Schulz K, Sever P, Simes J, Smeeth L, Wald N, Yusuf S, Peto R (2016) Interpretation of the evidence for the efficacy and safety of statin therapy. Lancet 388(10059):2532–2561PubMedCrossRefGoogle Scholar
  49. Courtwright AM, Goldberg HJ, Henske EP, El-Chemaly S (2017) The effect of mTOR inhibitors on respiratory infections in lymphangioleiomyomatosis. Eur Respir Rev 26(143):160004PubMedCrossRefGoogle Scholar
  50. da Luz PL, Tanaka L, Brum PC, Dourado PM, Favarato D, Krieger JE, Laurindo FR (2012) Red wine and equivalent oral pharmacological doses of resveratrol delay vascular ageing but do not extend life span in rats. Atherosclerosis 224(1):136–142PubMedCrossRefGoogle Scholar
  51. Dancey J (2010) mTOR signaling and drug development in cancer. Nat Rev Clin Oncol 7(4):209–219PubMedCrossRefGoogle Scholar
  52. Danilov A, Shaposhnikov M, Shevchenko O, Zemskaya N, Zhavoronkov A, Moskalev A (2015) Influence of non-steroidal anti-inflammatory drugs on Drosophila melanogaster longevity. Oncotarget 6(23):19428–19444PubMedPubMedCentralCrossRefGoogle Scholar
  53. Deblon N, Bourgoin L, Veyrat-Durebex C, Peyrou M, Vinciguerra M, Caillon A, Maeder C, Fournier M, Montet X, Rohner-Jeanrenaud F, Foti M (2012) Chronic mTOR inhibition by rapamycin induces muscle insulin resistance despite weight loss in rats. Br J Pharmacol 165(7):2325–2340PubMedPubMedCentralCrossRefGoogle Scholar
  54. Decensi A, Puntoni M, Goodwin P, Cazzaniga M, Gennari A, Bonanni B, Gandini S (2010) Metformin and cancer risk in diabetic patients: a systematic review and meta-analysis. Cancer Prev Res (Phila) 3(11):1451–1461CrossRefGoogle Scholar
  55. Desborough MJR, Keeling DM (2017) The aspirin story – from willow to wonder drug. Br J Haematol 177(5):674–683PubMedCrossRefGoogle Scholar
  56. Deshpande A, Pasupuleti V, Rothberg MB (2015) Statin therapy and mortality from sepsis: a meta-analysis of randomized trials. Am J Med 128(4):410–417PubMedCrossRefGoogle Scholar
  57. Di Daniele N, Noce A, Vidiri MF, Moriconi E, Marrone G, Annicchiarico-Petruzzelli M, D’Urso G, Tesauro M, Rovella V, De Lorenzo A (2017) Impact of Mediterranean diet on metabolic syndrome, cancer and longevity. Oncotarget 8(5):8947–8979PubMedCrossRefGoogle Scholar
  58. Diamanti-Kandarakis E, Alexandraki K, Piperi C, Aessopos A, Paterakis T, Katsikis I, Panidis D (2007) Effect of metformin administration on plasma advanced glycation end product levels in women with polycystic ovary syndrome. Metabolism 56(1):129–134PubMedCrossRefGoogle Scholar
  59. Dias-Santagata D, Fulga TA, Duttaroy A, Feany MB (2007) Oxidative stress mediates tau-induced neurodegeneration in Drosophila. J Clin Invest 117(1):236–245PubMedCrossRefGoogle Scholar
  60. Dilman VM (1994) Ageing, rate of ageing and cancer. A search for preventive treatment. Ann N Y Acad Sci 719:454–455PubMedCrossRefGoogle Scholar
  61. Din FV, Valanciute A, Houde VP, Zibrova D, Green KA, Sakamoto K, Alessi DR, Dunlop MG (2012) Aspirin inhibits mTOR signaling, activates AMP-activated protein kinase, and induces autophagy in colorectal cancer cells. Gastroenterology 142(7):1504–15.e3PubMedPubMedCentralCrossRefGoogle Scholar
  62. Dowling RJ, Niraula S, Chang MC, Done SJ, Ennis M, McCready DR, Leong WL, Escallon JM, Reedijk M, Goodwin PJ, Stambolic V (2015) Changes in insulin receptor signaling underlie neoadjuvant metformin administration in breast cancer: a prospective window of opportunity neoadjuvant study. Breast Cancer Res BCR 17(1):32PubMedCrossRefGoogle Scholar
  63. Dulai PS, Singh S, Marquez E, Khera R, Prokop LJ, Limburg PJ, Gupta S, Murad MH (2016) Chemoprevention of colorectal cancer in individuals with previous colorectal neoplasia: systematic review and network meta-analysis. BMJ 355:i6188PubMedPubMedCentralCrossRefGoogle Scholar
  64. Edwards C, Canfield J, Copes N, Rehan M, Lipps D, Bradshaw PC (2014) D-beta-hydroxybutyrate extends lifespan in C. elegans. Ageing (Albany NY) 6(8):621–644Google Scholar
  65. Edwards C, Canfield J, Copes N, Brito A, Rehan M, Lipps D, Brunquell J, Westerheide SD, Bradshaw PC (2015) Mechanisms of amino acid-mediated lifespan extension in Caenorhabditis elegans. BMC Genet 16:8PubMedPubMedCentralCrossRefGoogle Scholar
  66. Eisen DP, Moore EM, Leder K et al (2017) AspiriN To Inhibit SEPSIS (ANTISEPSIS) randomised controlled trial protocol. BMJ Open 7(1):e013636PubMedPubMedCentralCrossRefGoogle Scholar
  67. Elwood PC, Morgan G, Pickering JE et al (2016) Aspirin in the treatment of cancer: reductions in metastatic spread and in mortality: a systematic review and meta-analyses of published studies. Ali R, ed. PLoS ONE 11(4):e0152402PubMedPubMedCentralCrossRefGoogle Scholar
  68. Emilsson L, Holme Ø, Bretthauer M, Cook N, Buring JE, Løberg M, Adami HO, Sesso HD, Gaziano MJ, Kalager M (2017) Systematic review with meta-analysis: the comparative effectiveness of aspirin vs. screening for colorectal cancer prevention. Aliment Pharmacol Ther 45(2):193–204PubMedCrossRefGoogle Scholar
  69. Eriksson L, Nyström T (2015) Antidiabetic agents and endothelial dysfunction – beyond glucose control. Basic Clin Pharmacol Toxicol 117:15–25PubMedCrossRefGoogle Scholar
  70. Fabbri E, Zoli M, Gonzalez-Freire M, Salive ME, Studenski SA, Ferrucci L (2015) Ageing and multimorbidity: new tasks, priorities, and frontiers for integrated gerontological and clinical research. J Am Med Dir Assoc 16(8):640–647PubMedPubMedCentralCrossRefGoogle Scholar
  71. Flynn JM, O’Leary MN, Zambataro CA, Academia EC, Presley MP, Garrett BJ, Zykovich A, Mooney SD, Strong R, Rosen CJ, Kapahi P, Nelson MD, Kennedy BK, Melov S (2013) Late-life rapamycin treatment reverses age-related heart dysfunction. Ageing Cell 12(5):851–862CrossRefGoogle Scholar
  72. Fontana L, Villareal DT, Weiss EP, Racette SB, Steger-May K, Klein S, Holloszy JO, Washington University School of Medicine CALERIE Group (2007) Calorie restriction or exercise: effects on coronary heart disease risk factors. A randomized, controlled trial. Am J Physiol Endocrinol Metab 293(1):E197–E202PubMedCrossRefGoogle Scholar
  73. Fontana L, Partridge L, Longo VD (2010) Extending healthy life span – from yeast to humans. Science 328(5976):321–326PubMedPubMedCentralCrossRefGoogle Scholar
  74. Forbes SA, Bindal N, Bamford S, Cole C, Kok CY, Beare D, Jia M, Shepherd R, Leung K, Menzies A, Teague JW, Campbell PJ, Stratton MR, Futreal PA (2011) COSMIC: mining complete cancer genomes in the Catalogue of Somatic Mutations in Cancer. Nucleic Acids Res 39(Database issue):D945–D950PubMedCrossRefGoogle Scholar
  75. Fougère B, Boulanger E, Nourhashémi F, Guyonnet S, Cesari M (2017) Chronic inflammation: accelerator of biological ageing. J Gerontol A Biol Sci Med Sci 72(9):1218–1225PubMedCrossRefGoogle Scholar
  76. Franceschi C, Campisi J (2014) Chronic inflammation (inflammaging) and its potential contribution to age-associated diseases. J Gerontol A Biol Sci Med Sci 69(Suppl 1):S4–S9PubMedCrossRefGoogle Scholar
  77. Franciosi M, Lucisano G, Lapice E, Strippoli GFM, Pellegrini F, Nicolucci A (2013) Metformin therapy and risk of cancer in patients with type 2 diabetes: systematic review. PLoS One 8(8):e71583PubMedPubMedCentralCrossRefGoogle Scholar
  78. Fukushima Y, Daida H, Morimoto T, Kasai T, Miyauchi K, Yamagishi S, Takeuchi M, Hiro T, Kimura T, Nakagawa Y, Yamagishi M, Ozaki Y, Matsuzaki M, JAPAN-ACS Investigators (2013) Relationship between advanced glycation end products and plaque progression in patients with acute coronary syndrome: the JAPAN-ACS sub-study. Cardiovasc Diabetol 12:5PubMedPubMedCentralCrossRefGoogle Scholar
  79. Fulcher J, O’Connell R, Voysey M, Emberson J, Blackwell L, Mihaylova B, Simes J, Collins R, Kirby A, Colhoun H, Braunwald E, La Rosa J, Pedersen TR, Tonkin A, Davis B, Sleight P, Franzosi MG, Baigent C, Keech A (2015) Efficacy and safety of LDL-lowering therapy among men and women: meta-analysis of individual data from 174,000 participants in 27 randomised trials. Lancet 385(9976):1397–1405PubMedCrossRefGoogle Scholar
  80. Gao Z, Yin J, Zhang J, Ward RE, Martin RJ, Lefevre M, Cefalu WT, Ye J (2009) Butyrate improves insulin sensitivity and increases energy expenditure in mice. Diabetes 58(7):1509–1517PubMedPubMedCentralCrossRefGoogle Scholar
  81. Gao Y, Li Y, Xue J, Jia Y, Hu J (2010) Effect of the anti-diabetic drug metformin on bone mass in ovariectomized rats. Eur J Pharmacol 635:231–236PubMedCrossRefGoogle Scholar
  82. Garimella S, Seshayamma V, Rao HJ, Kumar S, Kumar U, Saheb SH (2016) Effect of metformin on lipid profile of type II diabetes. Int J Intg Med Sci 3(11):449–453Google Scholar
  83. Gholizadeh S, Visweswaran GRR, Storm G, Hennink WE, Kamps JAAM, Kok RJ (2017) E-selectin targeted immunoliposomes for rapamycin delivery to activated endothelial cells. Int J Pharm 548(2):759–770Google Scholar
  84. Gilbert R, Al-Janabi A, Tomkins-Netzer O, Lightman S (2017) Statins as anti-inflammatory agents: a potential therapeutic role in sight-threatening non-infectious uveitis. Porto Biomed J 2(2):33–39CrossRefGoogle Scholar
  85. Giovannucci E, Harlan DM, Archer MC, Bergenstal RM, Gapstur SM, Habel LA, Pollak M, Regensteiner JG, Yee D (2010) Diabetes and cancer: a consensus report. Diabetes Care 33:1674–1685PubMedPubMedCentralCrossRefGoogle Scholar
  86. Gore DC, Wolf SE, Sanford A, Herndon DN, Wolfe RR (2005) Influence of metformin on glucose intolerance and muscle catabolism following severe burn injury. Ann Surg 241(2):334–342PubMedPubMedCentralCrossRefGoogle Scholar
  87. Gospodaryov DV, Yurkevych IS, Jafari M, Lushchak VI, Lushchak OV (2013) Lifespan extension and delay of age-related functional decline caused by Rhodiola rosea depends on dietary macronutrient balance. Longev Healthspan 2(1):5PubMedPubMedCentralCrossRefGoogle Scholar
  88. Griffin SJ, Leaver JK, Irving GJ (2017) Impact of metformin on cardiovascular disease: a meta-analysis of randomised trials among people with type 2 diabetes. Diabetologia 60(9):1620–1629PubMedPubMedCentralCrossRefGoogle Scholar
  89. Gronich N, Rennert G (2013) Beyond aspirin-cancer prevention with statins, metformin and bisphosphonates. Nat Rev Clin Oncol 10(11):625–642PubMedCrossRefGoogle Scholar
  90. Gruber J, Halliwell B (2017) Approaches for extending human healthspan: from antioxidants to healthspan pharmacology. Essays Biochem 61(3):389–399PubMedCrossRefGoogle Scholar
  91. Haddad M, Knani I, Bouzidi H, Berriche O, Hammami M, Kerkeni M (2016) Plasma levels of pentosidine, carboxymethyl-lysine, soluble receptor for advanced glycation end products, and metabolic syndrome: the metformin effect. Dis Markers 2016:6248264PubMedPubMedCentralCrossRefGoogle Scholar
  92. Halliwell B (2013) The antioxidant paradox: less paradoxical now? Br J Clin Pharmacol 75(3):637–644PubMedPubMedCentralCrossRefGoogle Scholar
  93. Hansen M, Kennedy BK (2016) Does longer lifespan mean longer healthspan? Trends Cell Biol 26(8):565–568PubMedPubMedCentralCrossRefGoogle Scholar
  94. Harman AD (1956) Ageing: a theory based on free radical and radiation chemistry. J Gerontol 11(3):298–300PubMedCrossRefGoogle Scholar
  95. Harman D (1972) Free radical theory of ageing: dietary implications. Am J Clin Nutr 25(8):839–843PubMedCrossRefGoogle Scholar
  96. Harrington LA, Harley CB (1988) Effect of vitamin E on lifespan and reproduction in Caenorhabditis elegans. Mech Ageing Dev 43(1):71–78PubMedCrossRefGoogle Scholar
  97. 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, Miller RA (2009) Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. Nature 460(7253):392–395PubMedPubMedCentralCrossRefGoogle Scholar
  98. Hayashi S, McMahon AP (2002) Efficient recombination in diverse tissues by a tamoxifen-inducible form of Cre: a tool for temporally regulated gene activation/inactivation in the mouse. Dev Biol 244(2):305–318PubMedCrossRefGoogle Scholar
  99. Hedner T, Kjeldsen SE, Narkiewicz K, Oparil S (2016) The polypill: an emerging treatment alternative for secondary prevention of cardiovascular disease. Blood Press 25(5):276–279PubMedCrossRefGoogle Scholar
  100. Hegazy SK (2015) Evaluation of the anti-osteoporotic effects of metformin and sitagliptin in postmenopausal diabetic women. J Bone Miner Metab 33(2):207–212PubMedCrossRefGoogle Scholar
  101. Hervás D, Fornés-Ferrer V, Gómez-Escribano AP, Sequedo MD, Peiró C, Millán JM, Sequedo MD, Peiró C, Millán JM, Vázquez-Manrique RP (2017) Metformin intake associates with better cognitive function in patients with Huntington’s disease. PLoS One 12(6):e0179283PubMedPubMedCentralCrossRefGoogle Scholar
  102. Hochmuth F, Jochem M, Schlattmann P (2016) Meta-analysis of aspirin use and risk of lung cancer shows notable results. Eur J Cancer Prev 25(4):259–268PubMedCrossRefGoogle Scholar
  103. Holcombe A, Ammann E, Espeland MA, Kelley BJ, Manson JE, Wallace R, Robinson J (2017) Chronic use of aspirin and total white matter lesion volume: results from the women’s health initiative memory study of magnetic resonance imageing study. J Stroke Cerebrovasc Dis 26(10):2128–2136PubMedCrossRefGoogle Scholar
  104. Holman RR, Paul SK, Bethel MA, Matthews DR, Neil HAW (2008) 10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med 359:1577–1589PubMedCrossRefGoogle Scholar
  105. Holthoff JH, Wang Z, Seely KA, Gokden N, Mayeux PR (2012) Resveratrol improves renal microcirculation, protects the tubular epithelium, and prolongs survival in a mouse model of sepsis-induced acute kidney injury. Kidney Int 81(4):370–378PubMedCrossRefGoogle Scholar
  106. Hostalek U, Gwilt M, Hildemann S (2015) Therapeutic use of metformin in prediabetes and diabetes prevention. Drugs 75(10):1071–1094PubMedPubMedCentralCrossRefGoogle Scholar
  107. Hou YC, Hu Q, Huang J, Fang JY, Xiong H (2017) Metformin therapy and the risk of colorectal adenoma in patients with type 2 diabetes: a meta-analysis. Oncotarget 8(5):8843–8853PubMedCrossRefGoogle Scholar
  108. Huang TB, Yan Y, Guo ZF, Zhang XL, Liu H, Geng J, Yao XD, Zheng JH (2014) Aspirin use and the risk of prostate cancer: a meta-analysis of 24 epidemiologic studies. Int Urol Nephrol 46(9):1715–1728PubMedCrossRefGoogle Scholar
  109. Huang XZ, Gao P, Sun JX, Song YX, Tsai CC, Liu J, Chen XW, Chen P, Xu HM, Wang ZN (2015) Aspirin and nonsteroidal anti-inflammatory drugs after but not before diagnosis are associated with improved breast cancer survival: a meta-analysis. Cancer Causes Control 26(4):589–600PubMedCrossRefGoogle Scholar
  110. Huang X, Chen Y, Wu J, Zhang X, Wu CC, Zhang CY, Sun SS, Chen WJ (2017) Aspirin and non-steroidal anti-inflammatory drugs use reduce gastric cancer risk: a dose-response meta-analysis. Oncotarget 8(3):4781–4795PubMedGoogle Scholar
  111. Hubbard BP, Sinclair DA (2014) Small molecule SIRT1 activators for the treatment of ageing and age-related diseases. Trends Pharmacol Sci 35(3):146–154PubMedPubMedCentralCrossRefGoogle Scholar
  112. Hunt PR, Son TG, Wilson MA, Yu QS, Wood WH, Zhang Y, Becker KG, Greig NH, Mattson MP, Camandola S, Wolkow CA (2011) Extension of lifespan in C. elegans by naphthoquinones that act through stress hormesis mechanisms. PLoS One 6(7):e21922PubMedPubMedCentralCrossRefGoogle Scholar
  113. Ibanez B, James S, Agewall S, Antunes MJ, Bucciarelli-Ducci C, Bueno H, Caforio ALP, Crea F, Goudevenos JA, Halvorsen S, Hindricks G, Kastrati A, Lenzen MJ, Prescott E, Roffi M, Valgimigli M, Varenhorst C, Vranckx P, Widimský P, ESC Scientific Document Group (2018) 2017 ESC guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation: the Task Force for the management of acute myocardial infarction in patients presenting with ST-segment elevation of the European Society of Cardiology (ESC). Eur Heart J 39(2):119–177PubMedPubMedCentralCrossRefGoogle Scholar
  114. Ishibashi Y, Matsui T, Takeuchi M, Yamagishi S (2012) Metformin inhibits advanced glycation end products (AGEs)-induced renal tubular cell injury by suppressing reactive oxygen species generation via reducing receptor for AGEs (RAGE) expression. Horm Metab Res 44(12):891–895PubMedCrossRefGoogle Scholar
  115. Ishii N, Senoo-Matsuda N, Miyake K, Yasuda K, Ishii T, Hartman PS, Furukawa S (2004) Coenzyme Q10 can prolong C. elegans lifespan by lowering oxidative stress. Mech Ageing Dev 125(1):41–46PubMedCrossRefGoogle Scholar
  116. Islam MM, Yang HC, Nguyen PA, Poly TN, Huang CW, Kekade S, Khalfan AM, Debnath T, Li YJ, Abdul SS (2017) Exploring association between statin use and breast cancer risk: an updated meta-analysis. Arch Gynecol Obstet 296(6):1043–1053PubMedCrossRefGoogle Scholar
  117. Isoda K, Young JL, Zirlik A, MacFarlane LA, Tsuboi N, Gerdes N, Schönbeck U, Libby P (2006) Metformin inhibits proinflammatory responses and nuclear factor-κB in human vascular wall cells. Arterioscler Thromb Vasc Biol 26:611–617PubMedCrossRefGoogle Scholar
  118. Ittaman SV, VanWormer JJ, Rezkalla SH (2014) The role of aspirin in the prevention of cardiovascular disease. Clin Med Res 12(3–4):147–154PubMedPubMedCentralCrossRefGoogle Scholar
  119. Johnston O, Rose CL, Webster AC, Gill JS (2008) Sirolimus is associated with new-onset diabetes in kidney transplant recipients. J Am Soc Nephrol JASN 19(7):1411–1418PubMedCrossRefGoogle Scholar
  120. Joo SJ (2012) Anti-inflammatory effects of statins beyond cholesterol lowering. Korean Circ J 42(9):592–594PubMedPubMedCentralCrossRefGoogle Scholar
  121. Jyrkkä J, Enlund H, Korhonen MJ, Sulkava R, Hartikainen S (2009) Polypharmacy status as an indicator of mortality in an elderly population. Drugs Ageing 26(12):1039–1048CrossRefGoogle Scholar
  122. Kamal S, Khan MA, Seth A, Cholankeril G, Gupta D, Singh U, Kamal F, Howden CW, Stave C, Nair S, Satapathy SK, Ahmed A (2017) Beneficial effects of statins on the rates of hepatic fibrosis, hepatic decompensation, and mortality in chronic liver disease: a systematic review and meta-analysis. Am J Gastroenterol 112(10):1495–1505PubMedCrossRefGoogle Scholar
  123. Kang HL, Benzer S, Min KT (2002) Life extension in Drosophila by feeding a drug. Proc Natl Acad Sci U S A 99(2):838–843PubMedPubMedCentralCrossRefGoogle Scholar
  124. Kapahi P, Zid BM, Harper T, Koslover D, Sapin V, Benzer S (2004) Regulation of lifespan in Drosophila by modulation of genes in the TOR signaling pathway. Curr Biol 14(10):885–890PubMedPubMedCentralCrossRefGoogle Scholar
  125. Kapahi P, Chen D, Rogers AN, Katewa SD, Li PW, Thomas EL, Kockel L (2010) With TOR, less is more: a key role for the conserved nutrient-sensing TOR pathway in ageing. Cell Metab 11(6):453–465PubMedPubMedCentralCrossRefGoogle Scholar
  126. Kavalipati N, Shah J, Ramakrishan A, Vasnawala H (2015) Pleiotropic effects of statins. Indian J Endocrinol Metabol 19(5):554–562CrossRefGoogle Scholar
  127. Kelesidis T (2012) Statins as antiviral and anti-inflammatory therapy in HIV infection. Virol Mycol 1:e102CrossRefGoogle Scholar
  128. Khan S, Jena G (2014) Sodium butyrate, a HDAC inhibitor ameliorates eNOS, iNOS and TGF-β1-induced fibrogenesis, apoptosis and DNA damage in the kidney of juvenile diabetic rats. Food Chem Toxicol 73:127–139PubMedCrossRefGoogle Scholar
  129. Kim J, Takahashi M, Shimizu T, Shirasawa T, Kajitha M, Kanayama A, Miyamoto Y (2008) Effects of a potent antioxidant, platinum nanoparticle, on the lifespan of Caenorhabditis elegans. Mech Ageing Dev 129(6):322–331PubMedCrossRefGoogle Scholar
  130. Kim RG, Loomba R, Prokop LJ, Singh S (2017) Statin use and risk of cirrhosis and related complications in patients with chronic liver diseases: a systematic review and meta-analysis. Clin Gastroenterol Hepatol 15(10):1521–1530.e8PubMedPubMedCentralCrossRefGoogle Scholar
  131. Kitagawa K, Hosomi N, Nagai Y, Kagimura T, Ohtsuki T, Origasa H, Minematsu K, Uchiyama S, Nakamura M, Matsumoto M, J-STARS Investigators (2017) Reduction in high-sensitivity C-reactive protein levels in patients with ischemic stroke by statin treatment: Hs-CRP Sub-Study in J-STARS. J Atheroscler Thromb 24(10):1039–1047PubMedPubMedCentralCrossRefGoogle Scholar
  132. Knoll GA, Kokolo MB, Mallick R, Beck A, Buenaventura CD, Ducharme R, Barsoum R, Bernasconi C, Blydt-Hansen TD, Ekberg H, Felipe CR, Firth J, Gallon L, Gelens M, Glotz D, Gossmann J, Guba M, Morsy AA, Salgo R, Scheuermann EH, Tedesco-Silva H, Vitko S, Watson C, Fergusson D (2014) Effect of sirolimus on malignancy and survival after kidney transplantation: systematic review and meta-analysis of individual patient data. BMJ 349:g6679PubMedPubMedCentralCrossRefGoogle Scholar
  133. Ko HHT, Lareu RR, Dix BR, Hughes JD (2017) Statins: antimicrobial resistance breakers or makers?. Flores-Valdez MA. PeerJ 5:e3952PubMedPubMedCentralCrossRefGoogle Scholar
  134. Kolosova NG, Stefanova NA, Muraleva NA, Skulachev VP (2012) The mitochondria-targeted antioxidant SkQ1 but not N-acetylcysteine reverses ageing-related biomarkers in rats. Ageing (Albany NY) 4(10):686–694Google Scholar
  135. Kong P, Wu R, Liu X et al (2016) The effects of anti-inflammatory drug treatment in gastric cancer prevention: an update of a meta-analysis. J Cancer 7(15):2247–2257PubMedPubMedCentralCrossRefGoogle Scholar
  136. Konings IR, Verweij J, Wiemer EA, Sleijfer S (2009) The applicability of mTOR inhibition in solid tumors. Curr Cancer Drug Targets 9(3):439–450PubMedCrossRefGoogle Scholar
  137. Krackhardt F, Kočka V, Waliszewski MW, Utech A, Lustermann M, Hudec M, Studenčan M, Schwefer M, Yu J, Jeong MH, Ahn T, Wan Ahmad WA, Boxberger M, Schneider A, Leschke M (2017) Polymer-free sirolimus-eluting stents in a large-scale all-comers population. Open Heart 4:e000592PubMedPubMedCentralCrossRefGoogle Scholar
  138. Kraig E, Linehan LA, Liang H, Romo TQ, Liu Q, Wu Y, Benavides AD, Curiel TJ, Javors MA, Musi N, Chiodo L, Koek W, Gelfond JAL, Kellogg DL (2018) A randomized control trial to establish the feasibility and safety of rapamycin treatment in an older human cohort: immunological, physical performance, and cognitive effects. Exp Gerontol. pii: S0531-5565(17)30913-0Google Scholar
  139. Kuan YC, Huang KW, Lin CL, Hu CJ, Kao CH (2017) Effects of metformin exposure on neurodegenerative diseases in elderly patients with type 2 diabetes mellitus. Prog Neuropsychopharmacol Biol Psychiatry 79(Pt B):77–83PubMedCrossRefGoogle Scholar
  140. Kunchandy E, Rao MNA (1990) Oxygen radical scavenging activity of curcumin. Int J Pharm 58:237–240CrossRefGoogle Scholar
  141. Kurdi A, Martinet W, De Meyer GRY (2018) mTOR inhibition and cardiovascular diseases: dyslipidemia and atherosclerosis. Transplantation 102(2S Suppl 1):S44–S46PubMedGoogle Scholar
  142. Lafeber M, Spiering W, Visseren FLJ, Grobbee DE (2016) Multifactorial prevention of cardiovascular disease in patients with hypertension: the cardiovascular polypill. Curr Hypertens Rep 18:40PubMedPubMedCentralCrossRefGoogle Scholar
  143. Lamming DW, Ye L, Sabatini DM, Baur JA (2013) Rapalogs and mTOR inhibitors as anti-ageing therapeutics. J Clin Invest 123(3):980–989PubMedPubMedCentralCrossRefGoogle Scholar
  144. Lee KS, Lee BS, Semnnani S, Avanesian A, Um CY, Jeon HJ, Seong KM, Yu K, Min KJ, Jafari M (2010a) Curcumin extends life span, improves health span, and modulates the expression of age-associated ageing genes in Drosophila melanogaster. Rejuvenation Res 13(5):561–570PubMedCrossRefGoogle Scholar
  145. Lee SJ, Hwang AB, Kenyon C (2010b) Inhibition of respiration extends C. elegans life span via reactive oxygen species that increase HIF-1 activity. Curr Biol 20:2131–2136PubMedPubMedCentralCrossRefGoogle Scholar
  146. Leggio M, Bendini MG, Caldarone E, Lombardi M, Severi P, D’Emidio S, Stavri DC, Armeni M, Bravi V, Mazza A (2017) Low-dose aspirin for primary prevention of cardiovascular events in patients with diabetes: benefit or risk? Diabetes Metab 44(3):217–225Google Scholar
  147. Lei Y, Yi Y, Liu Y, Liu X, Keller ET, Qian CN, Zhang J, Lu Y (2017) Metformin targets multiple signaling pathways in cancer. Chin J Cancer 36:17PubMedPubMedCentralCrossRefGoogle Scholar
  148. Leya M, Stone NJ (2017) Statin prescribing in the elderly: special considerations. Curr Atheroscler Rep 19(11):47PubMedCrossRefGoogle Scholar
  149. Li BH, Ma XF, Wang Y, Tian WX (2005) Structure-activity relationship of polyphenols that inhibit fatty acid synthase. J Biochem (Tokyo) 138:679–685CrossRefGoogle Scholar
  150. Li Y, Liu L, Wang B, Wang J, Chen D (2013) Metformin in non-alcoholic fatty liver disease: a systematic review and meta-analysis. Biomed Rep 1(1):57–64PubMedCrossRefGoogle Scholar
  151. Li J, Kim SG, Blenis J (2014) Rapamycin: one drug, many effects. Cell Metab 19(3):373–379PubMedPubMedCentralCrossRefGoogle Scholar
  152. Li P, Wu H, Zhang H, Shi Y, Xu J, Ye Y, Xia D, Yang J, Cai J, Wu Y (2015) Aspirin use after diagnosis but not prediagnosis improves established colorectal cancer survival: a meta-analysis. Gut 64(9):1419–1425PubMedCrossRefGoogle Scholar
  153. Li X, Li T, Liu Z, Gou S, Wang C (2017) The effect of metformin on survival of patients with pancreatic cancer: a meta-analysis. Sci Rep 7:5825PubMedPubMedCentralCrossRefGoogle Scholar
  154. Li GM, Zhao J, Li B, Zhang XF, Ma JX, Ma XL, Liu J (2018) The anti-inflammatory effects of statins on patients with rheumatoid arthritis: a systemic review and meta-analysis of 15 randomized controlled trials. Autoimmun Rev 17(3):215–225Google Scholar
  155. Lin K, Dorman JB, Rodan A, Kenyon C (1997) daf-16: an HNF-3/forkhead family member that can function to double the life-span of Caenorhabditis elegans. Science 278:1319–1322PubMedCrossRefGoogle Scholar
  156. Lin WS, Chen JY, Wang JC, Chen LY, Lin CH, Hsieh TR, Wang MF, Fu TF, Wang PY (2014) The anti-ageing effects of Ludwigia octovalvis on Drosophila melanogaster and SAMP8 mice. Age (Dordr) 36(2):689–703CrossRefGoogle Scholar
  157. Ling Y, Yang L, Huang H, Hu X, Zhao C, Huang H, Ying Y (2015) Prognostic significance of statin use in colorectal cancer: a systematic review and meta-analysis. Medicine (Baltimore) 94(25):e908CrossRefGoogle Scholar
  158. Liu Y, Chen J-Q, Xie L, Wang J, Li T, He Y, Gao Y, Qin X, Li S (2014a) Effect of aspirin and other non-steroidal anti-inflammatory drugs on prostate cancer incidence and mortality: a systematic review and meta-analysis. BMC Med 12:55PubMedPubMedCentralCrossRefGoogle Scholar
  159. Liu YM, Shao YQ, He Q (2014b) Sirolimus for treatment of autosomal-dominant polycystic kidney disease: a meta-analysis of randomized controlled trials. Transplant Proc 46(1):66–74PubMedCrossRefGoogle Scholar
  160. Liu B, Yi Z, Guan X, Zeng YX, Ma F (2017a) The relationship between statins and breast cancer prognosis varies by statin type and exposure time: a meta-analysis. Breast Cancer Res Treat 164(1):1–11PubMedCrossRefGoogle Scholar
  161. Liu J, Liu D, Li J, Zhu L, Zhang C, Lei K, Xu Q, You R (2017b) Efficacy and safety of everolimus for maintenance immunosuppression of kidney transplantation: a meta-analysis of randomized controlled trials. PLoS One 12(1):e0170246PubMedPubMedCentralCrossRefGoogle Scholar
  162. Lockrow J, Prakasam A, Huang P, Bimonte-Nelson H, Sambamurti K, Granholm AC (2009) Cholinergic degeneration and memory loss delayed by vitamin E in a Down syndrome mouse model. Exp Neurol 216(2):278–289PubMedCrossRefGoogle Scholar
  163. Lu L, Shi L, Zeng J, Wen Z (2017) Aspirin as a potential modality for the chemoprevention of breast cancer: a dose-response meta-analysis of cohort studies from 857,831 participants. Oncotarget 8(25):40389–40401PubMedPubMedCentralGoogle Scholar
  164. Lucanic M, Lithgow GJ, Alavez S (2013) Pharmacological lifespan extension of invertebrates. Ageing Res Rev 12(1):445–458PubMedCrossRefGoogle Scholar
  165. Luo T, Yan HM, He P, Luo Y, Yang YF, Zheng H (2012) Aspirin use and breast cancer risk: a meta-analysis. Breast Cancer Res Treat 131(2):581–587PubMedCrossRefGoogle Scholar
  166. Luong N, Davies CR, Wessells RJ, Graham SM, King MT, Veech R, Bodmer R, Oldham SM (2006) Activated FOXO-mediated insulin resistance is blocked by reduction of TOR activity. Cell Metab 4(2):133–142PubMedCrossRefGoogle Scholar
  167. Ma TC, Buescher JL, Oatis B, Funk JA, Nash AJ, Carrier RL, Hoyt KR (2007) Metformin therapy in a transgenic mouse model of Huntington’s disease. Neurosci Lett 411:98–103PubMedCrossRefGoogle Scholar
  168. Maher RL, Hanlon JT, Hajjar ER (2014) Clinical consequences of polypharmacy in elderly. Expert Opin Drug Saf 13(1):57–65PubMedCrossRefGoogle Scholar
  169. Mai QG, Zhang ZM, Xu S, Lu M, Zhou RP, Zhao L, Jia CH, Wen ZH, Jin DD, Bai XC (2011) Metformin stimulates osteoprotegerin and reduces RANKL expression in osteoblasts and ovariectomized rats. J Cell Biochem 112:2902–2909PubMedCrossRefGoogle Scholar
  170. Manthravadi S, Shrestha A, Madhusudhana S (2016) Impact of statin use on cancer recurrence and mortality in breast cancer: a systematic review and meta-analysis. Int J Cancer 139(6):1281–1288PubMedCrossRefGoogle Scholar
  171. Markaki M, Tavernarakis N (2010) Modeling human diseases in Caenorhabditis elegans. Biotechnol J 5(12):1261–1276PubMedCrossRefGoogle Scholar
  172. Martinet W, De Loof H, De Meyer GR (2014) mTOR inhibition: a promising strategy for stabilization of atherosclerotic plaques. Atherosclerosis 233(2):601–607PubMedCrossRefGoogle Scholar
  173. Martin-Montalvo A, Mercken EM, Mitchell SJ, Palacios HH, Mote PL, Scheibye-Knudsen M, Gomes AP, Ward TM, Minor RK, Blouin MJ, Schwab M, Pollak M, Zhang Y, Yu Y, Becker KG, Bohr VA, Ingram DK, Sinclair DA, Wolf NS, Spindler SR, Bernier M, de Cabo R (2013) Metformin improves healthspan and lifespan in mice. Nat Commun 4:2192PubMedPubMedCentralCrossRefGoogle Scholar
  174. Massoud O, Wiesner RH (2012) The use of sirolimus should be restricted in liver transplantation. J Hepatol 56(1):288–290PubMedCrossRefGoogle Scholar
  175. Mattson MP (2008) Hormesis and disease resistance: activation of cellular stress response pathways. Hum Exp Toxicol 27(2):155–162PubMedCrossRefGoogle Scholar
  176. McColl G, Killilea DW, Hubbard AE, Vantipalli MC, Melov S, Lithgow GJ (2008) Pharmacogenetic analysis of lithium-induced delayed ageing in Caenorhabditis elegans. J Biol Chem 283(1):350–357PubMedCrossRefGoogle Scholar
  177. McDonald, Maizi BM, Arking R (2013) Chemical regulation of mid- and late-life longevities in Drosophila. Exp Gerontol 48:240–249PubMedCrossRefGoogle Scholar
  178. McNeil JJ, Woods RL, Nelson MR, Murray AM, Reid CM, Kirpach B, Storey E, Shah RC, Wolfe RS, Tonkin AM, Newman AB, Williamson JD, Lockery JE, Margolis KL, Ernst ME, Abhayaratna WP, Stocks N, Fitzgerald SM, Trevaks RE, Orchard SG, Beilin LJ, Donnan GA, Gibbs P, Johnston CI, Grimm RH, ASPREE Investigator Group (2017) Baseline characteristics of participants in the ASPREE (ASPirin in Reducing Events in the Elderly) study. J Gerontol A Biol Sci Med Sci 72(11):1586–1593PubMedPubMedCentralCrossRefGoogle Scholar
  179. McPhee JS, French DP, Jackson D, Nazroo J, Pendleton N, Degens H (2016) Physical activity in older age: perspectives for healthy ageing and frailty. Biogerontology 17:567–580PubMedPubMedCentralCrossRefGoogle Scholar
  180. Mehrbod P, Omar AR, Hair-Bejo M, Haghani A, Ideris A (2014) Mechanisms of action and efficacy of statins against influenza. Biomed Res Int 2014:872370PubMedPubMedCentralCrossRefGoogle Scholar
  181. Meireles CG, Pereira SA, Valadares LP, Rêgo DF, Simeoni LA, Guerra ENS, Lofrano-Porto A (2017) Effects of metformin on endometrial cancer: systematic review and meta-analysis. Gynecol Oncol 147(1):167–180PubMedCrossRefGoogle Scholar
  182. Melov S, Ravenscroft J, Malik S, Gill MS, Walker DW, Clayton PE, Wallace DC, Malfroy B, Doctrow SR, Lithgow GJ (2000) Extension of life-span with superoxide dismutase/catalase mimetics. Science 289(5484):1567–1569PubMedCrossRefGoogle Scholar
  183. Memisogullari R, Gümüştekin K, Dane Ş, Akçay F (2008) Effect of preinjury supplementation of selenium or vitamin E on lipid peroxidation and antioxidant enzymes in burn injury. Turk J Med Sci 38(6):545–548Google Scholar
  184. Meng F, Song L, Wang W (2017) Metformin improves overall survival of colorectal cancer patients with diabetes: a meta-analysis. J Diabetes Res 2017:5063239PubMedPubMedCentralCrossRefGoogle Scholar
  185. Messow CM, Isles C (2017) Meta-analysis of statins in chronic kidney disease: who benefits? QJM 110(8):493–500PubMedCrossRefGoogle Scholar
  186. Millburn GH, Crosby MA, Gramates LS, Tweedie S, FlyBase Consortium (2016) FlyBase portals to human disease research using Drosophila models. Dis Model Mech 9(3):245–252PubMedPubMedCentralCrossRefGoogle Scholar
  187. Miller RA, Harrison DE, Astle CM, Baur JA, Boyd AR, de Cabo R, Fernandez E, Flurkey K, Javors MA, Nelson JF, Orihuela CJ, Pletcher S, Sharp ZD, Sinclair D, Starnes JW, Wilkinson JE, Nadon NL, Strong R (2011) Rapamycin, but not resveratrol or simvastatin, extends life span of genetically heterogeneous mice. J Gerontol A Biol Sci Med Sci 66(2):191–201PubMedCrossRefGoogle Scholar
  188. Mills EJ, Wu P, Alberton M, Kanters S, Lanas A, Lester R (2012) Low-dose aspirin and cancer mortality: a meta-analysis of randomized trials. Am J Med 125(6):560–567PubMedCrossRefGoogle Scholar
  189. Miquel J, Fleming J, Economos AC (1982) Antioxidants, metabolic rate and ageing in Drosophila. Arch Gerontol Geriatr 1(2):159–165PubMedCrossRefGoogle Scholar
  190. Mortensen MB, Falk E (2018) Primary prevention with statins in the elderly. J Am Coll Cardiol 71(1):85–94PubMedCrossRefGoogle Scholar
  191. Moskalev A, Chernyagina E, Tsvetkov V, Fedintsev A, Shaposhnikov M, Krut'ko V, Zhavoronkov A, Kennedy BK (2016) Developing criteria for evaluation of geroprotectors as a key stage toward translation to the clinic. Ageing Cell 15(3):407–415CrossRefGoogle Scholar
  192. Moskalev A, Chernyagina E, Kudryavtseva A, Shaposhnikov M (2017) Geroprotectors: a unified concept and screening approaches. Ageing Dis 8(3):354–363CrossRefGoogle Scholar
  193. Muntoni S (1999) Metformin and fatty acids. Diabetes Care 22(1):179–180PubMedCrossRefGoogle Scholar
  194. Musi N, Hirshman MF, Nygren J, Svanfeldt M, Bavenholm P, Rooyackers O, Zhou G, Williamson JM, Ljunqvist O, Efendic S, Moller DE, Thorell A, Goodyear LJ (2002) Metformin increases AMP-activated protein kinase activity in skeletal muscle of subjects with type 2 diabetes. Diabetes 51(7):2074–2081PubMedCrossRefGoogle Scholar
  195. Muzumdar R, Allison DB, Huffman DM, Ma X, Atzmon G, Einstein FH, Fishman S, Poduval AD, McVei T, Keith SW, Barzilai N (2008) Visceral adipose tissue modulates mammalian longevity. Ageing Cell 7(3):438–440CrossRefGoogle Scholar
  196. Naci H, Brugts JJ, Fleurence R, Tsoi B, Toor H, Ades AE (2013) Comparative benefits of statins in the primary and secondary prevention of major coronary events and all-cause mortality: a network meta-analysis of placebo-controlled and active-comparator trials. Eur J Prev Cardiol 20(4):641–657PubMedCrossRefGoogle Scholar
  197. Nakashima K, Ishihara T, Yokota O, Terada S, Trojanowski JQ, Lee VM, Kuroda S (2004) Effects of alpha-tocopherol on an animal model of tauopathies. Free Radic Biol Med 37(2):176–186PubMedCrossRefGoogle Scholar
  198. Newman JC, Verdin E (2014) β-hydroxybutyrate: much more than a metabolite. Diabetes Res Clin Pract 106:173–181PubMedPubMedCentralCrossRefGoogle Scholar
  199. Newman JC, Milman S, Hashmi SK, Austad SN, Kirkland JL, Halter JB, Barzilai N (2016) Strategies and challenges in clinical trials targeting human ageing. J Gerontol Ser A Biol Med Sci 71(11):1424–1434CrossRefGoogle Scholar
  200. Ng TP, Feng L, Yap KB, Lee TS, Tan CH, Winblad B (2014) Long-term metformin usage and cognitive function among older adults with diabetes. J Alzheimers Dis 41(1):61–68PubMedCrossRefGoogle Scholar
  201. Nony PA, Kennett SB, Glasgow WC, Olden K, Roberts JD (2005) 15SLipoxygenase- 2 mediates arachidonic acid-stimulated adhesion of human breast carcinoma cells through the activation of TAK1, MKK6, and p38 MAPK. J Biol Chem 280:31413–31419PubMedCrossRefGoogle Scholar
  202. Oberdoerffer P, Michan S, McVay M, Mostoslavsky R, Vann J, Park SK, Hartlerode A, Stegmuller J, Hafner A, Loerch P, Wright SM, Mills KD, Bonni A, Yankner BA, Scully R, Prolla TA, Alt FW, Sinclair DA (2008) SIRT1 redistribution on chromatin promotes genomic stability but alters gene expression during ageing. Cell 135(5):907–918PubMedPubMedCentralCrossRefGoogle Scholar
  203. Oesterle A, Laufs U, Liao JK (2017) Pleiotropic effects of statins on the cardiovascular system. Circ Res 120(1):229–243PubMedPubMedCentralCrossRefGoogle Scholar
  204. Onken B, Driscoll M (2010) 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 5(1):e8758PubMedPubMedCentralCrossRefGoogle Scholar
  205. Opelz G, Unterrainer C, Süsal C, Döhler B (2016) Immunosuppression with mammalian target of rapamycin inhibitor and incidence of post-transplant cancer in kidney transplant recipients. Nephrol Dial Transplant 31(8):1360–1367PubMedCrossRefGoogle Scholar
  206. Orkaby AR, Gaziano JM, Djousse L, Driver JA (2017) Statins for primary prevention of cardiovascular events and mortality in older men. J Am Geriatr Soc 65(11):2362–2368. 15PubMedPubMedCentralCrossRefGoogle Scholar
  207. Ornelas A, Zacharias-Millward N, Menter DG, Davis JS, Lichtenberger L, Hawke D, Hawk E, Vilar E, Bhattacharya P, Millward S (2017) Beyond COX-1: the effects of aspirin on platelet biology and potential mechanisms of chemoprevention. Cancer Metastasis Rev 36(2):289–303PubMedPubMedCentralCrossRefGoogle Scholar
  208. Ott C, Jacobs K, Haucke E, Navarrete Santos A, Grune T, Simm A (2014) Role of advanced glycation end products in cellular signaling. Redox Biol 2:411–429PubMedPubMedCentralCrossRefGoogle Scholar
  209. Otto CM (2016) Statins for primary prevention of cardiovascular disease. BMJ 355:i6334PubMedCrossRefGoogle Scholar
  210. Oxenkrug G, Navrotskaya V, Vorobyova L, Summergrad P (2012) Minocycline effect on life and health span of Drosophila melanogaster. Ageing Dis 3(5):352–359Google Scholar
  211. Paleari L, Puntoni M, Clavarezza M, DeCensi M, Cuzick J, DeCensi A (2016) PIK3CA mutation, aspirin use after diagnosis and survival of colorectal cancer. A systematic review and meta-analysis of epidemiological studies. Clin Oncol (R Coll Radiol) 28(5):317–326CrossRefGoogle Scholar
  212. Palmer SC, Mavridis D, Nicolucci A, Johnson DW, Tonelli M, Craig JC, Maggo J, Gray V, De Berardis G, Ruospo M, Natale P, Saglimbene V, Badve SV, Cho Y, Nadeau-Fredette AC, Burke M, Faruque L, Lloyd A, Ahmad N, Liu Y, Tiv S, Wiebe N, Strippoli GF (2016) Comparison of clinical outcomes and adverse events associated with glucose-lowering drugs in patients with type 2 diabetes: a meta-analysis. JAMA 316:313–324PubMedPubMedCentralCrossRefGoogle Scholar
  213. Papanagnou P, Stivarou T, Papageorgiou I, Papadopoulos GE, Pappas A (2017) Marketed drugs used for the management of hypercholesterolemia as anticancer armament. Oncol Targets Ther 10:4393–4411CrossRefGoogle Scholar
  214. Papanas N, Maltezos E, Mikhailidis DP (2012) Metformin and heart failure: never say never again. Expert Opin Pharmacother 13(1):1–8PubMedCrossRefGoogle Scholar
  215. Park Y, Pariza MW (2001) Lipoxygenase inhibitors inhibit heparin-releasable lipoprotein lipase activity in 3T3-L1 adipocytes and enhance body fat reduction in mice by conjugatedlinoleic acid. Biochim Biophys Acta 1534:27–33PubMedCrossRefGoogle Scholar
  216. Pasyukova EG, Vaiserman AM (2017) HDAC inhibitors: a new promising drug class in anti-ageing research. Mech Ageing Dev 166:6–15PubMedCrossRefGoogle Scholar
  217. Patel R, Shah G (2017) Effect of metformin on clinical, metabolic and endocrine outcomes in women with polycystic ovary syndrome: a meta-analysis of randomized controlled trials. Curr Med Res Opin 33(9):1545–1557PubMedCrossRefGoogle Scholar
  218. Patrignani P, Patrono C (2016) Aspirin and cancer. J Am Coll Cardiol 68(9):967–976PubMedCrossRefGoogle Scholar
  219. 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, de Cabo R (2008) Resveratrol delays age-related deterioration and mimics transcriptional aspects of dietary restriction without extending life span. Cell Metab 8(2):157–168PubMedPubMedCentralCrossRefGoogle Scholar
  220. Perluigi M, Di Domenico F, Butterfield DA (2015) mTOR signaling in ageing and neurodegeneration: at the crossroad between metabolism dysfunction and impairment of autophagy. Neurobiol Dis 84:39–49PubMedCrossRefGoogle Scholar
  221. Phillips T, Leeuwenburgh C (2004) Lifelong aspirin supplementation as a means to extending life span. Rejuvenation Res 7:243–251PubMedCrossRefGoogle Scholar
  222. Pietsch K, Saul N, Menzel R, Stürzenbaum SR, Steinberg CE (2009) Quercetin mediated lifespan extension in Caenorhabditis elegans is modulated by age-1, daf-2, sek-1 and unc-43. Biogerontology 10(5):565–578PubMedCrossRefGoogle Scholar
  223. Poole JC, Thain A, Perkins ND, Roninson IB (2004) Induction of transcription by p21Waf1/Cip1/Sdi1: role of NFkappaB and effect of non-steroidal anti-inflammatory drugs. Cell Cycle 3(7):931–940PubMedCrossRefGoogle Scholar
  224. Porta EA, Joun NS, Nitta RT (1980) Effects of the type of dietary fat at two levels of vitamin E in Wistar male rats during development and ageing. I. Life span, serum biochemical parameters and pathological changes. Mech Ageing Dev 13(1):1–39PubMedCrossRefGoogle Scholar
  225. Pouwels KB, Widyakusuma NN, Bos JHJ, Hak E (2016) Association between statins and infections among patients with diabetes: a cohort and prescription sequence symmetry analysis. Pharmacoepidemiol Drug Saf 25:1124–1130PubMedPubMedCentralCrossRefGoogle Scholar
  226. Qin X, Dong H, Fang K, Lu F (2017) The effect of statins on renal outcomes in patients with diabetic kidney disease: a systematic review and meta-analysis. Diabetes Metab Res Rev 33(6)Google Scholar
  227. Raju N, Sobieraj-Teague M, Bosch J, Eikelboom JW (2016) Updated meta-analysis of aspirin in primary prevention of cardiovascular disease. Am J Med 129(5):35–36CrossRefGoogle Scholar
  228. Rangaraju S, Solis GM, Andersson SI, Gomez-Amaro RL, Kardakaris R, Broaddus CD, Niculescu AB 3rd, Petrascheck M (2015) Atypical antidepressants extend lifespan of Caenorhabditis elegans by activation of a non-cell-autonomous stress response. Ageing Cell 14(6):971–981CrossRefGoogle Scholar
  229. Reed MJ, Meszaros K, Entes LJ, Claypool MD, Pinkett JG, Brignetti D, Luo J, Khandwala A, Reaven GM (1999) Effect of masoprocol on carbohydrate and lipid metabolism in a rat model of type II diabetes. Diabetologia 42:102–106PubMedCrossRefGoogle Scholar
  230. Ridker PM (2016) A test in context: high-sensitivity C-reactive protein. J Am Coll Cardiol 67(6):712–723PubMedCrossRefGoogle Scholar
  231. Ritz MF, Curin Y, Mendelowitsch A, Andriantsitohaina R (2008a) Acute treatment with red wine polyphenols protects from ischemia-induced excitotoxicity, energy failure and oxidative stress in rats. Brain Res 1239:226–234. APubMedCrossRefGoogle Scholar
  232. Ritz MF, Ratajczak P, Curin Y, Cam E, Mendelowitsch A, Pinet F, Andriantsitohaina R (2008b) Chronic treatment with red wine polyphenol compounds mediates neuroprotection in a rat model of ischemic cerebral stroke. J Nutr 138:519–525PubMedCrossRefGoogle Scholar
  233. Robida-Stubbs S, Glover-Cutter K, Lamming DW, Mizunuma M, Narasimhan SD, Neumann-Haefelin E, Sabatini DM, Blackwell TK (2012) TOR signaling and rapamycin influence longevity by regulating SKN-1/Nrf and DAF-16/FoxO. Cell Metab 15(5):713–724PubMedPubMedCentralCrossRefGoogle Scholar
  234. Roffi M, Patrono C, Collet JP, Mueller C, Valgimigli M, Andreotti F, Bax JJ, Borger MA, Brotons C, Chew DP, Gencer B, Hasenfuss G, Kjeldsen K, Lancellotti P, Landmesser U, Mehilli J, Mukherjee D, Storey RF, Windecker S, Baumgartner H, Gaemperli O, Achenbach S, Agewall S, Badimon L, Baigent C, Bueno H, Bugiardini R, Carerj S, Casselman F, Cuisset T, Erol Ç, Fitzsimons D, Halle M, Hamm C, Hildick-Smith D, Huber K, Iliodromitis E, James S, Lewis BS, Lip GY, Piepoli MF, Richter D, Rosemann T, Sechtem U, Steg PG, Vrints C, Luis Zamorano J, Management of Acute Coronary Syndromes in Patients Presenting without Persistent ST-Segment Elevation of the European Society of Cardiology (2016) 2015 ESC guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation: task force for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation of the European Society of Cardiology (ESC). Eur Heart J 37(3):267–315PubMedCrossRefGoogle Scholar
  235. Rojas LBA, Gomes MB (2013) Metformin: an old but still the best treatment for type 2 diabetes. Diabetol Metab Syndr 5:6PubMedPubMedCentralCrossRefGoogle Scholar
  236. Rostami Z, Moteshaker Arani M, Salesi M, Safiabadi M, Einollahi B (2017) Effect of statins on patients and graft survival in kidney transplant recipients: a survival meta-analysis. Iran J Kidney Dis 11(5):329–338PubMedGoogle Scholar
  237. Rotundo MS, Galeano T, Tassone P, Tagliaferri P (2016) mTOR inhibitors, a new era for metastatic luminal HER2-negative breast cancer? A systematic review and a meta-analysis of randomized trials. Oncotarget 7(19):27055–27066PubMedPubMedCentralCrossRefGoogle Scholar
  238. RxList: The Internet Drug Index. Rapamune (Sirolimus, Last reviewed on RxList: 4/21/2017). https://www.rxlist.com/rapamune-drug.htm
  239. Sander M, Oxlund B, Jespersen A, Krasnik A, Mortensen EL, Westendorp RG, Rasmussen LJ (2015) The challenges of human population ageing. Age Ageing 44(2):185–187PubMedCrossRefGoogle Scholar
  240. Sanguankeo A, Upala S, Cheungpasitporn W, Ungprasert P, Knight EL (2015) Effects of statins on renal outcome in chronic kidney disease patients: a systematic review and meta-analysis. PLoS One 10(7):e0132970PubMedPubMedCentralCrossRefGoogle Scholar
  241. Sasongko TH, Ismail NFD, Zabidi-Hussin ZAMH (2016) Rapamycin and rapalogs for tuberous sclerosis complex. Cochrane Database Syst Rev 7:CD011272PubMedGoogle Scholar
  242. Schäfer I, Kaduszkiewicz H, Wagner H-O, Schön G, Scherer M, van den Bussche H (2014) Reducing complexity: a visualisation of multimorbidity by combining disease clusters and triads. BMC Public Health 14:1285PubMedPubMedCentralCrossRefGoogle Scholar
  243. Schlender L, Martinez YV, Adeniji C, Reeves D, Faller B, Sommerauer C, Al Qur’an T, Woodham A, Kunnamo I, Sönnichsen A, Renom-Guiteras A (2017) Efficacy and safety of metformin in the management of type 2 diabetes mellitus in older adults: a systematic review for the development of recommendations to reduce potentially inappropriate prescribing. BMC Geriatr 17(Suppl 1):227PubMedPubMedCentralCrossRefGoogle Scholar
  244. Schriner SE, Lee K, Truong S, Salvadora KT, Maler S, Nam A, Lee T, Jafari M (2013) Extension of Drosophila lifespan by Rhodiola rosea through a mechanism independent from dietary restriction. PLoS One 8(5):e63886PubMedPubMedCentralCrossRefGoogle Scholar
  245. Seifarth CB, Schehler H, Schneider J (2013) Effectiveness of metformin on weight loss in non-diabetic individuals with obesity. Exp Clin Endocrinol Diabetes 121:27–31PubMedGoogle Scholar
  246. Shen LR, Xiao F, Yuan P, Chen Y, Gao QK, Parnell LD, Meydani M, Ordovas JM, Li D, Lai CQ (2013) Curcumin-supplemented diets increase superoxide dismutase activity and mean lifespan in Drosophila. Age (Dordr) 35(4):1133–1142CrossRefGoogle Scholar
  247. Shi X, Min D, Zigang D, Fei C, Jiangping Y, Suwei W, Stephen S, Leonard Vince C, Val V (1999) Antioxidant properties of aspirin: characterization of the ability of aspirin to inhibit silica-induced lipid peroxidation, DNA damage, NF-+¦B activation, and TNF-+¦ production. Mol Cell Biochem 199:93–102PubMedCrossRefGoogle Scholar
  248. Shimomura M, Oyama J, Takeuchi M, Shibata Y, Yamamoto Y, Kawasaki T, Komoda H, Kodama K, Sakuma M, Toyoda S, Inoue Y, Mine D, Natsuaki M, Komatsu A, Hikichi Y, Yamagishi S, Inoue T, Node K (2016) Acute effects of statin on reduction of angiopoietin-like 2 and glyceraldehyde-derived advanced glycation end-products levels in patients with acute myocardial infarction: a message from SAMIT (Statin for Acute Myocardial Infarction Trial). Heart Vessel 31(10):1583–1589CrossRefGoogle Scholar
  249. Shishido Y, Furushiro M, Hashimoto S, Yokokura T (2001) Effect of nordihydroguaiaretic acid on behavioral impairment and neuronal cell death after forebrain ischemia. Pharmacol Biochem Behav 69(3–4):469–474PubMedCrossRefGoogle Scholar
  250. Siskind DJ, Leung J, Russell AW, Wysoczanski D, Kisely S (2016) Metformin for clozapine associated obesity: a systematic review and meta-analysis. PLoS One 11(6):e01562085CrossRefGoogle Scholar
  251. Slack C, Foley A, Partridge L (2012) Activation of AMPK by the putative dietary restriction mimetic metformin is insufficient to extend lifespan in Drosophila. PLoS One 7(10):e47699PubMedPubMedCentralCrossRefGoogle Scholar
  252. Smith DL Jr, Elam CF Jr, Mattison JA, Lane MA, Roth GS, Ingram DK, Allison DB (2010) Metformin supplementation and life span in Fischer-344 rats. J Gerontol A Biol Sci Med Sci 65(5):468–474PubMedCrossRefGoogle Scholar
  253. Smith SM, Wallace E, O’Dowd T, Fortin M (2016) Interventions for improving outcomes in patients with multimorbidity in primary care and community settings. Cochrane Database Syst Rev 3:CD006560PubMedGoogle Scholar
  254. Song C, Zhu C, Wu Q, Qi J, Gao Y, Zhang Z, Gaur U, Yang D, Fan X, Yang M (2017) Metabolome analysis of effect of aspirin on Drosophila lifespan extension. Exp Gerontol 95:54–62PubMedCrossRefGoogle Scholar
  255. Stark LA, Reid K, Sansom OJ, Din FV, Guichard S, Mayer I, Jodrell DI, Clarke AR, Dunlop MG (2007) Aspirin activates the NF-kappaB signalling pathway and induces apoptosis in intestinal neoplasia in two in vivo models of human colorectal cancer. Carcinogenesis 28:968–976PubMedCrossRefGoogle Scholar
  256. Stevens RJ, Ali R, Bankhead CR, Bethel MA, Cairns BJ, Camisasca RP, Crowe FL, Farmer AJ, Harrison S, Hirst JA, Home P, Kahn SE, McLellan JH, Perera R, Plüddemann A, Ramachandran A, Roberts NW, Rose PW, Schweizer A, Viberti G, Holman RR (2012) Cancer outcomes and all-cause mortality in adults allocated to metformin: systematic review and collaborative meta-analysis of randomised clinical trials. Diabetologia 55(10):2593–2603PubMedCrossRefGoogle Scholar
  257. Strandberg TE, Kolehmainen L, Vuorio A (2014) Evaluation and treatment of older patients with hypercholesterolemia: a clinical review. JAMA 312:1136–1144PubMedCrossRefGoogle Scholar
  258. Strong R, Miller RA, Astle CM, Floyd RA, Flurkey K, Hensley KL, Javors MA, Leeuwenburgh C, Nelson JF, Ongini E, Nadon NL, Warner HR, Harrison DE (2008) Nordihydroguaiaretic acid and aspirin increase lifespan of genetically heterogeneous male mice. Ageing Cell 7(5):641–650CrossRefGoogle Scholar
  259. Strong R, Miller RA, Astle CM, Baur JA, de Cabo R, Fernandez E, Guo W, Javors M, Kirkland JL, Nelson JF, Sinclair DA, Teter B, Williams D, Zaveri N, Nadon NL, Harrison DE (2013) Evaluation of resveratrol, green tea extract, curcumin, oxaloacetic acid, and medium-chain triglyceride oil on life span of genetically heterogeneous mice. J Gerontol A Biol Sci Med Sci 68(1):6–16PubMedCrossRefGoogle Scholar
  260. Su X, Zhang L, Lv J, Wang J, Hou W, Xie X, Zhang H (2016) Effect of statins on kidney disease outcomes: a systematic review and meta-analysis. Am J Kidney Dis 67(6):881–892PubMedCrossRefGoogle Scholar
  261. Suckow BK, Suckow MA (2006) Lifespan extension by the antioxidant curcumin in Drosophila. Int J Biomed Sci 2(4):401–404Google Scholar
  262. Sumantri S, Setiati S, Purnamasari D, Dewiasty E (2014) Relationship between metformin and frailty syndrome in elderly people with type 2 diabetes. Acta Med Indones 46(3):183–188PubMedGoogle Scholar
  263. Tang YL, Zhu LY, Li Y, Yu J, Wang J, Zeng XX, Hu KX, Liu JY, Xu JX (2017) Metformin use is associated with reduced incidence and improved survival of endometrial cancer: a meta-analysis. Biomed Res Int 2017:5905384PubMedPubMedCentralGoogle Scholar
  264. Tao LJ, Sun H, Zhao YM, Yuan ZG, Li XX, Huang BQ (2004) Trichostatin A extends the lifespan of Drosophila melanogaster by elevating hsp22 expression. Acta Biochim Biophys Sin (Shanghai) 36:618–622CrossRefGoogle Scholar
  265. Taylor F, Huffman MD, Macedo AF, Moore TH, Burke M, Davey Smith G, Ward K, Ebrahim S (2013) Statins for the primary prevention of cardiovascular disease. Cochrane Database Syst Rev 1:CD004816Google Scholar
  266. Thapa RK, Nguyen HT, Jeong JH, Kim JR, Choi HG, Yong CS, Kim JO (2017) Progressive slowdown/prevention of cellular senescence by CD9-targeted delivery of rapamycin using lactose-wrapped calcium carbonate nanoparticles. Sci Rep 7:43299PubMedPubMedCentralCrossRefGoogle Scholar
  267. Thoonsen H, Richard E, Bentham P, Gray R, van Geloven N, De Haan RJ, Van Gool WA, Nederkoorn PJ (2010) Aspirin in Alzheimer’s disease: increased risk of intracerebral hemorrhage: cause for concern? Stroke 41(11):2690–2692PubMedCrossRefGoogle Scholar
  268. Tolosa MJ, Chuguransky SR, Sedlinsky C, Schurman L, McCarthy AD, Molinuevo MS, Cortizo AM (2013) Insulin-deficient diabetes-induced bone microarchitecture alterations are associated with a decrease in the osteogenic potential of bone marrow progenitor cells: preventive effects of metformin. Diabetes Res Clin Pract 101:177–186PubMedCrossRefGoogle Scholar
  269. Trauer J, Muhi S, McBryde ES, Al Harbi SA, Arabi YM, Boyle AJ, Cartin-Ceba R, Chen W, Chen YT, Falcone M, Gajic O, Godsell J, Gong MN, Kor D, Lösche W, McAuley DF, O’Neal HR Jr, Osthoff M, Otto GP, Sossdorf M, Tsai MJ, Valerio-Rojas JC, van der Poll T, Violi F, Ware L, Widmer AF, Wiewel MA, Winning J, Eisen DP (2017) Quantifying the effects of prior acetyl-salicylic acid on sepsis-related deaths: an individual patient data meta-analysis using propensity matching. Crit Care Med 45(11):1871–1879PubMedPubMedCentralCrossRefGoogle Scholar
  270. Tseng CH (2016) Metformin reduces gastric cancer risk in patients with type 2 diabetes mellitus. Ageing (Albany NY) 8(8):1636–1649Google Scholar
  271. Tsilidis KK, Kasimis JC, Lopez DS, Ntzani EE, Ioannidis JP (2015) Type 2 diabetes and cancer: umbrella review of meta-analyses of observational studies. BMJ 350:g7607PubMedCrossRefGoogle Scholar
  272. Tuttle RS, Yager J, Northrup N (1988) Age and the antihypertensive effect of aspirin in rats. Br J Pharmacol 94(3):755–758PubMedPubMedCentralCrossRefGoogle Scholar
  273. Ugur B, Chen K, Bellen HJ (2016) Drosophila tools and assays for the study of human diseases. Dis Model Mech 9(3):235–244PubMedPubMedCentralCrossRefGoogle Scholar
  274. Undela K, Shah CS, Mothe RK (2017) Statin use and risk of cancer: an overview of meta-analyses. World J Meta-Anal 5(2):41–53CrossRefGoogle Scholar
  275. Vaiserman AM (2011) Hormesis and epigenetics: is there a link? Ageing Res Rev 10(4):413–421PubMedGoogle Scholar
  276. Vaiserman A, Lushchak O (2017a) Implementation of longevity-promoting supplements and medications in public health practice: achievements, challenges and future perspectives. J Transl Med 15(1):160PubMedPubMedCentralCrossRefGoogle Scholar
  277. Vaiserman AM, Lushchak OV (2017b) Anti-ageing drugs: where are we and where are we going? RSC Drug Discov Ser 2017(57):1–10Google Scholar
  278. Vaiserman А, Koliada AK, Koshel’ NM, Simonenko AV, Pasiukova EG (2013a) Effect of the histone deacetylase inhibitor sodium butyrate on the viability and lifespan in Drosophila melanogaster. Adv Gerontol 3:30–34CrossRefGoogle Scholar
  279. Vaiserman et al (2013b) Determination of geroprotective potential of sodium butyrate in Drosophila melanogaster: long-term effects. Adv Gerontol 26:111–116. In RussianGoogle Scholar
  280. Vaiserman AM, Lushchak OV, Koliada AK (2016) Anti-ageing pharmacology: promises and pitfalls. Ageing Res Rev 31:9–35PubMedCrossRefGoogle Scholar
  281. van den Hoek HL, Bos WJ, de Boer A, van de Garde EM (2011) Statins and prevention of infections: systematic review and meta-analysis of data from large randomised placebo controlled trials. BMJ 343:d7281PubMedPubMedCentralCrossRefGoogle Scholar
  282. Van Wyhe RD, Rahal OM, Woodward WA (2017) Effect of statins on breast cancer recurrence and mortality: a review. Breast Cancer Targets Ther 9:559–565CrossRefGoogle Scholar
  283. Vane SJ (2000) Aspirin and other anti-inflammatory drugs. Thorax 55:35–39CrossRefGoogle Scholar
  284. Veronese N, Stubbs B, Maggi S, Thompson T, Schofield P, Muller C, Tseng PT, Lin PY, Carvalho AF, Solmi M (2017) Low-dose aspirin use and cognitive function in older age: a systematic review and meta-analysis. J Am Geriatr Soc 65(8):1763–1768PubMedCrossRefGoogle Scholar
  285. Violan C, Foguet-Boreu Q, Flores-Mateo G, Salisbury C, Blom J, Freitag M, Glynn L, Muth C, Valderas JM (2014) Prevalence, determinants and patterns of multimorbidity in primary care: a systematic review of observational studies. PLoS One 9(7):e102149PubMedPubMedCentralCrossRefGoogle Scholar
  286. Wagner D, Kniepeiss D, Schaffellner S, Jakoby E, Mueller H, Fahrleitner-Pammer A, Stiegler P, Tscheliessnigg KH, Iberer F (2010) Sirolimus has a potential to influent viral recurrence in HCV positive liver transplant candidates. Int Immunopharmacol 10(8):990–993PubMedCrossRefGoogle Scholar
  287. Wan QL, Zheng SQ, Wu GS, Luo HR (2013) Aspirin extends the lifespan of Caenorhabditis elegans via AMPK and DAF-16/FOXO in dietary restriction pathway. Exp Gerontol 48(5):499–506PubMedCrossRefGoogle Scholar
  288. Wang D, Qian L, Xiong H, Liu J, Neckameyer WS, Oldham S, Xia K, Wang J, Bodmer R, Zhang Z (2006) Antioxidants protect PINK1-dependent dopaminergic neurons in Drosophila. Proc Natl Acad Sci U S A 103(36):13520–13525PubMedPubMedCentralCrossRefGoogle Scholar
  289. Wang C, Wheeler CT, Alberico T, Sun X, Seeberger J, Laslo M, Spangler E, Kern B, de Cabo R, Zou S (2013) The effect of resveratrol on lifespan depends on both gender and dietary nutrient composition in Drosophila melanogaster. Age (Dordr) 35(1):69–81CrossRefGoogle Scholar
  290. Wang CP, Lorenzo C, Espinoza SE (2014) Frailty attenuates the impact of metformin on reducing mortality in older adults with type 2 diabetes. J Endocrinol Diabetes Obes 2(2):1031PubMedPubMedCentralGoogle Scholar
  291. Wang HL, Sun ZO, Rehman RU, Wang H, Wang YF, Wang H (2017a) Rosemary extract-mediated lifespan extension and attenuated oxidative damage in Drosophila melanogaster fed on high-fat diet. J Food Sci 82(4):1006–1011PubMedCrossRefGoogle Scholar
  292. Wang Y, Xiong J, Niu M, Chen X, Gao L, Wu Q, Zheng K, Xu K (2017b) Statins and the risk of cirrhosis in hepatitis B or C patients: a systematic review and dose-response meta-analysis of observational studies. Oncotarget 8(35):59666–59676PubMedPubMedCentralGoogle Scholar
  293. Warner TD, Nylander S, Whatling C (2011) Anti-platelet therapy: cyclo-oxygenase inhibition and the use of aspirin with particular regard to dual anti-platelet therapy. Br J Clin Pharmacol 72(4):619–633PubMedPubMedCentralCrossRefGoogle Scholar
  294. Weissmann G (1991) Aspirin. Sci Am 264:84–90PubMedCrossRefGoogle Scholar
  295. Wiegant FA, Surinova S, Ytsma E, Langelaar-Makkinje M, Wikman G, Post JA (2009) Plant adaptogens increase lifespan and stress resistance in C. elegans. Biogerontology 10(1):27–42PubMedCrossRefGoogle Scholar
  296. Williams DS, Cash A, Hamadani L, Diemer T (2009) Oxaloacetate supplementation increases lifespan in Caenorhabditis elegans through an AMPK/FOXO-dependent pathway. Ageing Cell 8(6):765–768CrossRefGoogle Scholar
  297. Wilson MA, Shukitt-Hale B, Kalt W, Ingram DK, Joseph JA, Wolkow CA (2006) Blueberry polyphenols increase lifespan and thermotolerance in Caenorhabditis elegans. Ageing Cell 5(1):59–68CrossRefGoogle Scholar
  298. Wood JG, Rogina B, Lavu S, Howitz K, Helfand SL, Tatar M, Sinclair D (2004) Sirtuin activators mimic caloric restriction and delay ageing in metazoans. Nature 430:686–689PubMedCrossRefGoogle Scholar
  299. Wu Z, Smith JV, Paramasivam V, Butko P, Khan I, Cypser JR, Luo Y (2002) Ginkgo biloba extract EGb 761 increases stress resistance and extends life span of Caenorhabditis elegans. Cell Mol Biol (Noisy-le-Grand) 48(6):725–731Google Scholar
  300. Xie J, Wang X, Proud CG (2016) mTOR inhibitors in cancer therapy. F1000Research 5:F1000. Faculty Rev-2078PubMedPubMedCentralCrossRefGoogle Scholar
  301. Xie W, Ning L, Huang Y, Liu Y, Zhang W, Hu Y, Lang J, Yang J (2017) Statin use and survival outcomes in endocrine-related gynecologic cancers: a systematic review and meta-analysis. Oncotarget 8(25):41508–41517PubMedPubMedCentralCrossRefGoogle Scholar
  302. Xu H, Chen K, Jia X, Tian Y, Dai Y, Li D, Xie J, Tao M, Mao Y (2015) Metformin use is associated with better survival of breast cancer patients with diabetes: a meta-analysis. Oncologist 20(11):1236–1244PubMedPubMedCentralCrossRefGoogle Scholar
  303. Yamagishi S, Maeda S, Matsui T, Ueda S, Fukami K, Okuda S (2012) Role of advanced glycation end products (AGEs) and oxidative stress in vascular complications in diabetes. Biochim Biophys Acta 1820(5):663–671PubMedCrossRefGoogle Scholar
  304. Yang Y, Wu Z, Kuo YM, Zhou B (2005) Dietary rescue of fumble–a Drosophila model for pantothenate-kinase-associated neurodegeneration. J Inherit Metab Dis 28:1055–1064PubMedCrossRefGoogle Scholar
  305. Yang ZX, Wang YZ, Jia BB, Mao GX, Lv YD, Wang GF, Yu H (2016) Downregulation of miR-146a, cyclooxygenase-2 and advanced glycation end-products in simvastatin-treated older patients with hyperlipidemia. Geriatr Gerontol Int 16(3):322–328PubMedCrossRefGoogle Scholar
  306. Yanik EL, Chinnakotla S, Gustafson SK, Snyder JJ, Israni AK, Segev DL, Engels EA (2016) Effects of maintenance immunosuppression with sirolimus after liver transplant for hepatocellular carcinoma. Liver Transpl 22(5):627–634PubMedPubMedCentralCrossRefGoogle Scholar
  307. Yap AF, Thirumoorthy T, Kwan YH (2016) Medication adherence in the elderly. J Clin Gerontol Geriatr 7(20):64–67CrossRefGoogle Scholar
  308. Ye X, Fu J, Yang Y, Chen S (2013) Dose-risk and duration-risk relationships between aspirin and colorectal cancer: a meta-analysis of published cohort studies. PLoS One 8(2):e57578PubMedPubMedCentralCrossRefGoogle Scholar
  309. Ye X, Linton JM, Schork NJ, Buck LB, Petrascheck M (2014) A pharmacological network for lifespan extension in Caenorhabditis elegans. Ageing Cell 13(2):206–215CrossRefGoogle Scholar
  310. Yi C, Song Z, Wan M, Chen Y, Cheng X (2017) Statins intake and risk of liver cancer: a dose–response meta-analysis of prospective cohort studies. Castiella. A, ed. Medicine 96(27):e7435PubMedPubMedCentralCrossRefGoogle Scholar
  311. Yoo Y-E, Ko C-P (2011) Treatment with trichostatin A initiated after disease onset delays disease progression and increases survival in a mouse model of amyotrophic lateral sclerosis. Exp Neurol 231:147–159PubMedCrossRefGoogle Scholar
  312. Yu H, Yin L, Jiang X, Sun X, Wu J, Tian H, Gao X, He X (2014) Effect of metformin on cancer risk and treatment outcome of prostate cancer: a meta-analysis of epidemiological observational studies. Medeiros R, ed. PLoS ONE 9(12):e116327PubMedPubMedCentralCrossRefGoogle Scholar
  313. Yue W, Yang CS, DiPaola RS, Tan XL (2014) Repurposing of metformin and aspirin by targeting AMPK-mTOR and inflammation for pancreatic cancer prevention and treatment. Cancer Prev Res 7(4):388–397CrossRefGoogle Scholar
  314. Zhang ZJ, Zheng ZJ, Shi R, Su Q, Jiang Q, Kip KE (2012) Metformin for liver cancer prevention in patients with type 2 diabetes: a systematic review and meta-analysis. J Clin Endocrinol Metab 97(7):2347–2353PubMedCrossRefGoogle Scholar
  315. Zhang X, Xie J, Li G, Chen Q, Xu B (2014) Head-to-head comparison of sirolimus-eluting stents versus paclitaxel-eluting stents in patients undergoing percutaneous coronary intervention: a meta-analysis of 76 studies. PLoS One 9(5):e97934PubMedPubMedCentralCrossRefGoogle Scholar
  316. Zhang YP, Wan YD, Sun YL, Li J, Zhu RT (2015) Aspirin might reduce the incidence of pancreatic cancer: a meta-analysis of observational studies. Sci Rep 5:15460PubMedPubMedCentralCrossRefGoogle Scholar
  317. Zhao Y, Sun H, Lu J, Li X, Chen X, Tao D, Huang W, Huang B (2005) Lifespan extension and elevated hsp gene expression in Drosophila caused by histone deacetylase inhibitors. J Exp Biol 208:697–705PubMedCrossRefGoogle Scholar
  318. Zheng YX, Zhou PC, Zhou RR, Fan XG (2017) The benefit of statins in chronic hepatitis C patients: a systematic review and meta-analysis. Eur J Gastroenterol Hepatol 29(7):759–766PubMedCrossRefGoogle Scholar
  319. Zhong S, Chen L, Zhang X, Yu D, Tang J, Zhao J (2015a) Aspirin use and risk of breast cancer: systematic review and meta-analysis of observational studies. Cancer Epidemiol Biomark Prev 24(11):1645–1655CrossRefGoogle Scholar
  320. Zhong S, Zhang X, Chen L, Ma T, Tang J, Zhao J (2015b) Association between aspirin use and mortality in breast cancer patients: a meta-analysis of observational studies. Breast Cancer Res Treat 150(1):199–207PubMedCrossRefGoogle Scholar
  321. Zhong GC, Liu Y, Ye YY, Hao FB, Wang K, Gong JP (2016) Meta-analysis of studies using statins as a reducer for primary liver cancer risk. Sci Rep 6:26256PubMedPubMedCentralCrossRefGoogle Scholar
  322. Zhou YY, Zhu GQ, Wang Y, Zheng JN, Ruan LY, Cheng Z, Hu B, Fu SW, Zheng MH (2016) Systematic review with network meta-analysis: statins and risk of hepatocellular carcinoma. Oncotarget 7(16):21753–21762PubMedPubMedCentralGoogle Scholar
  323. Zhou XL, Xue WH, Ding XF, Li LF, Dou MM, Zhang WJ, Lv Z, Fan ZR, Zhao J, Wang LX (2017) Association between metformin and the risk of gastric cancer in patients with type 2 diabetes mellitus: a meta-analysis of cohort studies. Oncotarget 8(33):55622–55631PubMedPubMedCentralGoogle Scholar
  324. Zid BM, Rogers AN, Katewa SD, Vargas MA, Kolipinski MC, Lu TA, Benzer S, Kapahi P (2009) 4E-BP extends lifespan upon dietary restriction by enhancing mitochondrial activity in Drosophila. Cell 139(1):149–160PubMedPubMedCentralCrossRefGoogle Scholar
  325. Zimbron J, Khandaker GM, Toschi C, Jones PB, Fernandez-Egea E (2016) A systematic review and meta-analysis of randomised controlled trials of treatments for clozapine-induced obesity and metabolic syndrome. Eur Neuropsychopharmacol 26(9):1353–1365PubMedCrossRefGoogle Scholar
  326. Zou YX, Ruan MH, Luan J, Feng X, Chen S, Chu ZY (2017) Anti-ageing effect of riboflavin via endogenous antioxidant in fruit fly Drosophila melanogaster. J Nutr Health Ageing 21(3):314–319CrossRefGoogle Scholar
  327. Zulman DM, Sussman JB, Chen X, Cigolle CT, Blaum CS, Hayward RA (2011) Examining the evidence: a systematic review of the inclusion and analysis of older adults in randomized controlled trials. J Gen Intern Med 26(7):783–790PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer Nature Singapore Pte Ltd. 2019

Authors and Affiliations

  • Veronika Piskovatska
    • 1
  • Olha Strilbytska
    • 2
  • Alexander Koliada
    • 3
  • Alexander Vaiserman
    • 3
  • Oleh Lushchak
    • 2
    Email author
  1. 1.Clinic for Heart SurgeryUniversity Clinic of Martin Luther UniversityHalleGermany
  2. 2.Biochemistry and Biotechnology DepartmentVasyl Stefanyk Precarpathian National UniversityIvano-FrankivskUkraine
  3. 3.D.F. Chebotarev Institute of Gerontology, NAMSKyivUkraine

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