, Volume 17, Issue 1, pp 33–54 | Cite as

Living long and ageing well: is epigenomics the missing link between nature and nurture?

  • Irene Maeve ReaEmail author
  • Margaret Dellet
  • Ken I. Mills
  • The ACUME2 Project
Review Article


Human longevity is a complex trait and increasingly we understand that both genes and lifestyle interact in the longevity phenotype. Non-genetic factors, including diet, physical activity, health habits, and psychosocial factors contribute approximately 50 % of the variability in human lifespan with another 25 % explained by genetic differences. Family clusters of nonagenarian and centenarian siblings, who show both exceptional age-span and health-span, are likely to have inherited facilitatory gene groups, but also have nine decades of life experiences and behaviours which have interacted with their genetic profiles. Identification of their shared genes is just one small step in the link from genes to their physical and psychological profiles. Behavioural genomics is beginning to demonstrate links to biological mechanisms through regulation of gene expression, which directs the proteome and influences the personal phenotype. Epigenetics has been considered the missing link between nature and nurture. Although there is much that remains to be discovered, this article will discuss some of genetic and environmental factors which appear important in good quality longevity and link known epigenetic mechanisms to themes identified by nonagenarians themselves related to their longevity. Here we suggest that exceptional 90-year old siblings have adopted a range of behaviours and life-styles which have contributed to their ageing-well-phenotype and which link with important public health messages.


Longevity Epigenetics Diet Exercise Frailty Resilience 



The Super Vivere-ACUME2 project group include: Claudio Franceschi, University of Bologna, Italy, Vita Fortunati University of Bologna, Italy, Laura Celani, University of Bologna, Elisa Cevenni, University of Bologna, Antii Hervonen, Tampere School of Public Health, Finland, Anna Numminen, Tampere School of Public Health, Finland, Oskar Virras, Tampere School of Public Health, Finland, Ewa Sikora, Nencki Institute of Experimental Biology, Warsaw, Poland, Karsa Broczek, Nencki Institute of Experimental Biology, Warsaw, Poland, Irene Maeve Rea, Queens University Belfast and University of Ulster.

The authors thank Research Officer Ms Anne Murphy, and the BELFAST nonagenarian subjects who willingly participated in this study.


The study was funded in part by EU Socrates Erasmus Programme for Thematic Network, Interfacing Science, Literature and Humanities ACUME2 (227942-CP-1-2006-1-IT-ERASMUS-TN2006-2371/001 SO2-23RETH), Atlantic Philanthropies, Changing Ageing Partnership Grant, Queens Foundation Trust (R9158PHM) (IMR), Wellcome Trust Project Grant (045519/Z/95/Z) (IMR), Eastern Health and Social Care Board Research Fellowship Grant (IMR) and Belfast Trust Fund (Research and Education into Ageing (0-132) (IMR).


  1. Abadir PM, Foster DB, Crow M et al (2011) Identification and characterization of a functional mitochondrial angiotensin system. Proc Natl Acad Sci USA 108:14849–14854. doi: 10.1073/pnas.1101507108
  2. Alamdari N, Aversa Z, Castillero E et al (2012) Resveratrol prevents dexamethasone-induced expression of the muscle atrophy-related ubiquitin ligases atrogin-1 and MuRF1 in cultured myotubes through a SIRT1-dependent mechanism. Biochem Biophys Res Commun 417:528–533. doi: 10.1016/j.metabol.2012.03.019 PubMedCentralPubMedCrossRefGoogle Scholar
  3. Alamdari N, Aversa Z, Castillero E, Hasselgren P-O (2013) Acetylation and deacetylation–novel factors in muscle wasting. Metabolism 62:1–11. doi: 10.1016/j.metabol.2012.03.019 PubMedCentralPubMedCrossRefGoogle Scholar
  4. Anselmi CV, Malovini A, Roncarati R et al (2009) Association of the FOXO3A locus with extreme longevity in a southern Italian centenarian study. Rejuvenation Res 12:95–104. doi: 10.1089/rej.2008.0827 PubMedCrossRefGoogle Scholar
  5. Arem H, Moore SC, Patel A et al (2015) Leisure time physical activity and mortality: a detailed pooled analysis of the dose-response relationship. JAMA Intern Med 175(6):959–967. doi: 10.1001/jamainternmed.2015.0533 PubMedCrossRefGoogle Scholar
  6. Attaix D, Ventadour S, Codran A et al (2005) The ubiquitin-proteasome system and skeletal muscle wasting. Essays Biochem 41:173–186. doi: 10.1089/rej.2008.0827 PubMedCrossRefGoogle Scholar
  7. Ayyadevara S, Alla R, Thaden JJ, Shmookler Reis RJ (2008) Remarkable longevity and stress resistance of nematode PI3 K-null mutants. Aging Cell 7:13–22. doi: 10.1111/j.1474-9726.2007.00348.x
  8. Baer C, Claus R, Plass C (2013) Genome-wide epigenetic regulation of miRNAs in cancer. Cancer Res 73:473-477. 0008-5472.CAN-12-3731v1 73/2/473Google Scholar
  9. Bao JM, Song XL, Hong YQ et al (2014) Association between FOXO3A gene polymorphisms and human longevity: a meta-analysis. Asian J Androl 16:446–452. doi: 10.4103/1008-682X.123673 PubMedCentralPubMedCrossRefGoogle Scholar
  10. Barrès R, Yan J, Egan B, Treebak JT et al (2012) Acute exercise remodels promoter methylation in human skeletal muscle. Cell Metab 15:405–411. doi: 10.1016/j.cmet.2012.01.001 PubMedCrossRefGoogle Scholar
  11. Barthel A, Schmoll D, Unterman TG (2005) FoxO proteins in insulin action and metabolism. TEM 16:183–189. doi: 10.1016/j.tem.2005.03.010 PubMedGoogle Scholar
  12. Bathum L, Christiansen L, Jeune B et al (2006) Apolipoprotein E genotypes: relationship to cognitive functioning, cognitive decline, and survival in nonagenarians. J Am Geriatr Soc 54:654–658. doi: 10.1111/j.1532-5415.2005.53554.x PubMedCrossRefGoogle Scholar
  13. Beekman M, Blanché H, Perola M, GEHA Consortium et al (2013) Genome-wide linkage analysis for human longevity: genetics of healthy ageing study. Aging Cell 12:184–193. doi: 10.1111/acel.12039 PubMedCentralPubMedCrossRefGoogle Scholar
  14. Bekris LM, Lutz F, Yu C-E (2012) Functional analysis of APOE locus genetic variation implicates regional enhancers in the regulation of both TOMM40 and APOE. J Hum Genet 57:18–25. doi: 10.1038/jhg.2011.123 PubMedCentralPubMedCrossRefGoogle Scholar
  15. Bennati E, Murphy A, Cambien F et al (2010) BELFAST centenarians: a case of optimised cardiovascular risk? Curr Pharm Des 16:789–795. doi: 10.2174/138161210790883697 PubMedCrossRefGoogle Scholar
  16. Bennet AM, Angelantonio ED, Ye Z et al (2007) Association of apolipoprotein E genotypes with lipid levels and coronary risk. JAMA 298:1300–1311. doi: 10.1001/jama.298.11.1300 PubMedCrossRefGoogle Scholar
  17. Benny Klimek ME, Aydogdu T, Link MJ et al (2010) Acute inhibition of myostatin-family proteins preserves skeletal muscle in mouse models of cancer cachexia. Biochem Biophys Res Commun 391:1548–1554. doi: 10.1016/j.bbrc.2009.12.123
  18. Bladé C, Baselga-Escudero L, Salvadó MJ, Arola-Arnal A (2013) miRNAs, polyphenols, and chronic disease. Mol Nutr Food Res 57:58–70. doi: 10.1002/mnfr.201200454 PubMedCrossRefGoogle Scholar
  19. Blanché H, Cabanne L, Sahbatou M, Thomas G (2001) A study of French centenarians: are ACE and APOE associated with longevity? C R Acad Sci III 324:129–135. doi: 10.1016/S0764-4469(00)01274-9 PubMedCrossRefGoogle Scholar
  20. Bodine SC, Stitt TN, Gonzalez M et al (2001a) Akt/mTOR pathway is a crucial regulator of skeletal muscle hypertrophy and can prevent muscle atrophy in vivo. Nat Cell Biol 3:1014–1019. doi: 10.1038/ncb1101-1014 PubMedCrossRefGoogle Scholar
  21. Bodine SC, Latres E, Baumhueter S et al (2001b) Identification of ubiquitin ligases required for skeletal muscle atrophy. Science 294:1704–1708. doi: 10.1126/science.1065874 PubMedCrossRefGoogle Scholar
  22. Boehm A-M, Khalturin K, Anton-Erxleben F et al (2012) FoxO is a critical regulator of stem cell maintenance in immortal Hydra. PNAS 109:19697–19702. doi: 10.1073/pnas.1209714109 PubMedCentralPubMedCrossRefGoogle Scholar
  23. Bollati V, Favero C, Albetti B et al (2014) Nutrients intake is associated with DNA methylation of candidate inflammatory genes in a population of obese subjects. Nutrients 6:4625–4639. doi: 10.3390/nu6104625 PubMedCentralPubMedCrossRefGoogle Scholar
  24. Bonafe M, Olivieri F, Cavallone L et al (2001) A gender–dependent genetic predisposition to produce high levels of IL-6 is detrimental for longevity. Eur J Immunol 31:2357–2361. doi: 10.1002/1521-4141(200108)31:8<2357:AID-IMMU2357>3.0.CO;2-X PubMedCrossRefGoogle Scholar
  25. Bowers EM, Yan G, Mukherjee C et al (2010) Virtual ligand screening of the p300/CBP histone acetyltransferase: identification of a selective small molecule inhibitor. Chem Biol 17:471–482. doi: 10.1016/j.chembiol.2010.03.006 PubMedCentralPubMedCrossRefGoogle Scholar
  26. Braesch-Andersen S, Paulie S, Smedman C, Mia S, Kumagai-Braesch M (2013) ApoE production in human monocytes and Its regulation by inflammatory cytokines. PLoS ONE 8:e79908. doi: 10.1371/journal.pone.0079908 PubMedCentralPubMedCrossRefGoogle Scholar
  27. Broer B, Buchman AS, Deelen J, Evans DS, Faul JD, Murabito JM et al (2015) GWAS of longevity in CHARGE Consortium confirms APOE and FOXO3 candidacy. J Gerontol A Biol Sci Med Sci 70:110–118. doi: 10.1093/gerona/glu166 PubMedCentralPubMedCrossRefGoogle Scholar
  28. Brooks-Wilson AR (2013) Genetics of healthy aging and longevity. Hum Genet 132:1323–1338. doi: 10.1007/s00439-013-1342-z PubMedCentralPubMedCrossRefGoogle Scholar
  29. Brunet A, Sweeney LB, Sturgill JF, Chua KF, Greer PL et al (2004) Stress-dependent regulation of FOXO transcription factors by the SIRT1 deacetylase. Science 303:2011–2015. doi: 10.1126/science.1094637 PubMedCrossRefGoogle Scholar
  30. Buckingham M (1994) Molecular biology of muscle development. Cell 78:15–21. doi: 10.1016/0092-8674(94)90568-1 PubMedCrossRefGoogle Scholar
  31. Bunout D, Barrera G, de la Maza MP et al (2009) Effects of enalapril or nifedipine on muscle strength or functional capacity in elderly subjects. A double blind trial. J Renin Angiotensin Aldosterone Syst 10:77–84. doi: 10.1177/1470320309105338 PubMedCrossRefGoogle Scholar
  32. Burks TN, Andres-Mateos E, Marx R et al (2011) Losartan restores skeletal muscle remodeling and protects against disuse atrophy in sarcopenia. Sci Transl Med 3:82ra37. doi: 10.1126/scitranslmed.3002227 PubMedCentralPubMedCrossRefGoogle Scholar
  33. Calnan DR, Brunet A (2008) The FoxO code. Oncogene 27:2276–2288. doi: 10.1038/onc.2008.21 PubMedCrossRefGoogle Scholar
  34. Calnan DR, Webb AE, White JL, Stowe TR, Goswami T et al (2012) Methylation by Set9 modulates FoxO3 stability and transcriptional activity. Aging (Albany NY) 7:462–479Google Scholar
  35. Calura E, Cagnin S, Raffaello A et al (2008) Meta-analysis of expression signatures of muscle atrophy: gene interaction networks in early and late stages. BMC Genom 9:630. doi: 10.1186/1471-2164-9-630 CrossRefGoogle Scholar
  36. Camargo A, Ruano J, Fernandez JM, Parnell LD, Jimenez A, Santos-Gonzalez M et al (2010) Gene expression changes in mononuclear cells in patients with metabolic syndrome after acute intake of phenol-rich virgin olive oil. BMC Genom 11:253. doi: 10.1186/1471-2164-11-253 CrossRefGoogle Scholar
  37. Carmago A, Delgado-Lista J, Garcia-Rios A, Cruz-Teno C, Yubero-Serrano EM et al (2012) Expression of pro-inflammatory, pro-atherogenicgenes is reduced by the Mediterranean diet in elderly people. Br J Nutr 108:500–508. doi: 10.1017/S0007114511005812 CrossRefGoogle Scholar
  38. Carter HN, Chen CCW, Hood DA (2015) Mitochondria, muscle health, and exercise with advancing Ag. Physiol (Bethesda) 30:208–223. doi: 10.1152/physiol.00039.2014 Google Scholar
  39. Carvalho A, Rea IM, Parimon T, Cusack BJ (2014) Physical activity and cognitive function in individuals over 60 years of age: a systematic review. Clin Interv Aging 9:661–682. doi: 10.2147/CIA.S55520 PubMedCentralPubMedGoogle Scholar
  40. Cedar H, Bergman Y (2009) Linking DNS methylation and histone modification: patterns and paradigms. Nat Rev Genet 10:295–304. doi: 10.1038/nrg2540 PubMedCrossRefGoogle Scholar
  41. Cesari M, Pedone C, Incalzi RA, Pahor M (2010) ACE-inhibition and physical function: results from the trial of angiotensin-converting enzyme inhibition and novel cardiovascular risk factors (TRAIN) study. J Am Med Dir Assoc 11:26–32. doi: 10.1016/j.jamda.2009.09.014 PubMedCentralPubMedCrossRefGoogle Scholar
  42. Christiansen L, Bathum L, Andersen-Ranberg K, Jeune B, Christensen K (2004) Modest implication of interleukin-6 promoter polymorphisms in longevity. Mech Ageing Dev 125:391–395. doi: 10.1016/j.mad.2004.03.004
  43. Chuang YF, Hayden KM, Norton MC, Tschanz J, Breitner JC, Welsh-Bohmer KA, Zandi PP (2010) Association between APOE epsilon4 allele and vascular dementia: the Cache County study. Dement Geriatr Cogn Disord 29:248–253. doi: 10.1159/000285166 PubMedCentralPubMedCrossRefGoogle Scholar
  44. Chung H-E, Dao R-L, Chen L-K, Hung S-L (2010) The role of genetic variants in human longevity. Ageing Res Rev 9(Suppl):67–67. doi: 10.1016/j.arr.2010.08.001 CrossRefGoogle Scholar
  45. Conradt E, Lester BM, Appleton AA, Armstrong DA, Marsit CJ (2013) The roles of DNA methylation of NR3C1 and 11β-HSD2 and exposure to maternal mood disorder in utero on newborn neurobehavior. Epigenetics 8:1321–1329. doi: 10.4161/epi.26634 PubMedCentralPubMedCrossRefGoogle Scholar
  46. Consalvi S, Saccone V, Giordani L et al (2011) Histone deacetylase inhibitors in the treatment of muscular dystrophies: epigenetic drugs for genetic diseases. Mol Med 17:457–465. doi: 10.2119/molmed.2011.00049 PubMedCentralPubMedCrossRefGoogle Scholar
  47. Corder EH, Saunders AM, Strittmatter WJ, Schmechel DE, Gaskell PC et al (1993) Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late onset families. Science 261:921–923. doi: 10.1126/science.8346443 PubMedCrossRefGoogle Scholar
  48. Corder EH, Lannfelt L, Viitanen M, Corder LS, Manton KG, Winblad B, Basun H (1996) Apolipoprotein E genotype determines survival in the oldest old (85 years or older) who have good cognition. Arch Neurol 53:418–422. doi: 10.1001/archneur.1996.00550050048022 PubMedCrossRefGoogle Scholar
  49. Corella D, Ordovas JM (2014) How does the Mediterranean diet promote cardiovascular health? Current progress towards molecular mechanisms. Gene diet interactions at the genomic, transcriptomic and epigenomic levels provide novel insights into mechanisms. BioEssays 36:526–537. doi: 10.1002/bies.201300180 PubMedCrossRefGoogle Scholar
  50. Corella D, Carrasco P, Sorlí JV, Estruch R, Rico-Sanz J, Martínez-González MÁ et al (2013) Mediterranean diet reduces the adverse effect of the TCF7L2-rs7903146 polymorphism on cardiovascular risk factors and stroke incidence: a randomized controlled trial in a high-cardiovascular-risk population. Diabetes Care 36:3803–3811. doi: 10.2337/dc13-0955 PubMedCentralPubMedCrossRefGoogle Scholar
  51. Crott JW, Choi S-W, Ordovas JM, Ditelberg JS, Mason JB (2004) Effects of dietary folate and aging on gene expression in the colonic mucosa of rats: implications for carcinogenesis. Carcinogenesis 25:69–76. doi: 10.1093/carcin/bgg150 PubMedCrossRefGoogle Scholar
  52. Crunkhorn S, Dearie F, Mantzoros C et al (2007) Peroxisome proliferator activator receptor γ coactivator-1 expression is reduced in obesity: potential pathogenic role of saturated fatty acids and p38 mitogen-activated protein kinase activation. J Biol Chem 282:15439–15450. doi: 10.1074/jbc.M611214200 PubMedCrossRefGoogle Scholar
  53. Cruz-Jentoft AJ, Baeyens JP, Bauer JM et al (2010) Sarcopenia: European consensus on definition and diagnosis Report of the European Working Group on Sarcopenia in Older People. Age Ageing 39:412–423. doi: 10.1093/ageing/afq034 PubMedCentralPubMedCrossRefGoogle Scholar
  54. Dalagard OS, Bjork S, Tambs K (1995) Social support negative life events and mental health. Br J Psychiatry 166:29–34CrossRefGoogle Scholar
  55. Dali-Youcef N, Lagouge M, Froelich S, Koehl C, Schoonjans K, Auwerx J (2007) Sirtuins: the ‘magnificent seven’, function, metabolism and longevity. Ann Med 39:335–345. doi: 10.1080/07853890701408194 PubMedCrossRefGoogle Scholar
  56. Dashwood RH, Ho E (2008) Dietary agents as histone deacetylase inhibitors sulforaphane and structurally related isothiocyanates. Nutr Rev 66(Suppl 1):S36–S38. doi: 10.1111/j.1753-4887.2008.00065.x PubMedCentralPubMedCrossRefGoogle Scholar
  57. Daskalakis NP, Yehuda R (2014) Site-specific methylation changes in the glucocorticoid receptor exon 1F promoter in relation to life adversity: systematic review of contributing factors. Front Neurosci 8:369. doi: 10.3389/fnins.2014.00369 PubMedCentralPubMedCrossRefGoogle Scholar
  58. Davies G, Harris SE, Reynolds CA, Payton A, Knight HM, Liewald DC et al (2014) A genome-wide association study implicates the APOE locus in nonpathological cognitive ageing. Mol Psychiatry 19(1):76–87. doi: 10.1038/mp.2012.159 PubMedCrossRefGoogle Scholar
  59. Davies G, Armstrong N, Bis JC, Bressler J, Chouraki V, Giddaluru S et al (2015) Genetic contributions to variation in general cognitive function: a meta-analysis of genome-wide association studies in the CHARGE consortium (N = 53 949). Mol Psychiatry 20:183–192. doi: 10.1038/mp.2014.188 PubMedCentralPubMedCrossRefGoogle Scholar
  60. Davignon J, Gregg RE, Sing CF (1988) Apolipoprotein E polymorphism and atherosclerosis. Arteriosclerosis 8:1–21. doi: 10.1161/01.ATV.8.1.1 PubMedCrossRefGoogle Scholar
  61. Dayeh TA, Olsson AH, Volkov P, Almgren P, Rönn T, Ling C (2013) Identification of CpG-SNPs associated with type 2 diabetes and differential DNA methylation in human pancreatic islets. Diabetologia 56:1036–1046. doi: 10.1007/s00125-012-2815-7 PubMedCentralPubMedCrossRefGoogle Scholar
  62. De Cavanagh EMV, Piotrkowski B, Basso N et al (2003) Enalapril and losartan attenuate mitochondrial dysfunction in aged rats. FASEB J 17:1096–1098PubMedGoogle Scholar
  63. De Vol DL, Rotwein P, Sadow JL et al (1990) Activation of insulin–like growth factor 1 (IGF-1) in skeletal muscle growth. Am J Physiol 259:E89–E95Google Scholar
  64. Deelan J, Beekman M, Hae-Won Uh, Helmer Q, Kuningas M, Christiansen L, Kremer D et al (2011) Genome-wide association study identifies a single major locus contributing to survival into old age: the APOE locus revisited. Aging Cell 10:686–698. doi: 10.1111/j.1474-9726.2011.00705.x CrossRefGoogle Scholar
  65. Deelen J, Beekman M, Uh H-W, Broer L, Ayers KL, Tan Q, Kamatani Y et al (2014) Genome-wide association meta-analysis of human longevity identifies a novel locus conferring survival beyond 90 years of age. Hum Mol Genet 23:4420–4432. doi: 10.1093/hmg/ddu139 PubMedCentralPubMedCrossRefGoogle Scholar
  66. Dellett M, Colyer HA, Pettigrew KA, McMullin M-F, Rea IM, Mills KI (2013) Altered methylation levels in elderly acute myeloid leukaemia patients compared to elderly well individuals. Br J Haematol 161:294–296. doi: 10.1111/bjh.12221 PubMedCrossRefGoogle Scholar
  67. Dhamrait SS, Williams AG, Day SH et al (2012) Variation in the uncoupling protein 2 and 3 genes and human performance. J Appl Physiol 112:1122–1127. doi: 10.1152/japplphysiol.00766.2011 PubMedCentralPubMedCrossRefGoogle Scholar
  68. Di Bona D, Vasto S, Capurso C, Christensen L, Deiana L, Franceschi C et al (2009) Effect of interleukin-6 polymorphisms on human longevity: a systemic review and meta-analysis. Ageing Res Rev 8:36–42. doi: 10.1016/j.arr.2008.09.001 PubMedCrossRefGoogle Scholar
  69. Doane LD, Adam EK (2010) Loneliness and cortisol: momentary, day-to-day, and trait associations. Psychoneuroendocrinology 35:430–441. doi: 10.1016/j.psyneuen.2009.08.005 PubMedCentralPubMedCrossRefGoogle Scholar
  70. Drysdale C, Dellett M, Murphy A, Mills K, Rea M (2011) Nutrition and epigenetic change in Belfast elderly longitudinal free-living ageing study (BELFAST). Irish J Med Sci 180:S344–s344. doi: 10.1007/s11845-011-0742-0 Google Scholar
  71. Duthie SJ (2011) Folate and cancer: how DNA damage, repair and methylation impact on colon carcinogenesis. J Inherit Metab Dis 34:101–109. doi: 10.1007/s10545-010-9128-0 PubMedCrossRefGoogle Scholar
  72. Dyle MC, Ebert SM, Cook DP (2014) Systems-based discovery of Tomatidine as a natural small molecule inhibitor of skeletal muscle atrophy. J Biol Chem 289:14913–14924. doi: 10.1074/jbc.M114.556241 PubMedCentralPubMedCrossRefGoogle Scholar
  73. Egerman MA, Cadena SM, Gilbert JA et al (2015) GDF11 increases with age and inhibits skeletal muscle regeneration. Cell Metab 18. pii: S1550-4131(15)00222-3. doi:  10.1016/j.cmet.2015.05.010. doi: 10.1016/j.cmet.2015.05.010
  74. Eggertsen G, Tegelman R, Ericsson S, Angelin B, Berglund L (1993) Apolipoprotein E polymorphism in a healthy Swedish population: variation of allele frequency with age and relation to serum lipid concentrations. Clin Chem 39:2125–2129PubMedGoogle Scholar
  75. Eichner JE, Dunn ST, Perveen G, Thompson DM, Stewart KE, Stroehla BC (2002) Apolipoprotein E polymorphism and cardiovascular disease: a HuGE review. Am J Epidemiol 155:487–495. doi: 10.1093/aje/155.6.487 PubMedCrossRefGoogle Scholar
  76. Eisenberg DT, Kuzawa CW, Hayes MG (2010) Worldwide allele frequencies of the human apoliprotein E (APOE) gene: climate, local adaptations and evolutionary history. Am J Phys Anthropol 143:13–20. doi: 10.1002/ajpa.21298 CrossRefGoogle Scholar
  77. Elkina Y, von Haehling S, Anker SD, Springer J (2011) The role of myostatin in muscle wasting: an overview. J Cachexia Sarcopenia Muscle 2:143–151. doi: 10.1007/s13539-011-0035-5 PubMedCentralPubMedCrossRefGoogle Scholar
  78. Epstein J, Sanderson IR, MacDonald TT (2010) Curcumin as a therapeutic agent: the evidence from in vitro, animal and human studies. Br J Nutr 103:1545–1557. doi: 10.1017/S0007114509993667 PubMedCrossRefGoogle Scholar
  79. Estruch R, Martínez-González MA, Corella D, Salas-Salvadó J, Ruiz-Gutiérrez V, PREDIMED Study Investigators et al (2006) Effects of a Mediterranean-style diet on cardiovascular risk factors: a randomized trial. Ann Intern Med 145:1–11. doi: 10.7326/0003-4819-145-1-200607040-00004 PubMedCrossRefGoogle Scholar
  80. Fang MZ, Wang Y, Ai N, Hou Z, Sun Y, Lu H, Welsh W, Yang CS (2003) Tea polyphenol Epigallocatechin-3-gallate inhibits DNA methyltransferase and reactivates methylation-silenced genes in cancer cell lines. Cancer Res 63:7563–7570PubMedGoogle Scholar
  81. Farrer LA, Cupples LA, Haines JL, Hyman B, Kukull WA, Mayeux R et al (1997) Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease. A meta-analysis. APOE and Alzheimer Disease Meta Analysis Consortium. JAMA 278:1349–1356. doi: 10.1001/jama.1997.03550160069041 PubMedCrossRefGoogle Scholar
  82. Fenaux P, Mufti GJ, Hellström-Lindberg E et al (2010) Azacitidine prolongs overall survival compared with conventional care regimens in elderly patients with low bone marrow blast count acute myeloid leukemia. J Clin Oncol 28:562–569. doi: 10.1200/JCO.2009.23.8329 PubMedCrossRefGoogle Scholar
  83. Ferrucci L, Harris TB, Guralnik JM, Tracy RP, Corti MC, Cohen HJ, Penninx B et al (1999) Serum IL-6 level and the development of disability in older persons. J Am Geriatr Soc 47:639–646PubMedCrossRefGoogle Scholar
  84. Flachsbart F, Caliebe A, Kleindorp R, Blanché H, von Eller-Eberstein H et al (2009) Association of FOXO3A variation with human longevity confirmed in German centenarians. PNAS 106:2700–2705. doi: 10.1073/pnas.0809594106 PubMedCentralPubMedCrossRefGoogle Scholar
  85. Folstein MF, Folstein SE, McHugh PR (1975) Mini mental state. A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 12:189–198. doi: 10.1016/0022-3956(75)90026-6 PubMedCrossRefGoogle Scholar
  86. Frisoni GB, Louhija J, Geroldi C, Trabucchi M (2001) Longevity and the epsilon2 allele of apolipoprotein E: the Finnish Centenarians Study. J Gerontol A 56:M75–M78. doi: 10.1093/gerona/56.2.M75 CrossRefGoogle Scholar
  87. Ganzevoort RR. and Bouwer J (2007) Life story methods and care for the elderly: An empirical research project in practical theology. In: (eds) Ziebertz H-G and Schweitzer F Dreaming the land: Theologies of resistance and hope. International Academy of Practical Theology, Brisbane 2005, Münster: LIT, pp140-151Google Scholar
  88. Garagnani P, Giuliani C, Pirazzini C, Olivieri F, Bacalini MG et al (2013) Centenarians as super-controls to assess the biological relevance of genetic risk factors for common age-related diseases: a proof of principle on type 2 diabetes. Aging (Albany NY) 5:373–385Google Scholar
  89. Gintjee TJJ, Magh ASH, Bertoni C (2014) High throughput screening in duchenne muscular dystrophy: from drug discovery to functional genomics. Biology 3:752–780. doi: 10.3390/biology3040752 PubMedCentralPubMedCrossRefGoogle Scholar
  90. Glaser BG, Strauss AL (1967) The discovery of grounded theory: strategies for qualitative research. Aldine De Gruyter, New York. ISBN 978-0-202-30260-7Google Scholar
  91. Gluckman PD, Hanson MA, Buklijas T, Low FM, Beedle AS (2009) Epigenetic mechanisms that underpin metabolic and cardiovascular diseases. Nat Rev Endocrinol 5:401–408. doi: 10.1038/nrendo.2009.102 PubMedCrossRefGoogle Scholar
  92. Gomes MD, Lecker SH, Jagoe RT et al (2001) Atrogin-1, a muscle-specific F-box protein highly expressed during muscle atrophy. Proc Natl Acad Sci USA 98:14440–14445. doi: 10.1073/pnas.251541198
  93. Goodpaster BH, Thaete FL, Kelley DE (2000) Thigh adipose tissue distribution is associated with insulin resistance in obesity and in type 2 diabetes mellitus. Am J Clin Nutr 71:885–892Google Scholar
  94. Greer EL, Brunet A (2005) FOXO transcription factors at the interface between longevity and tumor suppression. Oncogene 24:7410–7425. doi: 10.1038/sj.onc.1209086 PubMedCrossRefGoogle Scholar
  95. Grobet L, Martin LJ, Poncelet D et al (1997) A deletion in the bovine myostatin gene causes the double-muscled phenotype in cattle. Nat Genet 17:71–74. doi: 10.1038/ng0997-71 PubMedCrossRefGoogle Scholar
  96. Guasconi V, Puri PL (2008) Epigenetic drugs in the treatment of skeletal muscle atrophy. Curr Opin Clin Nutr Metab Care 11:233–241. doi: 10.1097/MCO.0b013e3282fa1810 PubMedCentralPubMedCrossRefGoogle Scholar
  97. Guinan KJ (2012) Worldwide distribution of Type 11 diabetes-associated TCF7L2 SNPs: evidence for stratification in Europe. Biochem Genet 50:159–179. doi: 10.1007/s10528-011-9456-2 PubMedCrossRefGoogle Scholar
  98. Hamer M, Lavoie KL, Bacon SL (2013) Taking up physical activity in later life and healthy ageing: the English longitudinal study of ageing. Br J Sports Med 48:239–243. doi: 10.1136/bjsports-2013-092993 PubMedCentralPubMedCrossRefGoogle Scholar
  99. Harris TB, Ferrucci L, Tracy RP, Corti MC, Wacholder S, Ettinger WH Jr et al (1999) Associations of elevated interleukin-6 and C-reactive protein levels with mortality in the elderly. Am J Med 106:506–512. doi: 10.1016/S0002-9343(99)00066-2 PubMedCrossRefGoogle Scholar
  100. Hasselgren P (2007) Ubiquitination, phosphorylation, and acetylation: triple threat in muscle wasting. J Cell Physiol 213:679–689. doi: 10.1002/jcp.21190 PubMedCrossRefGoogle Scholar
  101. Hasselgren P-O, Alamdari N, Aversa Z (2010) Corticosteroids and muscle wasting role of transcription factors, nuclear cofactors, and hyperacetylation. Curr Opin Clin Nutr Metab Care 13:423–428. doi: 10.1097/MCO.0b013e32833a5107 PubMedCentralPubMedCrossRefGoogle Scholar
  102. He YH, Lu X, Yang LQ, Xu LY, Kong QP (2014) Association of the insulin-like growth factor binding protein 3 (IGFBP-3) polymorphism with longevity in Chinese nonagenarians and centenarians. Aging (Albany NY) 6:944–956Google Scholar
  103. Heijmans BT, Tobi EW, Stein AD, Putter H, Blauw GJ, Susser ES, Slagboom PE, Lumey LH (2008) Persistent epigenetic differences associated with prenatal exposure to famine in humans. PNAS 105:17046–17049. doi: 10.1073/pnas.0806560105 PubMedCentralPubMedCrossRefGoogle Scholar
  104. Hepple RT (2014) Mitochondrial involvement and impact in aging skeletal muscle. Front Aging Neurosci 6:211. doi: 10.3389/fnagi.2014.00211 PubMedCentralPubMedCrossRefGoogle Scholar
  105. Hiona A, Leeuwenburgh C (2008) The role of mitochondrial DNA mutations in aging and sarcopenia: implications for the mitochondrial vicious cycle theory of aging. Exp Gerontol 43:24–33. doi: 10.1016/j.exger.2007.10.001 PubMedCentralPubMedCrossRefGoogle Scholar
  106. Hompes T, Izzi B, Gellens E, Morreels M, Fieuws S, Pexsters A et al (2013) Investigating the influence of maternal cortisol and emotional state during pregnancy on the DNA methylation status of the glucocorticoid receptor gene (NR3C1) promoter region in cord blood. J Psychiatr Res 47:880–891. doi: 10.1016/j.jpsychires.2013.03.009 PubMedCrossRefGoogle Scholar
  107. Hutcheon SD, Gillespie ND, Crombie IK et al (2002) Perindopril improves six minute walking distance in older patients with left ventricular systolic dysfunction: a randomised double blind placebo controlled trial. Heart 88:373–377. doi: 10.1136/heart.88.4.373 PubMedCentralPubMedCrossRefGoogle Scholar
  108. Ibebunjo C, Chick JM, Kendall T et al (2013) Genomic and proteomic profiling reveals reduced mitochondrial function and disruption of the neuromuscular junction driving rat sarcopenia. Mol Cell Biol 33:194–212. doi: 10.1128/MCB.01036-12 PubMedCentralPubMedCrossRefGoogle Scholar
  109. Jennings BA, Willis G (2015) How folate metabolism affects colorectal cancer development and treatment: a story of heterogeneity and pleiotropy. Cancer Lett 356(2):224–230. doi: 10.1016/j.canlet.2014.02.024 PubMedCrossRefGoogle Scholar
  110. Jian-Gang Z, Yong-Xing M, Chuan-Fu W, Pei-Fang L, Song-Bai Z et al (1998) Apolipoprotein E and longevity among Han Chinese population. Mech Ageing Dev 104:159–167. doi: 10.1016/S0047-6374(98)00067-0 PubMedCrossRefGoogle Scholar
  111. Jofre-Monseny L, Minihane AM, Rimbach G (2008) Impact of apoE genotype on oxidative stress, inflammation and disease risk. Mol Nutr Food Res 52:131–145. doi: 10.1002/mnfr.200700322 PubMedCrossRefGoogle Scholar
  112. Joseph AM, Adhihetty PJ, Buford TW et al (2012) The impact of aging on mitochondrial function and biogenesis pathways in skeletal muscle of sedentary high and low-functioning elderly individuals. Aging Cell 11:801–809. doi: 10.1111/j.1474-9726.2012.00844.x PubMedCentralPubMedCrossRefGoogle Scholar
  113. Kala R, Peek GW, Hardy TM, Tollefsbol TO (2013) MicroRNAs: an emerging science in cancer epigenetics. J Clin Bioinforma 3:6. doi: 10.1186/2043-9113-3-6 PubMedCentralPubMedCrossRefGoogle Scholar
  114. Kang C, Ji LL (2013) Role of PGC-1α in muscle function and aging. J Sport Health Sci 2:81–86. doi: 10.1016/j.jshs.2013.03.005 CrossRefGoogle Scholar
  115. Kervinen K, Savolainen MJ, Salokannel J, Hynninen A, Heikkinen J et al (1994) Apolipoprotein E and B polymorphisms—longevity factors assessed in nonagenarians. Atherosclerosis 105:89–95PubMedCrossRefGoogle Scholar
  116. Khoury MJ, Davis R, Gwinn M et al (2005) Do we need genomic research for the prevention of common diseases with environmental causes. Am J Epid 161:799–805. doi: 10.1093/aje/kwi113 CrossRefGoogle Scholar
  117. Kim S-H, Kang H-J, Na H, Lee M-O (2010) Trichostatin A enhances acetylation as well as protein stability of ERα through induction of p300 protein. Breast Cancer Res 12:R22. doi: 10.1186/bcr2562 PubMedCentralPubMedCrossRefGoogle Scholar
  118. Kops GPL, Dansen TB, Polderman PE, Saarloos I, Wirtz KWA et al (2002) Forkhead transcription factor FOXO3a protects quiescent cells from oxidative stress. Nature 419:316–321. doi: 10.1038/nature01036 PubMedCrossRefGoogle Scholar
  119. Laland KN, Odling-Smee J, Myles S (2010) How culture shaped the human genome: bridging genetics and the human sciences together. Nat Rev Gen 11:137–148. doi: 10.1038/nrg2734 CrossRefGoogle Scholar
  120. Lambert JC, Pasquier F, Cottel D, Frigard B, Amouyel P, Chartier-Harlin MC (1998) A new polymorphism in the APOE promoter associated with risk of developing Alzheimer’s disease. Hum Mol Genet 7:533–540. doi: 10.1093/hmg/7.3.533 PubMedCrossRefGoogle Scholar
  121. Lambert JC, Brousseau T, Defosse V, Evans A, Arveiler D, Ruidavets JB, Haas B et al (2000) Independent association of an APOE gene promoter polymorphism with increased risk of myocardial infarction and decreased APOE plasma concentrations-the ECTIM study. Hum Mol Genet 9:57–61. doi: 10.1093/hmg/9.1.57 PubMedCrossRefGoogle Scholar
  122. Lan F, Yue X, Han L, Shi Z, Yang Y, Pu P, Yao Z, Kang C (2012) Genome-wide identification of TCF7L2/TCF4 target miRNAs reveals a role for miR-21 in Wnt-driven epithelial cancer. Int J Oncol 40:519–526. doi: 10.3892/ijo.2011.1215 PubMedGoogle Scholar
  123. Lewis BP, Burge CB, Bartel DP (2005) Conserved seed pairing, often flanked by adenosines, indicates that thousands of human genes are microRNA targets. Cell 120:15–20. doi: 10.1016/j.cell.2004.12.035 PubMedCrossRefGoogle Scholar
  124. Li Y, Wang WJ, Cao H, Lu J, Wu C, Hu FY, Guo J, Zhao L et al (2009) Genetic association of FOXO1A and FOXO3A with longevity trait in Han Chinese populations. Hum Mol Genet 18:4897–4904. doi: 10.1093/hmg/ddp459 PubMedCentralPubMedCrossRefGoogle Scholar
  125. Lightart GJ, Corberand JX, Fornier C, Galanaud P, Hijmans W et al (1984) Admission criteria for immunogerontological studies in man: the SENIEUR protocol. Mech Ageing Dev 28:47–55CrossRefGoogle Scholar
  126. Lin L, Hron JD, Peng SL (2004) Regulation of NF-κB, Th activation, and autoinflammation by the forkhead transcription factor Foxo3a. Immunity 21:203–213. doi: 10.1016/j.immuni.2004.06.016 PubMedCrossRefGoogle Scholar
  127. Lindahl T (1981) DNA methylation and control of gene expression. Nature 290:363–364Google Scholar
  128. Ling C, Groop L (2009) Epigenetics: a molecular link between environmental factors and type diabetes 2. Diabetes 58:2718–2725. doi: 10.2337/db09-1003 PubMedCentralPubMedCrossRefGoogle Scholar
  129. Ling C, Poulsen P, Simonsson S, Ronn T, Holmkvist J, Almgren P, Hagert P et al (2007) Genetic and epigenetic factors are associated with expression of respiratory chain component NDUFB6 in human skeletal muscle. J Clin Invest 117:3427–3435. doi: 10.1172/JCI30938 PubMedCentralPubMedCrossRefGoogle Scholar
  130. Lister R, Pelizzola M, Dowen RH, Hawkins RD, Hon G, Tonti-Filippini J et al (2009) Human DNA methylomes at base resolution show widespread epigenomic differences. Nature 462:315–322. doi: 10.1038/nature08514 PubMedCentralPubMedCrossRefGoogle Scholar
  131. Liu FJ, Lim KY, Kaur P, Sepramaniam S, Armugam A et al (2013) MicroRNAs involved in regulating spontaneous recovery in embolic stroke model. PLoS ONE 8(6):e66393. doi: 10.1371/journal.pone.0066393 PubMedCentralPubMedCrossRefGoogle Scholar
  132. Loffredo FS, Steinhauser ML, Jay SM et al (2013) Growth differentiation factor 11 is a circulating factor that reverses age-related cardiac hypertrophy. Cell 153:828–839. doi: 10.1016/j.cell.2013.04.015 PubMedCentralPubMedCrossRefGoogle Scholar
  133. Lotito SB, Frei B (2006) Consumption of flavonoid-rich foods and increased plasma antioxidant capacity in humans: cause, consequence, or epiphenomenon? Free Radic Biol Med 41:1727–1746. doi: 10.1016/j.freeradbiomed.2006.04.033 PubMedCrossRefGoogle Scholar
  134. Lu F, Guan H, Gong B, Liu X, Zhu R, Wang Y, Qian J et al (2014) Genetic variants in PVRL2-TOMM40-APOE region are associated with human longevity in a Han Chinese Population. PLoS ONE 9(6):e99580. doi: 10.1371/journal.pone.0099580 PubMedCentralPubMedCrossRefGoogle Scholar
  135. Lucotte G, Loirat F Hazout S (1997) Brief communications: pattern of gradient of apolipoprotein E allele 4 frequencies in Western Europe. Hum Biol, 69(2): 253–262.
  136. Ma Y, Smith CE, Lai CQ, Irvin MR, Parnell LD, Lee YC, Tsai MY et al (2015) Genetic variants modify the effect of age on APOE methylation in the genetics of lipid lowering drugs and diet network study. Aging Cell 14:49–59. doi: 10.1111/acel.12293 PubMedCentralPubMedCrossRefGoogle Scholar
  137. Mahley RW, Rall SC Jr (2000) Apolipoprotein E: far more than a lipid transport protein. Annu Rev Genomics Hum Genet 1:507–537. doi: 10.1146/annurev.genom.1.1.507 PubMedCrossRefGoogle Scholar
  138. Marcus RL, Addison O, Kidde JP (2010) Skeletal muscle fat infiltration: impact of age, inactivity, and exercise. J Nut Health Aging 14:362–366. doi: 10.1007/s12603-010-0081-2 CrossRefGoogle Scholar
  139. Marmot MG, Bosma H, Hemingway H, Brunner E, Stansfeld S (1997) Contribution of job control and other risk factors to social variations in coronary heart disease incidence. Lancet 350:235–239PubMedCrossRefGoogle Scholar
  140. Mateos M-V, Hernández J-M, Hernández M-T et al (2006) Bortezomib plus melphalan and prednisone in elderly untreated patients with multiple myeloma: results of a multicenter phase 1/2 study. Blood 108:2165–2172. doi: 10.1182/blood-2006-04-019778 PubMedCrossRefGoogle Scholar
  141. McGue M, Vaupel JW, Holm N, Harvald B (1993) Longevity is moderately heritable in a sample of Danish twins born 1870–1880. J Gerontol 48:B237–B244PubMedCrossRefGoogle Scholar
  142. McKay GJ, Silvestri G, Chakravarthy U, Dasari S, Fritsche LG, Weber BH, Keilhauer CN, Klein ML, Francis PJ et al (2011) Variations in apolipoprotein E frequency with age in a pooled analysis of a large group of older people. Am J Epidemiol 173:1357–1364. doi: 10.1093/aje/kwr015 PubMedCentralPubMedCrossRefGoogle Scholar
  143. Meaney MJ (2001) Maternal care, gene expression, and the transmission of individual differences in stress reactivity across generations. Annu Rev Neurosci 24:1161–1192. doi: 10.1146/annurev.neuro.24.1.1161 PubMedCrossRefGoogle Scholar
  144. Meaney MJ, Szyf M (2005) Environmental programming of stress responses through DNA methylation: life at the interface between a dynamic environment and a fixed genome. Dialogues Clin Neurosci 7:103–123PubMedCentralPubMedGoogle Scholar
  145. Meeran SM, Patel SN, Tollefsbol TO (2010) Sulforaphane causes epigenetic repression of hTERT expression in human breast cancer cell lines. PLoS ONE 5(7):e11457. doi: 10.1371/journal.pone.0011457 PubMedCentralPubMedCrossRefGoogle Scholar
  146. Mena MP, Sacanella E, Vazquez-Agell M, Morales M, Fitó M et al (2009) Inhibition of circulating immune cell activation: a molecular anti-inflammatory effect of the Mediterranean diet. Am J Clin Nutr 89:248–256. doi: 10.3945/ajcn.2008.26094 PubMedCrossRefGoogle Scholar
  147. Menzies K, Auwerx J (2013) An acetylation rheostat for the control of muscle energy homeostasis. J Mol Endocrinol 51:T101–T113. doi: 10.1530/JME-13-0140 PubMedCrossRefGoogle Scholar
  148. Minucci S, Pelicci PG (2006) Histone deacetylase inhibitors and the promise of epigenetic (and more) treatments for cancer. Nat Rev Cancer 6:38–51. doi: 10.1038/nrc1779 PubMedCrossRefGoogle Scholar
  149. Mitchell BD, Hsueh WC, King T, Pollin TI, Sorkin J, Agarwala R, Schaffer AA, Shuldiner AR (2001) Heritability of life span in the old order Amish. Am J Med Genet 102:346–352. doi: 10.1002/ajmg.1483 PubMedCrossRefGoogle Scholar
  150. Mootha VK, Lindfren CM, Eriksson KF et al (2003) PGC-1alpha-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes. Nat Genet 34:267–273. doi: 10.1038/ng1180
  151. Morley JE, Baumgartner RN, Roubenoff R et al (2001) Sarcopenia. J Lab Clin Med 137:231–243. doi: 10.1067/mlc.2001.113504 PubMedCrossRefGoogle Scholar
  152. Morley JE, Vellas B, Abellan van Kan G et al (2013) Frailty consensus: a call to action. JAMDA 14:392–397. doi: 10.1016/j.jamda.2013.03.022 PubMedCentralPubMedGoogle Scholar
  153. Musaro A, McCullagh K, Paul A et al (2001) Localised Igf-1 transgene expression sustains hypertrophy and regeneration in senescent skeletal muscle. Nat Genet 27:195–200. doi: 10.1038/84839 PubMedCrossRefGoogle Scholar
  154. Myerson S, Hemingway H, Budget R (1999) Human angiotensin I-converting enzyme gene and endurance performance. J Appl Physiol 87:1313–1316PubMedGoogle Scholar
  155. Nichols M, Townsend N, Scarborough P Rayner M (2012) European Cardiovascular Disease Statistics:2012 edition British Heart Foundation Health Promotion Research Group Department of Public Health, University of Oxford, The European Heart Network (EHN), Brussels.
  156. Oberlander TF, Weinberg J, Papsdorf M, Grunau R, Misri S, Devlin AM (2008) Prenatal exposure to maternal depression, neonatal methylation of human glucocorticoid receptor gene (NR3C1) and infant cortisol stress responses. Epigenetics 3:97–106. doi: 10.4161/epi.3.2.6034 PubMedCrossRefGoogle Scholar
  157. Ossenkoppele G, Löwenberg B (2015) How I treat the older patient with acute myeloid leukemia. Blood 125:767–774. doi: 10.1182/blood-2014-08-551499 PubMedCrossRefGoogle Scholar
  158. Paaby AB, Schmidt PS (2009) Dissecting the genetics of longevity in Drosophila melanogaster. Fly 3:29–38. doi: 10.4161/fly.3.1.7771 PubMedCrossRefGoogle Scholar
  159. Park SW, Goodpaster BH, Strotmeyer ES et al (2006) Decreased muscle strength and quality in older adults with type 2 diabetes: the health, aging, and body composition study. Diabetes 55:1813–1818. doi: 10.2337/db05-1183 PubMedCrossRefGoogle Scholar
  160. Peng S, Zhu Y, Lü B, Xu F, Li X, Lai M (2013) TCF7L2 gene polymorphisms and type 2 diabetes risk: a comprehensive and updated meta-analysis involving 121,174 subjects. Mutagenesis 28:25–37. doi: 10.1093/mutage/ges048 PubMedCrossRefGoogle Scholar
  161. Pettigrew KA, Armstrong RN, Colyer HA, Zhang SD, Rea IM, Jones RE et al (2012) Differential TERT promoter methylation and response to 5-aza-2′-deoxycytidine in acute myeloid leukemia cell lines: TERT expression, telomerase activity, telomere length, and cell death. Genes Chromosomes Cancer 51:768–780. doi: 10.1002/gcc.21962 PubMedCrossRefGoogle Scholar
  162. Philippou A, Maridaki M, Halapas A, Koutsilieris M (2007) The role of the insulin-like growth factor 1 (IGF-1) in muscle physiology. In Vivo 21:45–54PubMedGoogle Scholar
  163. Plotsky PM, Meaney MJ (1993) Early, postnatal experience alters hypothalamic corticotropin-releasing factor (CRF) mRNA, median eminence CRF content and stress-induced release in adult rats. Brain Res Mol Brain Res 18:195–200PubMedCrossRefGoogle Scholar
  164. Poylin V, Fareed MU, O’Neal P et al (2008) The NF-kB inhibitor curcumin blocks sepsis-induced muscle proteolysis. Mediat Inflam 2008:317851. doi: 10.1155/2008/317851 CrossRefGoogle Scholar
  165. Ramírez CM, Rotllan N, Vlassov AV, Dávalos A, Li M, Goedeke L et al (2013) Control of cholesterol metabolism and plasma high-density lipoprotein levels by microRNA-144. Circ Res 112:1592–1601. doi: 10.1161/CIRCRESAHA.112.300626 PubMedCentralPubMedCrossRefGoogle Scholar
  166. Rea Maeve (2013) Living long and ageing well: insights from nonagenarians. In: Davidson S, Goodwin J, Rossall P (eds) Improving later life: understanding the oldest old age, UK, pp 74–77. ISBN 978-0-9568731-6-3.
  167. Rea M, Rea S (2011) Super vivere: reflections on long life and ageing well. Blackstaff Press, Belfast. ISBN 978-0-85640-866-3Google Scholar
  168. Rea IM, McDowell I, McMaster D, Smye M, Stout R, Evans A, MONICA Group (Belfast) (2001) Apolipoprotein E alleles in nonagenarian subjects in the Belfast Elderly Longitudinal Free-Living Ageing Study (BELFAST). Mech Ageing Dev 122:1367–1372. doi: 10.1016/S0047-6374(01)00278-0
  169. Rea IM, Ross OA, Armstrong M, McNerlan S, Alexander DH, Curran MD, Middleton D (2003) Interleukin-6-gene C/G 174 polymorphism in nonagenarian and octogenarian subjects in the BELFAST study. Reciprocal effects on IL-6, soluble IL-6 receptor and for IL-10 in serum and monocyte supernatants. Mech Ageing Dev 124:555–561. doi: 10.1016/S0047-6374(03)00036-8
  170. Rea IM, Myint PK, Mueller H, Murphy A, Archbold GP, McNulty H, Patterson CC (2009) Nature or nurture; BMI and blood pressure at 90. Findings from the Belfast Elderly Longitudinal Free-living Aging Study (BELFAST). Age (Dordr) 31:261–267. doi: 10.1007/s11357-009-9096-1
  171. Rea JN, Carvalho A, McNerlan SE, Alexander HD, Rea IM (2015) Genes and life-style factors in BELFAST nonagenarians: nature, nurture and narrative. Biogerontology. doi: 10.1007/s10522-015-9567-y
  172. Reddy MA, Sumanth P, Lanting L (2014) Losartan reverses permissive epigenetic changes in renal glomeruli of diabetic db/db mice. Kidney Int 85:362–373. doi: 10.1038/ki.2013.387
  173. Rönn T, Poulsen P, Hansson O, Holmkvist J, Almgren P, Nilsson P, Tuomi T, Isomaa B, Groop L, Vaag A, Ling C (2008) Age influences DNA methylation and gene expression of COX7A1 in human skeletal muscle. Diabetologia 51(7):1159–1168. doi: 10.1007/s00125-008-1018-8 PubMedCrossRefGoogle Scholar
  174. Rönn T, Volkov P, Davegårdh C, Dayeh T, Hall E, Olsson AH, Nilsson E, Tomberg A, Nitert MD, Eriksson K-K, Jones HA, Groop L, Ling C (2013) A six months exercise intervention influences the genome-wide DNA methylation pattern in human adipose tissue. PLoS Genet 9(6):e1003572. doi: 10.1371/journal.pgen.1003572 PubMedCentralPubMedCrossRefGoogle Scholar
  175. Rosenberg IH (1997) Sarcopenia: origins and clinical relevance. J Nutr 127:990S–991SPubMedGoogle Scholar
  176. Roses AD, Lutz MW, Amrine-Madsen H, Saunders AM, Crenshaw DG et al (2010) A TOMM40 variable-length polymorphism predicts the age of late-onset Alzheimer’s disease. Pharmacogenomics J 10:375–384. doi: 10.1038/tpj.2009.69 PubMedCentralPubMedCrossRefGoogle Scholar
  177. Sadoul K, Boyault C, Pabion M et al (2008) Regulation of protein turnover by acetyltransferases and deacetylases. Biochimie 90:306–312PubMedCrossRefGoogle Scholar
  178. Sakuma K, Yamaguchi A (2012) Novel intriguing strategies attenuating to sarcopenia. J Aging Res. doi:  10.1155/2012/251217
  179. Sandri M, Lin J, Handschin C et al (2006) PGC-1alpha protects skeletal muscle from atrophy by suppressing FoxO3 action and atrophy-specific gene transcription. Proc Natl Acad Sci USA 103:16260–16265. doi: 10.1073/pnas.0607795103 PubMedCentralPubMedCrossRefGoogle Scholar
  180. Saunders AM, Strittmatter WJ, Schmechel D, George-Hyslop PH, Gusella JF et al (1993) Association of apolipoprotein E allele epsilon 4 with late-onset familial and sporadic Alzheimer’s disease. Neurology 43:1467–1472PubMedCrossRefGoogle Scholar
  181. Savic D, Bell GI, Nobrega MA (2012) An in vivo cis-regulatory screen at the type 2 diabetes associated TCF7L2 locus identifies multiple tissue-specific enhancers. PLoS ONE 7(5):e36501. doi: 10.1371/journal.pone.0036501 PubMedCentralPubMedCrossRefGoogle Scholar
  182. Saxena R, Elbers CC, Guo Y, Peter I, Gaunt TR, Mega JL, Lanktree MB et al (2012) Large-scale gene-centric meta-analysis across 39 studies identifies type 2 diabetes loci. Am J Hum Genet 90:410–425. doi: 10.1016/j.ajhg.2011.12.022 PubMedCentralPubMedCrossRefGoogle Scholar
  183. Sayer AA, Syddall HE, Dennison EM et al (2004) Birth weight, weight at one year and body composition in older men: findings from the Hertfordshire Cohort Study. Am J Clin Nutr 80:199–203PubMedGoogle Scholar
  184. Sayer AA, Syddall H, Martin H et al (2008) The developmental origins of sarcopenia. J Nutr Health Aging 12:427–432PubMedCentralPubMedCrossRefGoogle Scholar
  185. Schachter F, Faure-Delanef L, Guenot F, Rouger H, Froguel P et al (1994) Genetic associations with human longevity at the APOE and ACE loci. Nat Genet 6:29–32. doi: 10.1038/ng0194-29 PubMedCrossRefGoogle Scholar
  186. Schuelke M, Wagner KR, Stolz LE et al (2004) Myostatin mutation associated with gross muscle hypertrophy in a child. N Engl J Med 350:2682–2688. doi: 10.1056/NEJMoa040933 PubMedCrossRefGoogle Scholar
  187. Schulz LC (2010) The Dutch Hunger Winter and the developmental origins of health and disease. PNAS 107:16757–16758. doi: 10.1073/pnas.1012911107 PubMedCentralPubMedCrossRefGoogle Scholar
  188. Shah MS, Davidson LA, Chapkin RS (2012) Mechanistic insights into the role of microRNAs in cancer: influence of nutrient crosstalk. Front Genet 3:305. doi: 10.3389/fgene.2012.00305 PubMedCentralPubMedCrossRefGoogle Scholar
  189. Shao W, Wang D, Chiang YT, Ip W, Zhu L, Xu F, Columbus J, Belsham DD et al (2013) The Wnt signaling pathway effector TCF7L2 controls gut and brain proglucagon gene expression and glucose homeostasis. Diabetes 62:789–800. doi: 10.2337/db12-0365 PubMedCentralPubMedCrossRefGoogle Scholar
  190. Shenderov BA, Midtvedt T (2014) Epigenomic programing: a future way to health? Microb Ecol Health Dis 8:25. doi: 10.3402/mehd.v25.24145 Google Scholar
  191. Simon CB, Lee-McMullen B, Phelan D et al (2015) The renin-angiotensin system and prevention of age-related functional decline: where are we now? Age (Dordr) 37:9753. doi: 10.1007/s11357-015-9753-5 CrossRefGoogle Scholar
  192. Singh PP, Singh M, Mastana SS (2006) APOE distribution in world populations with new data from India and the UK. Ann Hum Biol 33:279–308. doi: 10.1080/03014460600594513 PubMedCrossRefGoogle Scholar
  193. Sinha M, Jang YC, Oh J et al (2014) Restoring systemic GDF11 levels reverses age-related dysfunction in mouse skeletal muscle. Science 344:649–652. doi: 10.1126/science.1251152 PubMedCentralPubMedCrossRefGoogle Scholar
  194. Smith RC, Lin BK (2013) Myostatin inhibitors as therapies for muscle wasting associated with cancer and other disorders. Curr Opin Support Palliat Care 7(4):352–360. doi: 10.1097/SPC.0000000000000013
  195. Soerensen M, Dato S, Christensen K, McGue M, Stevnsner T, Bohr VA, Christiansen L (2010) Replication of an association of variation in the FOXO3A gene with human longevity using both case-control and longitudinal data. Aging Cell 9:1010–1017. doi: 10.1111/j.1474-9726.2010.00627.x PubMedCentralPubMedCrossRefGoogle Scholar
  196. Sousa AGP, Marquezine GF, Lemos PA, Martinez E, Lopes N (2009) TCF7L2 polymorphism rs7903146 is associated with coronary artery disease severity and mortality. PLoS ONE 4(11):e7697. doi: 10.1371/journal.pone.0007697 PubMedCentralPubMedCrossRefGoogle Scholar
  197. Spannhoff A, Kim YK, Raynal NJ, Gharibyan V, Su MB, Zhou YY, Li J et al (2011) Histone deacetylase inhibitor activity in royal jelly might facilitate caste switching in bees. EMBO Rep 12:238–243. doi: 10.1038/embor.2011.9 PubMedCentralPubMedCrossRefGoogle Scholar
  198. Sparks LM, Xie H, Koza RA, Mynatt R et al (2005) A high-fat diet coordinately downregulates genes required for mitochondrial oxidative phosphorylation in skeletal muscle. Diabetes 54:1926–1933. doi: 10.2337/diabetes.54.7.1926 PubMedCrossRefGoogle Scholar
  199. Spoto B, Mattace-Raso F, Sijbrands E, Leonardis D, Testa A, Pisano A, Pizzini P, Cutrupi S et al (2014) Association of IL-6 and a functional polymorphism in the IL-6 Gene with cardiovascular events in patients with CKD. Clin J Am Soc Nephrol 10:232–240. doi: 10.2215/CJN.07000714 PubMedCrossRefGoogle Scholar
  200. Stitt TN, Drujan D, Clarke BA et al (2004) The IGF-1/PI3 K/Akt pathway prevents expression of muscle atrophy-induced ubiquitin ligases by inhibiting FOXO transcription factors. Mol Cell 14:395–403. doi: 10.1016/S1097-2765(04)00211-4 PubMedCrossRefGoogle Scholar
  201. Strauss A, Corbin J (1990) Basics of qualitative research: grounded theory procedures and techniques. Sage Publications Inc, Newbury ParkGoogle Scholar
  202. Strittmatter WJ, Saunders AM, Schmechel D (1993) Apolipoprotein E: high-avidity binding to beta-amyloid and increased frequency of type 4 allele in late-onset familial Alzheimer disease. PNAS 90:1977–1981PubMedCentralPubMedCrossRefGoogle Scholar
  203. Sugii S, Evans RM (2011) Epigenetic codes of PPARγ in metabolic disease. FEBS Lett 585:2121–2128. doi: 10.1016/j.febslet.2011.05.007 PubMedCentralPubMedCrossRefGoogle Scholar
  204. Sumukadas D, Witham MD, Struthers AD, McMurdo ME (2007) Effect of perindopril on physical function in elderly people with functional impairment: a randomized controlled trial. CMAJ 177:867–874PubMedCentralPubMedCrossRefGoogle Scholar
  205. Sumukadas D, Band M, Miller S et al (2014) Do ACE inhibitors improve the response to exercise training in functionally impaired older adults? a randomized controlled trial. J Gerontol Ser A 69:736–743. doi: 10.1093/gerona/glt142 CrossRefGoogle Scholar
  206. Szyf M, Weaver IC, Champagne FA, Diorio J, Meaney MJ (2005) Maternal programming of steroid receptor expression and phenotype through DNA methylation in the rat. Front Neuroendocrinol 26:139–162. doi: 10.1016/j.yfrne.2005.10.002 PubMedCrossRefGoogle Scholar
  207. Tabuchi T, Satoh M, Itoh T, Nakamura M (2012) MicroRNA-34a regulates the longevity-associated protein SIRT1 in coronary artery disease: effect of statins on SIRT1 and microRNA-34a expression. Clin Sci 123:161–171. doi: 10.1042/CS20110563 PubMedCrossRefGoogle Scholar
  208. Tassara M, Döhner K, Brossart P et al (2014) Valproic acid in combination with all-trans retinoic acid and intensive therapy for acute myeloid leukemia in older patients. Blood 123:4027–4036. doi: 10.1182/blood-2013-12-546283 PubMedCrossRefGoogle Scholar
  209. Thornton SN and Norgren R (2011) Losartan-induced hydration of muscle cells protects against disuse atrophy in sarcopenia. Sci Transl Med 3: 82ra37Google Scholar
  210. Tissenbaum HA, Guarente L (2002) Model organisms as a guide to mammalian aging. Dev Cell 2:9–19PubMedCrossRefGoogle Scholar
  211. Tollefsbol TO (2014) Dietary epigenetics in cancer and aging. Cancer Treat Res 159:257–267. doi: 10.1007/978-3-642-38007-5_15 PubMedCrossRefGoogle Scholar
  212. Tong Y, Lin Y, Zhang Y, Yang J, Zhang Y, Liu H, Zhang B (2009) Association between TCF7L2 gene polymorphisms and susceptibility to type 2 diabetes mellitus: a large Human Genome Epidemiology (HuGE) review and meta-analysis. BMC Med Genet 10:15. doi: 10.1186/1471-2350-10-15 PubMedCentralPubMedCrossRefGoogle Scholar
  213. Vigushin DM, Ali S, Pace PE (2001) Trichostatin A is a histone deacetylase inhibitor with potent antitumor activity against breast cancer in vivo. Clin Cancer Res 7:971–976Google Scholar
  214. Viitanen L, Pihlajamäki J, Miettinen R, Kärkkäinen P, Vauhkonen I et al (2001) Apolipoprotein E gene promoter (−219G/T) polymorphism is associated with premature coronary heart disease. J Mol Med (Berl) 79:732–737CrossRefGoogle Scholar
  215. Viollet B, Guigas B, Sanz Garcia N, Leclerc J, Foretz M, Andreelli F (2012) Cellular and molecular mechanisms of metformin: an overview. Clin Sci (Lond) 122:253–270. doi: 10.1042/CS20110386 CrossRefGoogle Scholar
  216. Vogt PK, Jiang H, Aoki M (2005) Triple layer control: phosphorylation, acetylation and ubiquitination of FOXO proteins. Cell Cycle 4:908–913. doi: 10.4161/cc.4.7.1796 PubMedCrossRefGoogle Scholar
  217. Wagner KR, Fleckenstein JL, Amato AA et al (2008) A phase I/II trial of MYO-029 in adult subjects with muscular dystrophy. Ann Neurol 63:561–571. doi: 10.1002/ana.21338 PubMedCrossRefGoogle Scholar
  218. Walston JD (2012) Sarcopenia in older adults. Curr Opin Rheumatol 24:623–627. doi: 10.1097/BOR.0b013e328358d59b PubMedCentralPubMedCrossRefGoogle Scholar
  219. Wang F, Nguyen M, Qin FX, Tong Q (2007) SIRT2 deacetylates FOXO3a in response to oxidative stress and caloric restriction. Aging Cell 6:505–514. doi: 10.1111/j.1474-9726.2007.00304 PubMedCrossRefGoogle Scholar
  220. Wang S-C, Oelze B, Schumacher A (2008) Age-specific epigenetic drift in late-onset alzheimer’s disease. PLoS ONE 3(7):e2698. doi: 10.1371/journal.pone.0002698 PubMedCentralPubMedCrossRefGoogle Scholar
  221. Weisgraber KH, Innerarity TL, Mahley RW (1982) Abnormal lipoprotein receptor-binding activity of the human E apoprotein due to cysteine-arginine interchange at a single site. J Biol Chem 257:2518–2521PubMedGoogle Scholar
  222. Wen CP, Wai JPM, Tsai MK, Yang YC, Cheng TYD, Lee M-C et al (2011) Minimum amount of physical activity for reduced mortality and extended life expectancy: a prospective cohort study. Lancet 378:1244–1253. doi: 10.1016/S0140-6736(11)60749-6 PubMedCrossRefGoogle Scholar
  223. Wenz T, Rossi SG, Rotundo RL et al (2009) Increased muscle PGC-1α expression protects from sarcopenia and metabolic disease during aging. Proc Natl Acad Sci USA 106:20405–20410. doi: 10.1073/pnas.0911570106 PubMedCentralPubMedCrossRefGoogle Scholar
  224. Willcox BJ, Timothy A, Donlon TA, He Q, Chen R, Grove JS, Yano K et al (2008) FOXO3A genotype is strongly associated with human longevity. PNAS 105:13987–13992. doi: 10.1073/pnas.0801030105 PubMedCentralPubMedCrossRefGoogle Scholar
  225. Williams AG, Rayson MP, Jubb M et al (2000) Physiology—the ACE gene and muscle performance. Nature 403:614. doi: 10.1038/35001141 PubMedCrossRefGoogle Scholar
  226. Yang Q, Bostick RM, Friedman JM, Flanders WD (2009) Serum folate and cancer mortality among U.S. adults: findings from the Third National Health and Nutritional Examination Survey linked mortality file. Cancer Epidemiol Biomark Prev 18:1439–1447. doi: 10.1158/1055-9965.EPI-08-0908 CrossRefGoogle Scholar
  227. Yang H, Li Q, Lee JH, Shu Y (2012) Reduction in TCH7L2 expression decreases diabetic susceptibility in mice. Int J Sci 8:791–802. doi: 10.7150/ijbs.4568 Google Scholar
  228. Yates LB, Djousse L, Kurth T, Buring JE, Gaziano M (2008) Exceptional longevity in men: modificable factors associated with survival and function to age 90 years. Arch Intern Med 168:284–290. doi: 10.1001/archinternmed.2007.77 PubMedCrossRefGoogle Scholar
  229. Yehuda R, Daskalakis NP, Lehrner A, Desarnaud F, Bader HN et al (2014) Influences of maternal and paternal PTSD on epigenetic regulation of the glucocorticoid receptor gene in Holocaust survivor offspring. Am J Psychiatry 171:872–880. doi: 10.1176/appi.ajp.2014.13121571 PubMedCentralPubMedCrossRefGoogle Scholar
  230. Yehuda R, Flory JD, Bierer LM, Henn-Haase C, Lehrner A, Desarnaud F et al (2015) Lower methylation of glucocorticoid receptor gene promoter 1F in peripheral blood of veterans with posttraumatic stress disorder. Biol Psychiatry 77:356–364. doi: 10.1016/j.biopsych.2014.02.006 PubMedCrossRefGoogle Scholar
  231. Yim JE, Heshka S, Albu J et al (2007) Intermuscular adipose tissue rivals visceral adipose tissue in independent associations with cardiovascular risk. Int J Obes (Lond) 31:1400–1405. doi: 10.1038/sj.ijo.0803621 CrossRefGoogle Scholar
  232. Yoshida M, Matsuyama A, Komatsu Y et al (2003) From discovery to the coming generation of histone deacetylase inhibitors. Curr Med Chem 10:2351–2358. doi: 10.2174/0929867033456602 PubMedCrossRefGoogle Scholar
  233. Yu CE, Cudaback E, Foraker J, Thomson Z, Leong L, Lutz F, Gill JA, Saxton A, Kraemer B, Navas P, Keene D, Montine T, Bekris LM (2013) Epigenetic signature and enhancer activity of the human APOE gene. Hum Mol Genet 22:5036–5047. doi: 10.1093/hmg/ddt354 PubMedCentralPubMedCrossRefGoogle Scholar
  234. Yuan R, Peters LL, Paigen B (2011) Mice as a mammalian model for research on the genetics of aging. ILAR J 52:4–15PubMedCentralPubMedCrossRefGoogle Scholar
  235. Zhang K, Faiola F, Martinez E (2005) Six lysine residues on c-Myc are direct substrates for acetylation by p300. Biochem Biophys Res Commun 336:274–280. doi: 10.1016/j.bbrc.2005.08.075
  236. Zhang H, Wu L-M, Wu J (2011) Cross-talk between Apolipoprotein E and cytokines. Mediat Inflamm. doi: 10.1155/2011/949072 Google Scholar
  237. Zhi D, Aslibekeyan S, Irvin MR, Claas SA, Borecki IB, Ordovas JM, Absher DM, Arnett DK (2013) SNPs located at CpG sites modulate genome-epigenome interaction. Epigenetics 8:802–806. doi: 10.4161/epi.25501 PubMedCentralPubMedCrossRefGoogle Scholar
  238. Zhou Y, Park SY, Su J, Bailey K, Ottosson E, Laakso E, Shcerbina L, Oskolkov N et al (2014) TCF7L2 is a master regulator of insulin production and processing. Hum Mol Genet. doi: 10.1093/hmg/ddu359 Google Scholar
  239. Ziller MJ, Gu H, Müller F, Donaghey J, Linus T-Y, Tsai LT, Kohlbacher O et al (2013) Charting a dynamic DNA methylation landscape of the human genome. Nature 500:477–481. doi: 10.1038/nature12433 PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media Dordrecht 2015

Authors and Affiliations

  • Irene Maeve Rea
    • 1
    • 4
    Email author
  • Margaret Dellet
    • 1
    • 2
  • Ken I. Mills
    • 1
    • 3
  • The ACUME2 Project
  1. 1.School of Medicine, Dentistry and Biomedical ScienceQueens University BelfastBelfastNorthern Ireland, UK
  2. 2.Centre for Experimental Medicine, School of Medicine, Dentistry and Biomedical ScienceQueens University Belfast BelfastNorthern Ireland, UK
  3. 3.Centre for Cancer Research and Cell Biology, School of Medicine, Dentistry and Biomedical ScienceQueens University BelfastBelfastNorthern Ireland, UK
  4. 4.School of Biomedical SciencesUniversity of UlsterColeraineNorthern Ireland, UK

Personalised recommendations