Widespread sex dimorphism in aging and age-related diseases

  • Nirmal K. Sampathkumar
  • Juan I. Bravo
  • Yilin Chen
  • Prakroothi S. Danthi
  • Erin K. Donahue
  • Rochelle W. Lai
  • Ryan Lu
  • Lewis T. Randall
  • Nika Vinson
  • Bérénice A. BenayounEmail author
Part of the following topical collections:
  1. Molecular Genetics of Aging and Longevity


Although aging is a conserved phenomenon across evolutionary distant species, aspects of the aging process have been found to differ between males and females of the same species. Indeed, observations across mammalian studies have revealed the existence of longevity and health disparities between sexes, including in humans (i.e. with a female or male advantage). However, the underlying mechanisms for these sex differences in health and lifespan remain poorly understood, and it is unclear which aspects of this dimorphism stem from hormonal differences (i.e. predominance of estrogens vs. androgens) or from karyotypic differences (i.e. XX vs. XY sex chromosome complement). In this review, we discuss the state of the knowledge in terms of sex dimorphism in various aspects of aging and in human age-related diseases. Where the interplay between sex differences and age-related differences has not been explored fully, we present the state of the field to highlight important future research directions. We also discuss various dietary, drug or genetic interventions that were shown to improve longevity in a sex-dimorphic fashion. Finally, emerging tools and models that can be leveraged to decipher the mechanisms underlying sex differences in aging are also briefly discussed.



We apologize to the authors whose work we could not cite due to space constraints. J.I.B.’s work was supported by NIA T32-AG052374 and NSF graduate research fellowship DGE-1842487. L.T.R.’s work was supported by NIA T32-AG052374 and a USC Provost’s Fellowship. B.A.B.’s work was supported by by NIA R00AG049934, NIA R21AG063739, an innovator Grant from the Rose Hills foundation, a seed grant from the NAVIGAGE foundation, and a generous gift from the Hanson-Thorell Family.

Compliance with ethical standards

Conflict of interest

On behalf of all authors, the corresponding author states that there is no conflict of interest.


  1. Adams JM (2019) GRG world supercentenarian rankings list. Accessed 10 May 2019
  2. Agba OB, Lausser L, Huse K, Bergmeier C, Jahn N, Groth M, Bens M, Sahm A, Gall M, Witte OW, Kestler HA, Schwab M, Platzer M (2017) Tissue-, sex-, and age-specific DNA methylation of rat glucocorticoid receptor gene promoter and insulin-like growth factor 2 imprinting control region. Physiol Genom 49:690–702. CrossRefGoogle Scholar
  3. Allan CA, Strauss BJG, Burger HG, Forbes EA, McLachlan RI (2008) Testosterone therapy prevents gain in visceral adipose tissue and loss of skeletal muscle in nonobese aging men. J Clin Endocrinol Metab 93:139–146. CrossRefPubMedGoogle Scholar
  4. Alves G, Müller B, Herlofson K, HogenEsch I, Telstad W, Aarsland D, Tysnes OB, Larsen JP (2009) Incidence of Parkinson’s disease in Norway: the Norwegian ParkWest study. J Neurol Neurosurg Psychiatry 80:851–857. CrossRefPubMedGoogle Scholar
  5. Ambati BK, Anand A, Joussen AM, Kuziel WA, Adamis AP, Ambati J (2003) Sustained inhibition of corneal neovascularization by genetic ablation of CCR5. Investig Ophthalmol Vis Sci 44:590–593. CrossRefGoogle Scholar
  6. Ambrosy AP, Fonarow GC, Butler J, Chioncel O, Greene SJ, Vaduganathan M, Nodari S, Lam CS (2014) The global health and economic burden of hospitalizations for heart failure: lessons learned from hospitalized heart failure registries. J Am Coll Cardiol 63:1123–1133. CrossRefPubMedGoogle Scholar
  7. Anderson DC (1974) Sex-hormone-binding globulin. Clin Endocrinol 3:69–96. CrossRefGoogle Scholar
  8. Anisimov V, Popovich IG, Zabezhinski MA, Egormin PA, Yurova MN, Semenchenko AV, Tyndyk ML, Panchenko AV, Trashkov AP, Vasiliev AG, Khaitsev NV (2015) Sex differences in aging, life span and spontaneous tumorigenesis in 129/Sv mice neonatally exposed to metformin. Cell Cycle 14:46–55. CrossRefPubMedPubMedCentralGoogle Scholar
  9. Arnold AP (2009) Mouse models for evaluating sex chromosome effects that cause sex differences in non-gonadal tissues. J Neuroendocrinol 21:377–386. CrossRefPubMedPubMedCentralGoogle Scholar
  10. Arnold AP, Breedlove SM (1985) Organizational and activational effects of sex steroids on brain and behavior: a reanalysis. Horm Behav 19:469–498CrossRefPubMedGoogle Scholar
  11. Arnold AP, Chen X (2009) What does the “four core genotypes” mouse model tell us about sex differences in the brain and other tissues? Front Neuroendocrinol 30:1–9. CrossRefPubMedGoogle Scholar
  12. Arum O, Boparai RK, Saleh JK, Wang F, Dirks AL, Turner JG, Kopchick JJ, Liu JL, Khardori RK, Bartke A (2014) Specific suppression of insulin sensitivity in growth hormone receptor gene-disrupted (GHR-KO) mice attenuates phenotypic features of slow aging. Aging Cell 13:981–1000. CrossRefPubMedPubMedCentralGoogle Scholar
  13. Austad SN (2011) Sex differences in longevity and aging. In: Handbook of the biology of aging, pp 479–495. CrossRefGoogle Scholar
  14. Austad SN, Fischer KE (2016) Sex differences in lifespan. Cell Metab 23:1022–1033. CrossRefPubMedPubMedCentralGoogle Scholar
  15. Baker JM, Al-Nakkash L, Herbst-Kralovetz MM (2017) Estrogen–gut microbiome axis: physiological and clinical implications. Maturitas 103:45–53. CrossRefPubMedGoogle Scholar
  16. Beebe DC, Holekamp NM, Shui YB (2010) Oxidative damage and the prevention of age-related cataracts. Ophthalmic Res 44:155–165. CrossRefPubMedPubMedCentralGoogle Scholar
  17. Bekris LM, Yu CE, Bird TD, Tsuang DW (2010) Genetics of Alzheimer disease. J Geriatr Psychiatry Neurol 23:213–227. CrossRefPubMedPubMedCentralGoogle Scholar
  18. Benayoun BA, Pollina EA, Brunet A (2015) Epigenetic regulation of ageing: linking environmental inputs to genomic stability. Nat Rev Mol Cell Biol 16:593–610. CrossRefPubMedPubMedCentralGoogle Scholar
  19. Benayoun BA, Pollina EA, Singh PP, Mahmoudi S, Harel I, Casey KM, Dulken BW, Kundaje A, Brunet A (2019) Remodeling of epigenome and transcriptome landscapes with aging in mice reveals widespread induction of inflammatory responses. Genome Res. CrossRefPubMedPubMedCentralGoogle Scholar
  20. Berchtold NC, Cribbs DH, Coleman PD, Rogers J, Head E, Kim R, Beach T, Miller C, Troncoso J, Trojanowski JQ, Zielke HR, Cotman CW (2008) Gene expression changes in the course of normal brain aging are sexually dimorphic. Proc Natl Acad Sci USA 105:15605–15610. CrossRefPubMedGoogle Scholar
  21. Berg BN, Simms HS (1960) Nutrition and longevity in the rat. II. Longevity and onset of disease with different levels of food intake. J Nutr 71:255–263CrossRefPubMedGoogle Scholar
  22. Berletch JB, Yang F, Xu J, Carrel L, Disteche CM (2011) Genes that escape from X inactivation. Hum Genet 130:237–245. CrossRefPubMedPubMedCentralGoogle Scholar
  23. Bianconi E, Piovesan A, Facchin F, Beraudi A, Casadei R, Frabetti F, Vitale L, Pelleri MC, Tassani S, Piva F, Perez-Amodio S, Strippoli P, Canaider S (2013) An estimation of the number of cells in the human body. Ann Hum Biol 40:463–471. CrossRefPubMedGoogle Scholar
  24. Bokov AF, Garg N, Ikeno Y, Thakur S, Musi N, DeFronzo RA, Zhang N, Erickson RC, Gelfond J, Hubbard GB, Adamo ML, Richardson A (2011) Does reduced IGF-1R signaling in Igf1r +/ mice alter aging? PLoS One 6:e26891. CrossRefPubMedPubMedCentralGoogle Scholar
  25. Bonkowski MS, Rocha JS, Masternak MM, Al Regaiey KA, Bartke A (2006) Targeted disruption of growth hormone receptor interferes with the beneficial actions of calorie restriction. Proc Natl Acad Sci USA 103:7901–7905. CrossRefPubMedGoogle Scholar
  26. Bourque G, Leong B, Vega VB, Chen X, Lee YL, Srinivasan KG, Chew J-L, Ruan Y, Wei C-L, Ng HH, Liu ET (2008) Evolution of the mammalian transcription factor binding repertoire via transposable elements. Genome Res 18:1752–1762. CrossRefPubMedPubMedCentralGoogle Scholar
  27. Brandt JD, Beiser JA, Kass MA, Gordon MO (2001) Central corneal thickness in the ocular hypertension treatment study (OHTS). Ophthalmology 108:1779–1788. CrossRefPubMedGoogle Scholar
  28. Bronikowski AM, Altmann J, Brockman DK, Cords M, Fedigan LM, Pusey A, Stoinski T, Morris WF, Strier KB, Alberts SC (2011) Aging in the natural world: comparative data reveal similar mortality patterns across primates. Science 331:1325–1328. CrossRefPubMedPubMedCentralGoogle Scholar
  29. Brown EJ, Bachtrog D (2017) The Y chromosome contributes to sex-specific aging in Drosophila. bioRxiv. CrossRefGoogle Scholar
  30. Brown CJ, Hendrich BD, Rupert JL, Lafreniere RG, Xing Y, Lawrence J, Willard HF (1992) The human XIST gene: analysis of a 17 kb inactive X-specific RNA that contains conserved repeats and is highly localized within the nucleus. Cell 71:527–542CrossRefPubMedPubMedCentralGoogle Scholar
  31. Brown-Borg HM, Borg KE, Meliska CJ, Bartke A (1996) Dwarf mice and the ageing process. Nature 384:33. CrossRefPubMedGoogle Scholar
  32. Burgoyne PS, Arnold AP (2016) A primer on the use of mouse models for identifying direct sex chromosome effects that cause sex differences in non-gonadal tissues. Biol Sex Differ 7:68. CrossRefPubMedPubMedCentralGoogle Scholar
  33. Buskiewicz IA, Huber SA, Fairweather D (2016) Chapter 4—sex hormone receptor expression in the immune system. In: Neigh GN, Mitzelfelt MM (eds) Sex differences in physiology. Academic Press, Boston, pp 45–60CrossRefGoogle Scholar
  34. Calabresi P, Picconi B, Tozzi A, Ghiglieri V, Di Filippo M (2014) Direct and indirect pathways of basal ganglia: a critical reappraisal. Nat Neurosci 17:1022–1030. CrossRefPubMedGoogle Scholar
  35. Cani PD, Amar J, Iglesias MA, Poggi M, Knauf C, Bastelica D, Neyrinck AM, Fava F, Tuohy KM, Chabo C, Waget A, Delmee E, Cousin B, Sulpice T, Chamontin B, Ferrieres J, Tanti JF, Gibson GR, Casteilla L, Delzenne NM, Alessi MC, Burcelin R (2007) Metabolic endotoxemia initiates obesity and insulin resistance. Diabetes 56:1761–1772. CrossRefPubMedGoogle Scholar
  36. Cani PD, Bibiloni R, Knauf C, Waget A, Neyrinck AM, Delzenne NM, Burcelin R (2008) Changes in gut microbiota control metabolic endotoxemia-induced inflammation in high-fat diet-induced obesity and diabetes in mice. Diabetes 57:1470–1481. CrossRefGoogle Scholar
  37. Carlson AJ, Hoelzel F (1946) Apparent prolongation of the life span of rats by intermittent fasting. J Nutr 31:363–375. CrossRefPubMedGoogle Scholar
  38. Celojevic D, Petersen A, Karlsson J-O, Behndig A, Zetterberg M (2011) Effects of 17β-estradiol on proliferation, cell viability and intracellular redox status in native human lens epithelial cells. Mol Vis 17:1987–1996PubMedPubMedCentralGoogle Scholar
  39. Chakravarthy U, Wong TY, Fletcher A, Piault E, Evans C, Zlateva G, Buggage R, Pleil A, Mitchell P (2010) Clinical risk factors for age-related macular degeneration: a systematic review and meta-analysis. BMC Ophthalmol. CrossRefPubMedPubMedCentralGoogle Scholar
  40. Chénais B, Caruso A, Hiard S, Casse N (2012) The impact of transposable elements on eukaryotic genomes: from genome size increase to genetic adaptation to stressful environments. Gene 509:7–15. CrossRefPubMedGoogle Scholar
  41. Chow J, Heard E (2009) X inactivation and the complexities of silencing a sex chromosome. Curr Opin Cell Biol 21:359–366. CrossRefPubMedGoogle Scholar
  42. Claesson MJ, Jeffery IB, Conde S, Power SE, O’Connor EM, Cusack S, Harris HM, Coakley M, Lakshminarayanan B, O’Sullivan O, Fitzgerald GF, Deane J, O’Connor M, Harnedy N, O’Connor K, O’Mahony D, van Sinderen D, Wallace M, Brennan L, Stanton C, Marchesi JR, Fitzgerald AP, Shanahan F, Hill C, Ross RP, O’Toole PW (2012) Gut microbiota composition correlates with diet and health in the elderly. Nature 488:178–184. CrossRefPubMedGoogle Scholar
  43. Clark RI, Salazar A, Yamada R, Fitz-Gibbon S, Morselli M, Alcaraz J, Rana A, Rera M, Pellegrini M, Ja WW, Walker DW (2015) Distinct shifts in microbiota composition during Drosophila aging impair intestinal function and drive mortality. Cell Rep 12:1656–1667. CrossRefPubMedPubMedCentralGoogle Scholar
  44. Clocchiatti A, Cora E, Zhang Y, Dotto GP (2016) Sexual dimorphism in cancer. Nat Rev Cancer 16:330–339. CrossRefPubMedGoogle Scholar
  45. Clutton-Brock TH, Isvaran K (2007) Sex differences in ageing in natural populations of vertebrates. Proc Biol Sci 274:3097–3104. CrossRefPubMedPubMedCentralGoogle Scholar
  46. Conley MN, Wong CP, Duyck KM, Hord N, Ho E, Sharpton TJ (2016) Aging and serum MCP-1 are associated with gut microbiome composition in a murine model. PeerJ 4:e1854. CrossRefPubMedPubMedCentralGoogle Scholar
  47. Conway G, Dewailly D, Diamanti-Kandarakis E, Escobar-Morreale HF, Franks S, Gambineri A, Kelestimur F, Macut D, Micic D (2014) The polycystic ovary syndrome: a position statement from the European Society of Endocrinology. Eur J Endocrinol 171:P1–P29. CrossRefPubMedGoogle Scholar
  48. Cordaux R, Batzer MA (2009) The impact of retrotransposons on human genome evolution. Nat Rev Genet 10:691–703. CrossRefPubMedPubMedCentralGoogle Scholar
  49. Corder EH, Saunders AM, Strittmatter WJ, Schmechel DE, Gaskell PC, Small GW, Roses AD, Haines JL, Pericak-Vance MA (1993) Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late onset families. Science 261:921–923. CrossRefGoogle Scholar
  50. Davis EJ, Lobach I, Dubal DB (2018) Female XX sex chromosomes increase survival and extend lifespan in aging mice. Aging Cell. CrossRefPubMedPubMedCentralGoogle Scholar
  51. De Cecco M, Criscione SW, Peterson AL, Neretti N, Sedivy JM, Kreiling JA (2013) Transposable elements become active and mobile in the genomes of aging mammalian somatic tissues. Aging (Albany NY) 5:867–883CrossRefGoogle Scholar
  52. De Cecco M, Ito T, Petrashen AP, Elias AE, Skvir NJ, Criscione SW, Caligiana A, Brocculi G, Adney EM, Boeke JD, Le O, Beauséjour C, Ambati J, Ambati K, Simon M, Seluanov A, Gorbunova V, Slagboom PE, Helfand SL, Neretti N, Sedivy JM (2019) L1 drives IFN in senescent cells and promotes age-associated inflammation. Nature 566:73–78. CrossRefPubMedPubMedCentralGoogle Scholar
  53. Deasy BM, Lu A, Tebbets JC, Feduska JM, Schugar RC, Pollett JB, Sun B, Urish KL, Gharaibeh BM, Cao B, Rubin RT, Huard J (2007) A role for cell sex in stem cell-mediated skeletal muscle regeneration: female cells have higher muscle regeneration efficiency. J Cell Biol 177:73–86. CrossRefPubMedPubMedCentralGoogle Scholar
  54. Della Torre S, Mitro N, Meda C, Lolli F, Pedretti S, Barcella M, Ottobrini L, Metzger D, Caruso D, Maggi A (2018) Short-term fasting reveals amino acid metabolism as a major sex-discriminating factor in the liver. Cell Metab 28(256–267):e5. CrossRefGoogle Scholar
  55. Dennis S, Sheth U, Feldman JL, English KA, Priess JR (2012) C. elegans germ cells show temperature and age-dependent expression of Cer1, a Gypsy/Ty3-related retrotransposon. PLoS Pathogens 8:e1002591. CrossRefPubMedPubMedCentralGoogle Scholar
  56. Deumens R, Blokland A, Prickaerts J (2002) Modeling Parkinson’s disease in rats: an evaluation of 6-OHDA lesions of the nigrostriatal pathway. Exp Neurol 175:303–317. CrossRefPubMedGoogle Scholar
  57. Dhindsa S, Miller MG, McWhirter CL, Mager DE, Ghanim H, Chaudhuri A, Dandona P (2010) Testosterone concentrations in diabetic and nondiabetic obese men. Diabetes Care 33:1186–1192. CrossRefPubMedPubMedCentralGoogle Scholar
  58. Dong X, Greven MC, Kundaje A, Djebali S, Brown JB, Cheng C, Gingeras TR, Gerstein M, Guigo R, Birney E, Weng Z (2012) Modeling gene expression using chromatin features in various cellular contexts. Genome Biol 13:R53. CrossRefPubMedPubMedCentralGoogle Scholar
  59. Drange S, Anderson DR, Schulzer M (2001) Risk factors for progression of visual field abnormalities in normal-tension glaucoma. Am J Ophthalmol 131:699–708. CrossRefGoogle Scholar
  60. Dulken B, Brunet A (2015) Stem cell aging and sex: are we missing something? Cell Stem Cell 16:588–590. CrossRefPubMedGoogle Scholar
  61. Dunham I, Kundaje A, Aldred SF, Collins PJ, Davis C, Doyle F, Epstein CB, Frietze S, Harrow J, Kaul R, Khatun J, Lajoie BR, Landt SG, Lee BK, Pauli F, Rosenbloom KR, Sabo P, Safi A, Sanyal A, Shoresh N, Simon JM, Song L, Trinklein ND, Altshuler RC, Birney E, Brown JB, Cheng C, Djebali S, Dong XJ, Dunham I, Ernst J, Furey TS, Gerstein M, Giardine B, Greven M, Hardison RC, Harris RS, Herrero J, Hoffman MM, Iyer S, Kellis M, Khatun J, Kheradpour P, Kundaje A, Lassmann T, Li QH, Lin X, Marinov GK, Merkel A, Mortazavi A, Parker SCJ, Reddy TE, Rozowsky J, Schlesinger F, Thurman RE, Wang J, Ward LD, Whitfield TW, Wilder SP, Wu W, Xi HLS, Yip KY, Zhuang JL, Bernstein BE, Birney E, Dunham I, Green ED, Gunter C, Snyder M, Pazin MJ, Lowdon RF, Dillon LAL, Adams LB, Kelly CJ, Zhang J, Wexler JR, Green ED, Good PJ, Feingold EA, Bernstein BE, Birney E, Crawford GE, Dekker J, Elnitski L, Farnham PJ, Gerstein M, Giddings MC, Gingeras TR, Green ED, Guigo R, Hardison RC, Hubbard TJ, Kellis M, Kent WJ, Lieb JD, Margulies EH, Myers RM, Snyder M, Stamatoyannopoulos JA, Tenenbaum SA et al (2012) An integrated encyclopedia of DNA elements in the human genome. Nature 489:57–74. CrossRefGoogle Scholar
  62. Dworatzek E, Baczko I, Kararigas G (2016) Effects of aging on cardiac extracellular matrix in men and women. Proteom Clin Appl 10:84–91. CrossRefGoogle Scholar
  63. Efe YK, Ugurbas SC, Alpay A, Ugurbas SH (2012) The course of corneal and intraocular pressure changes during pregnancy. Can J Ophthalmol 47:150–154. CrossRefPubMedGoogle Scholar
  64. Elbay A, Ercan C, Akbas F, Bulut H, Ozdemir H (2019) Three new circulating microRNAs may be associated with wet age-related macular degeneration. Scand J Clin Lab Investig. CrossRefGoogle Scholar
  65. Elbaz A, Bower JH, Maraganore DM, McDonnell SK, Peterson BJ, Ahlskog JE, Schaid DJ, Rocca WA (2002) Risk tables for parkinsonism and Parkinson’s disease. J Clin Epidemiol 55:25–31. CrossRefPubMedGoogle Scholar
  66. Elder J, Pan J, Duncan C, Weissman S (1981) Transcriptional analysis of interspersed repetitive polymerase III transcription units in human DNA. Nucleic Acids Res 9:1171–1189CrossRefPubMedPubMedCentralGoogle Scholar
  67. El-Maarri O, Walier M, Behne F, van Üüm J, Singer H, Diaz-Lacava A, Nüsgen N, Niemann B, Watzka M, Reinsberg J, van der Ven H, Wienker T, Stoffel-Wagner B, Schwaab R, Oldenburg J (2011) Methylation at global LINE-1 repeats in human blood are affected by gender but not by age or natural hormone cycles. PLoS One 6:e16252. CrossRefPubMedPubMedCentralGoogle Scholar
  68. El-Mir MY, Nogueira V, Fontaine E, Avéret N, Rigoulet M, Leverve X (2000) Dimethylbiguanide inhibits cell respiration via an indirect effect targeted on the respiratory chain complex I. J Biol Chem 275:223–228. CrossRefPubMedGoogle Scholar
  69. Enns LC, Morton JF, Treuting PR, Emond MJ, Wolf NS, Dai D-F, McKnight GS, Rabinovitch PS, Ladiges WC (2009) Disruption of protein kinase A in mice enhances healthy aging. PLoS One 4:e5963. CrossRefPubMedPubMedCentralGoogle Scholar
  70. Estep PW 3rd, Warner JB, Bulyk ML (2009) Short-term calorie restriction in male mice feminizes gene expression and alters key regulators of conserved aging regulatory pathways. PLoS One 4:e5242. CrossRefPubMedPubMedCentralGoogle Scholar
  71. Fang Y, Hill CM, Darcy J, Reyes-Ordonez A, Arauz E, McFadden S, Zhang C, Osland J, Gao J, Zhang T, Frank SJ, Javors MA, Yuan R, Kopchick JJ, Sun LY, Chen J, Bartke A (2018) Effects of rapamycin on growth hormone receptor knockout mice. Proc Natl Acad Sci USA 115:E1495–E1503. CrossRefPubMedGoogle Scholar
  72. Farrer LA, Adrienne Cupples L, Van Duijn CM, Kurz A, Zimmer R, Müller U, Green RC, Clarke V, Shoffner J, Wallace DC, Chui H, Flanagan SD, Duara R, George-Hyslop PS, Auerbach SA, Volicer L, Wells JM, Van Broeckhoven C, Growdon JH, Haines JL (1995) Apolipoprotein E genotype in patients with alzheimer’s disease: implications for the risk of dementia among relatives. Ann Neurol 38:797–808. CrossRefPubMedGoogle Scholar
  73. Ferrini RL, Barrett-Connor E (1998) Sex hormones and age: a cross-sectional study of testosterone and estradiol and their bioavailable fractions in community-dwelling men. Am J Epidemiol 147:750–754. CrossRefPubMedGoogle Scholar
  74. Finch C (1990) Longevity, senescence, and the genome. University of Chicago Press, ChicagoGoogle Scholar
  75. Fischer KE, Gelfond JAL, Soto VY, Han C, Someya S, Richardson A, Austad SN (2015) Health effects of long-term rapamycin treatment: the impact on mouse health of enteric rapamycin treatment from four months of age throughout life. PLoS One 10:1–18. CrossRefGoogle Scholar
  76. Fischer KE, Hoffman JM, Sloane LB, Gelfond JA, Soto VY, Richardson AG, Austad SN (2016) A cross-sectional study of male and female C57BL/6Nia mice suggests lifespan and healthspan are not necessarily correlated. Aging (Albany NY) 8:2370–2391. CrossRefGoogle Scholar
  77. Fontana L, Partridge L (2015) Promoting health and longevity through diet: from model organisms to humans. Cell 161:106–118. CrossRefPubMedPubMedCentralGoogle Scholar
  78. 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–S9. CrossRefPubMedGoogle Scholar
  79. Frantz S, Calvillo L, Tillmanns J, Elbing I, Dienesch C, Bischoff H, Ertl G, Bauersachs J (2005) Repetitive postprandial hyperglycemia increases cardiac ischemia/reperfusion injury: prevention by the alpha-glucosidase inhibitor acarbose. FASEB J 19:591–593. CrossRefPubMedGoogle Scholar
  80. Freeman EE, Munoz B, Schein OD, West SK (2001) Hormone replacement therapy and lens opacities: the Salisbury eye evaluation project. Arch Ophthalmol 119:1687–1692. CrossRefPubMedGoogle Scholar
  81. Freeze BS, Kravitz AV, Hammack N, Berke JD, Kreitzer AC (2013) Control of basal ganglia output by direct and indirect pathway projection neurons. J Neurosci 33:18531–18539. CrossRefPubMedPubMedCentralGoogle Scholar
  82. Fuhrman SA, Deininger PL, LaPorte P, Friedmann T, Peter Geiduschek E (1981) Analysis of transcription of the human Alu family ubiquitous repeating element by eukaryotic RNA polymerase III. Nucleic Acids Res 9:6439–6456. CrossRefPubMedPubMedCentralGoogle Scholar
  83. Gambineri A, Pelusi C (2019) Sex hormones, obesity and type 2 diabetes: is there a link? Endocr Connect 8:R1–R9. CrossRefPubMedGoogle Scholar
  84. Garratt M, Bower B, Garcia GG, Miller RA (2017) Sex differences in lifespan extension with acarbose and 17-α estradiol: gonadal hormones underlie male-specific improvements in glucose tolerance and mTORC2 signaling. Aging Cell 16:1256–1266. CrossRefPubMedPubMedCentralGoogle Scholar
  85. Gesing A, Masternak MM, Lewinski A, Karbownik-Lewinska M, Kopchick JJ, Bartke A (2013) Decreased levels of proapoptotic factors and increased key regulators of mitochondrial biogenesis constitute new potential beneficial features of long-lived growth hormone receptor gene-disrupted mice. J Gerontol A Biol Sci Med Sci 68:639–651. CrossRefPubMedGoogle Scholar
  86. Gesing A, Wiesenborn D, Do A, Menon V, Schneider A, Victoria B, Stout MB, Kopchick JJ, Bartke A, Masternak MM (2017) A long-lived mouse lacking both growth hormone and growth hormone receptor: a new animal model for aging studies. J Gerontol A Biol Sci Med Sci 72:1054–1061. CrossRefPubMedGoogle Scholar
  87. Geurtsen GJ, Hoogland J, Goldman JG, Schmand BA, Troster AI, Burn DJ, Litvan I, Criteria MDSSGotVoP-M (2014) Parkinson’s disease mild cognitive impairment: application and validation of the criteria. J Parkinsons Dis 4:131–137. CrossRefPubMedPubMedCentralGoogle Scholar
  88. Gibbs VK, Brewer RA, Miyasaki ND, Patki A, Smith DL (2018) Sex-dependent differences in liver and gut metabolomic profiles with acarbose and calorie restriction in C57BL/6 mice. J Gerontol Ser A Biol Sci Med Sci 73:157–165. CrossRefGoogle Scholar
  89. Gillies GE, Pienaar IS, Vohra S, Qamhawi Z (2014) Frontiers in neuroendocrinology sex differences in Parkinson’s disease. Front Neuroendocrinol 35:370–384. CrossRefPubMedPubMedCentralGoogle Scholar
  90. Gilliver SC, Ruckshanthi JP, Hardman MJ, Nakayama T, Ashcroft GS (2008) Sex dimorphism in wound healing: the roles of sex steroids and macrophage migration inhibitory factor. Endocrinology 149:5747–5757. CrossRefPubMedGoogle Scholar
  91. Gordon MO, Beiser JA, Brandt JD, Heuer DK, Higginbotham EJ, Johnson CA, Keltner JL, Miller JP, Parrish RK II, Wilson MR, Kass MA (2002) The ocular hypertension treatment study: baseline factors that predict the onset of primary open-angle glaucoma. Arch Ophthalmol 120:714–720. (discussion 829–30) CrossRefPubMedGoogle Scholar
  92. Gubbels Bupp MR (2015) Sex, the aging immune system, and chronic disease. Cell Immunol 294:102–110. CrossRefPubMedGoogle Scholar
  93. Guneykaya D, Ivanov A, Hernandez DP, Haage V, Wojtas B, Meyer N, Maricos M, Jordan P, Buonfiglioli A, Gielniewski B, Ochocka N, Cömert C, Friedrich C, Artiles LS, Kaminska B, Mertins P, Beule D, Kettenmann H, Wolf SA (2018) Transcriptional and translational differences of microglia from male and female brains. Cell Rep 24:2773–2783.e6. CrossRefPubMedGoogle Scholar
  94. Haaxma CA, Bloem BR, Borm GF, Oyen WJG, Leenders KL, Eshuis S, Booij J, Dluzen DE, Horstink MWIM (2007) Gender differences in Parkinson’s disease. J Neurol Neurosurg Psychiatry 78:819–824. CrossRefPubMedGoogle Scholar
  95. Hadad N, Masser DR, Logan S, Wronowski B, Mangold CA, Clark N, Otalora L, Unnikrishnan A, Ford MM, Giles CB, Wren JD, Richardson A, Sonntag WE, Stanford DR, Freeman W (2016) Absence of genomic hypomethylation or regulation of cytosine-modifying enzymes with aging in male and female mice. Epigenetics Chromatin 9:30. CrossRefPubMedPubMedCentralGoogle Scholar
  96. Haig D (2004) The inexorable rise of gender and the decline of sex: social change in academic titles, 1945–2001. Arch Sex Behav 33:87–96CrossRefPubMedGoogle Scholar
  97. Hammes SR, Levin ER (2019) Impact of estrogens in males and androgens in females. J Clin Investig 129:1818–1826. CrossRefPubMedGoogle Scholar
  98. Harman SM, Metter EJ, Tobin JD, Pearson J, Blackman MR (2001) Longitudinal effects of aging on serum total and free testosterone levels in healthy men. Baltimore Longitudinal Study of Aging. J Clin Endocrinol Metab 86:724–731. CrossRefPubMedGoogle Scholar
  99. Harrison DE, Strong R, Allison DB, Ames BN, Astle CM, Atamna H, Fernandez E, Flurkey K, Javors MA, Nadon NL, Nelson JF, Pletcher S, Simpkins JW, Smith D, Wilkinson JE, Miller RA (2014) Acarbose, 17-alpha-estradiol, and nordihydroguaiaretic acid extend mouse lifespan preferentially in males. Aging Cell 13:273–282. CrossRefPubMedGoogle Scholar
  100. Harrison DE, Strong R, Alavez S, Astle CM, DiGiovanni J, Fernandez E, Flurkey K, Garratt M, Gelfond JAL, Javors MA, Levi M, Lithgow GJ, Macchiarini F, Nelson JF, Sukoff Rizzo SJ, Slaga TJ, Stearns T, Wilkinson JE, Miller RA (2019) Acarbose improves health and lifespan in aging HET3 mice. Aging Cell 18:1–13. CrossRefGoogle Scholar
  101. Hodgkin J (1992) Genetic sex determination mechanisms and evolution. BioEssays 14:253–261. CrossRefPubMedGoogle Scholar
  102. Hoffman MM, Ernst J, Wilder SP, Kundaje A, Harris RS, Libbrecht M, Giardine B, Ellenbogen PM, Bilmes JA, Birney E, Hardison RC, Dunham I, Kellis M, Noble WS (2013) Integrative annotation of chromatin elements from ENCODE data. Nucleic Acids Res 41:827–841. CrossRefPubMedGoogle Scholar
  103. Holzenberger M, Dupont J, Ducos B, Leneuve P, Geloen A, Even PC, Cervera P, Le Bouc Y (2003) IGF-1 receptor regulates lifespan and resistance to oxidative stress in mice. Nature 421:182–187. CrossRefPubMedGoogle Scholar
  104. Hong K, Choi Y (2018) Role of estrogen and RAS signaling in repeated implantation failure. BMB Rep 51:225–229CrossRefPubMedPubMedCentralGoogle Scholar
  105. Hong JS, Yi SW, Kang HC, Jee SH, Kang HG, Bayasgalan G, Ohrr H (2007) Age at menopause and cause-specific mortality in South Korean women: Kangwha Cohort Study. Maturitas 56:411–419. CrossRefPubMedGoogle Scholar
  106. Honjoh S, Ihara A, Kajiwara Y, Yamamoto T, Nishida E (2017) The sexual dimorphism of dietary restriction responsiveness in Caenorhabditis elegans. Cell Rep 21:3646–3652. CrossRefPubMedGoogle Scholar
  107. Horstman AM, Dillon EL, Urban RJ, Sheffield-Moore M (2012) The role of androgens and estrogens on healthy aging and longevity. J Gerontol Ser A Biol Sci Med Sci 67:1140–1152. CrossRefGoogle Scholar
  108. Høvding G, Aasved H (1986) Prognostic factors in the development of manifest open angle glaucoma: a long-term follow-up study of hypertensive and normotensive eyes. Acta Ophthalmol 64:601–608. CrossRefGoogle Scholar
  109. Hughes JF, Rozen S (2012) Genomics and genetics of human and primate Y chromosomes. Annu Rev Genom Hum Genet 13:83–108. CrossRefGoogle Scholar
  110. Hulsman CAA, Westendorp ICD, Ramrattan RS, Wolfs RCW, Witteman JCM, Vingerling JR, Hofman A, De Jong PTVM (2001) Is open-angle glaucoma associated with early menopause? The rotterdam study. Am J Epidemiol 154:138–144. CrossRefPubMedGoogle Scholar
  111. Imtiaz B, Taipale H, Tanskanen A, Tiihonen M, Kivipelto M, Heikkinen AM, Tiihonen J, Soininen H, Hartikainen S, Tolppanen AM (2017) Risk of Alzheimer’s disease among users of postmenopausal hormone therapy: a nationwide case-control study. Maturitas 98:7–13. CrossRefPubMedGoogle Scholar
  112. Isensee J, Witt H, Pregla R, Hetzer R, Regitz-Zagrosek V, Noppinger PR (2008) Sexually dimorphic gene expression in the heart of mice and men. J Mol Med (Berl) 86:61–74. CrossRefGoogle Scholar
  113. Jenuwein T, Allis CD (2001) Translating the histone code. Science 293:1074–1080. CrossRefPubMedPubMedCentralGoogle Scholar
  114. Jiang Y, Tian W (2017) The effects of progesterones on blood lipids in hormone replacement therapy. Lipids Health Dis 16:1–8. CrossRefGoogle Scholar
  115. Jura M, Kozak LP (2016) Obesity and related consequences to ageing. Age. CrossRefPubMedPubMedCentralGoogle Scholar
  116. Kahn HA, Leibowitz HM, Ganley JP, Kini MM, Colton T, Nickerson RS, Dawber TR (1977) The Framingham Eye Study. I. Outline and major prevalence findings. Am J Epidemiol 106:17–32. CrossRefPubMedGoogle Scholar
  117. Kalia LV, Lang AE (2015) Parkinson’s disease. Lancet 386:896–912. CrossRefPubMedGoogle Scholar
  118. Kaliannan K, Robertson RC, Murphy K, Stanton C, Kang C, Wang B, Hao L, Bhan AK, Kang JX (2018) Estrogen-mediated gut microbiome alterations influence sexual dimorphism in metabolic syndrome in mice. Microbiome 6:205. CrossRefPubMedPubMedCentralGoogle Scholar
  119. Kanfi Y, Naiman S, Amir G, Peshti V, Zinman G, Nahum L, Bar-Joseph Z, Cohen HY (2012) The sirtuin SIRT6 regulates lifespan in male mice. Nature 483:218–221. CrossRefPubMedGoogle Scholar
  120. Kidwell MG, Lisch D (1997) Transposable elements as sources of variation in animals and plants. Proc Natl Acad Sci 94:7704–7711. CrossRefPubMedGoogle Scholar
  121. Klein C, Westenberger A (2012) Genetics of Parkinson’s disease. Cold Spring Harb Perspect Med 2:a008888. CrossRefPubMedPubMedCentralGoogle Scholar
  122. Klein BEK, Klein R, Linton KLP (1992) Prevalence of age-related lens opacities in a population: the Beaver Dam Eye Study. Ophthalmology 99:546–552. CrossRefPubMedGoogle Scholar
  123. Kok E, Haikonen S, Luoto T, Huhtala H, Goebeler S, Haapasalo H, Karhunen PJ (2009) Apolipoprotein E-dependent accumulation of Alzheimer disease-related lesions begins in middle age. Ann Neurol 65:650–657. CrossRefPubMedGoogle Scholar
  124. Kozakowski J, Gietka-Czernel M, Leszczyńska D, Majos A (2017) Obesity in menopause—our negligence or an unfortunate inevitability? Prz Menopauzalny 16:61–65. CrossRefPubMedPubMedCentralGoogle Scholar
  125. Kua EH, Ho E, Tan HH, Tsoi C, Thng C, Mahendran R (2014) The natural history of dementia. Psychogeriatrics 14:196–201. CrossRefPubMedGoogle Scholar
  126. Kuk JL, Saunders TJ, Davidson LE, Ross R (2009) Age-related changes in total and regional fat distribution. Ageing Res Rev 8:339–348. CrossRefPubMedGoogle Scholar
  127. Kwa M, Plottel CS, Blaser MJ, Adams S (2016) The intestinal microbiome and estrogen receptor-positive female breast cancer. J Natl Cancer Inst 108:djw029. CrossRefPubMedCentralGoogle Scholar
  128. Labonte B, Engmann O, Purushothaman I, Menard C, Wang J, Tan C, Scarpa JR, Moy G, Loh YE, Cahill M, Lorsch ZS, Hamilton PJ, Calipari ES, Hodes GE, Issler O, Kronman H, Pfau M, Obradovic ALJ, Dong Y, Neve RL, Russo S, Kazarskis A, Tamminga C, Mechawar N, Turecki G, Zhang B, Shen L, Nestler EJ (2017) Sex-specific transcriptional signatures in human depression. Nat Med. CrossRefPubMedPubMedCentralGoogle Scholar
  129. Lai RW, Lu R, Danthi PS, Bravo JI, Goumba A, Sampathkumar NK, Benayoun BA (2019) Multi-level remodeling of transcriptional landscapes in aging and longevity. BMB Rep 52:86–108CrossRefPubMedPubMedCentralGoogle Scholar
  130. Lamming DW, Ye L, Katajisto P, Goncalves MD, Saitoh M, Stevens DM, Davis JG, Salmon AB, Richardson A, Ahima RS, Guertin DA, Sabatini DM, Baur JA (2012) Rapamycin-induced insulin resistance is mediated by mTORC2 loss and uncoupled from longevity. Science 335:1638–1643. CrossRefPubMedPubMedCentralGoogle Scholar
  131. Lander ES, Linton LM, Birren B, Nusbaum C, Zody MC, Baldwin J, Devon K, Dewar K, Doyle M, FitzHugh W, Funke R, Gage D, Harris K, Heaford A, Howland J, Kann L, Lehoczky J, LeVine R, McEwan P, McKernan K, Meldrim J, Mesirov JP, Miranda C, Morris W, Naylor J, Raymond C, Rosetti M, Santos R, Sheridan A, Sougnez C, Stange-Thomann N, Stojanovic N, Subramanian A, Wyman D, Rogers J, Sulston J, Ainscough R, Beck S, Bentley D, Burton J, Clee C, Carter N, Coulson A, Deadman R, Deloukas P, Dunham A, Dunham I, Durbin R, French L, Grafham D, Gregory S, Hubbard T, Humphray S, Hunt A, Jones M, Lloyd C, McMurray A, Matthews L, Mercer S, Milne S, Mullikin JC, Mungall A, Plumb R, Ross M, Shownkeen R, Sims S, Waterston RH, Wilson RK, Hillier LW, McPherson JD, Marra MA, Mardis ER, Fulton LA, Chinwalla AT, Pepin KH, Gish WR, Chissoe SL, Wendl MC, Delehaunty KD, Miner TL, Delehaunty A, Kramer JB, Cook LL, Fulton RS, Johnson DL, Minx PJ, Clifton SW, Hawkins T, Branscomb E, Predki P, Richardson P, Wenning S, Slezak T, Doggett N, Cheng J-F, Olsen A, Lucas S, Elkin C, Uberbacher E, Frazier M et al (2001) Initial sequencing and analysis of the human genome. Nature 409:860–921. CrossRefGoogle Scholar
  132. Laurent MR, Hammond GL, Blokland M, Jardí F, Antonio L, Dubois V, Khalil R, Sterk SS, Gielen E, Decallonne B, Carmeliet G, Kaufman J-M, Fiers T, Huhtaniemi IT, Vanderschueren D, Claessens F (2016) Sex hormone-binding globulin regulation of androgen bioactivity in vivo: validation of the free hormone hypothesis. Sci Rep 6:35539. CrossRefPubMedPubMedCentralGoogle Scholar
  133. Lavie L, Maldener E, Brouha B, Meese EU, Mayer J (2004) The human L1 promoter: variable transcription initiation sites and a major impact of upstream flanking sequence on promoter activity. Genome Res 14:2253–2260. CrossRefPubMedPubMedCentralGoogle Scholar
  134. Laws KR, Irvine K, Gale TM (2016) Sex differences in cognitive impairment in Alzheimer's disease. World J Psychiatry 6:54–65. CrossRefPubMedPubMedCentralGoogle Scholar
  135. Lee AJ, Mitchell P, Rochtchina E, Healey PR (2003) Female reproductive factors and open angle glaucoma: the Blue Mountains Eye Study. Br J Ophthalmol 87:1324–1328. CrossRefPubMedPubMedCentralGoogle Scholar
  136. Legro RS (2003) Polycystic ovary syndrome and cardiovascular disease: a premature association? Endocr Rev 24:302–312. CrossRefPubMedGoogle Scholar
  137. Lemos B, Branco AT, Hartl DL (2010) Epigenetic effects of polymorphic Y chromosomes modulate chromatin components, immune response, and sexual conflict. Proc Natl Acad Sci USA 107:15826–15831. CrossRefPubMedGoogle Scholar
  138. Levine ME, Lu AT, Chen BH, Hernandez DG, Singleton AB, Ferrucci L, Bandinelli S, Salfati E, Manson JE, Quach A, Kusters CDJ, Kuh D, Wong A, Teschendorff AE, Widschwendter M, Ritz BR, Absher D, Assimes TL, Horvath S (2016) Menopause accelerates biological aging. Proc Natl Acad Sci 113:9327–9332. CrossRefPubMedGoogle Scholar
  139. Li W, Prazak L, Chatterjee N, Gruninger S, Krug L, Theodorou D, Dubnau J (2013) Activation of transposable elements during aging and neuronal decline in Drosophila. Nat Neurosci 16:529–531. CrossRefPubMedPubMedCentralGoogle Scholar
  140. Liao C-Y, Rikke BA, Johnson TE, Diaz V, Nelson JF (2010) Genetic variation in the murine lifespan response to dietary restriction: from life extension to life shortening. Aging Cell 9:92–95. CrossRefPubMedGoogle Scholar
  141. Lin FC, Chuang YS, Hsieh HM, Lee TC, Chiu KF, Liu CK, Wu MT (2015) Early statin use and the progression of Alzheimer disease: a total population-based case-control study. Medicine (United States) 94:e2143. CrossRefGoogle Scholar
  142. Lombardi P, Goldin B, Boutin E, Gorbach SL (1978) Metabolism of androgens and estrogens by human fecal microorganisms. J Steroid Biochem 9:795–801. CrossRefPubMedGoogle Scholar
  143. Longo VD (2003) The Ras and Sch9 pathways regulate stress resistance and longevity. Exp Gerontol 38:807–811CrossRefPubMedGoogle Scholar
  144. López-Otín C, Blasco MA, Partridge L, Serrano M, Kroemer G (2013) The hallmarks of aging. Cell 153:1194–1217CrossRefPubMedPubMedCentralGoogle Scholar
  145. Lu Y, Feng F, Yang Y, Gao X, Cui J, Zhang C, Zhang F, Xu Z, Qv J, Wang C, Zeng Z, Zhu Y, Yang Y (2013) LINE-1 ORF-1p functions as a novel androgen receptor co-activator and promotes the growth of human prostatic carcinoma cells. Cell Signal 25:479–489. CrossRefPubMedGoogle Scholar
  146. Lu S, Niu Z, Chen Y, Tu Q, Zhang Y, Chen W, Tong W, Zhang Z (2018) Repetitive element DNA methylation is associated with menopausal age. Aging Dis 9:435–443. CrossRefPubMedPubMedCentralGoogle Scholar
  147. Lundström M, Stenevi U, Thorburn W (1999) Gender and cataract surgery in Sweden 1992–1997. Acta Ophthalmol Scand 77:204–208. CrossRefPubMedGoogle Scholar
  148. Lundström M, Stenevi U, Thorburn W (2002) The swedish national cataract register: a 9-year review. Acta Ophthalmol Scand 80:248–257. CrossRefPubMedGoogle Scholar
  149. Magwere T, Chapman T, Partridge L (2004) Sex differences in the effect of dietary restriction on life span and mortality rates in female and male Drosophila melanogaster. J Gerontol Ser A Biol Sci Med Sci 59:B3–B9. CrossRefGoogle Scholar
  150. Maki PM, Henderson VW (2012) Hormone therapy, dementia, and cognition: the Women’s Health Initiative 10 years on. Climacteric 15:256–262. CrossRefPubMedPubMedCentralGoogle Scholar
  151. Manolopoulos KN, Karpe F, Frayn KN (2010) Gluteofemoral body fat as a determinant of metabolic health. Int J Obes 34:949–959. CrossRefGoogle Scholar
  152. Marais GAB, Gaillard JM, Vieira C, Plotton I, Sanlaville D, Gueyffier F, Lemaitre JF (2018) Sex gap in aging and longevity: can sex chromosomes play a role? Biol Sex Differ 9:1–14. CrossRefGoogle Scholar
  153. Markle JG, Frank DN, Mortin-Toth S, Robertson CE, Feazel LM, Rolle-Kampczyk U, von Bergen M, McCoy KD, Macpherson AJ, Danska JS (2013) Sex differences in the gut microbiome drive hormone-dependent regulation of autoimmunity. Science 339:1084–1088. CrossRefPubMedGoogle Scholar
  154. Martinez-Martin P, Pecurariu CF, Odin P, Van Hilten JJ, Antonini A, Rojo-Abuin JM, Borges V, Trenkwalder C, Aarsland D, Brooks DJ, Chaudhuri KR (2012) Gender-related differences in the burden of non-motor symptoms in Parkinson’s disease. J Neurol 259:1639–1647. CrossRefPubMedGoogle Scholar
  155. Mason CE, Shu F-J, Wang C, Session RM, Kallen RG, Sidell N, Yu T, Liu MH, Cheung E, Kallen CB (2010) Location analysis for the estrogen receptor-alpha reveals binding to diverse ERE sequences and widespread binding within repetitive DNA elements. Nucleic Acids Res 38:2355–2368. CrossRefPubMedPubMedCentralGoogle Scholar
  156. Masser DR, Hadad N, Porter HL, Mangold CA, Unnikrishnan A, Ford MM, Giles CB, Georgescu C, Dozmorov MG, Wren JD, Richardson A, Stanford DR, Freeman WM (2017) Sexually divergent DNA methylation patterns with hippocampal aging. Aging Cell 16:1342–1352. CrossRefPubMedPubMedCentralGoogle Scholar
  157. Masternak MM, Bartke A, Wang F, Spong A, Gesing A, Fang Y, Salmon AB, Hughes LF, Liberati T, Boparai R, Kopchick JJ, Westbrook R (2012) Metabolic effects of intra-abdominal fat in GHRKO mice. Aging Cell 11:73–81. CrossRefPubMedGoogle Scholar
  158. Maxwell PH, Burhans WC, Curcio MJ (2011) Retrotransposition is associated with genome instability during chronological aging. Proc Natl Acad Sci USA 108:20376–20381. CrossRefPubMedGoogle Scholar
  159. Mayne BT, Bianco-Miotto T, Buckberry S, Breen J, Clifton V, Shoubridge C, Roberts CT (2016) Large scale gene expression meta-analysis reveals tissue-specific, sex-biased gene expression in humans. Front Genet 7:183. CrossRefPubMedPubMedCentralGoogle Scholar
  160. McCay CM, Crowell MF, Maynard LA (1935) The effect of retarded growth upon the length of life span and upon the ultimate body size. J Nutr 10:63–79CrossRefGoogle Scholar
  161. McClintock B (1953) Induction of instability at selected loci in maize. Genetics 38:579–599PubMedPubMedCentralGoogle Scholar
  162. Medzikovic L, Aryan L, Eghbali M (2019) Connecting sex differences, estrogen signaling, and microRNAs in cardiac fibrosis. J Mol Med. CrossRefPubMedGoogle Scholar
  163. Menazza S, Murphy E (2016) The expanding complexity of estrogen receptor signaling in the cardiovascular system. Circ Res 118:994–1007. CrossRefPubMedPubMedCentralGoogle Scholar
  164. Metchnikoff E (1907) The prolongation of life: optimistic studies, trans. P. Chalmers Mitchell. GP Putnam’s Sons, New YorkGoogle Scholar
  165. Miller IN, Cronin-Golomb A (2010) Gender differences in Parkinson’s disease: clinical characteristics and cognition. Mov Disord 25:2695–2703. CrossRefPubMedPubMedCentralGoogle Scholar
  166. 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 66:191–201. CrossRefPubMedGoogle Scholar
  167. Miller RA, Harrison DE, Astle CM, Fernandez E, Flurkey K, Han M, Javors MA, Li X, Nadon NL, Nelson JF, Pletcher S, Salmon AB, Sharp ZD, Van Roekel S, Winkleman L, Strong R (2014) Rapamycin-mediated lifespan increase in mice is dose and sex dependent and metabolically distinct from dietary restriction. Aging Cell 13:468–477. CrossRefPubMedPubMedCentralGoogle Scholar
  168. Miller LR, Marks C, Becker JB, Hurn PD, Chen WJ, Woodruff T, McCarthy MM, Sohrabji F, Schiebinger L, Lee Wetherington C, Makris S, Arnold AP, Einstein G, Miller VM, Sandberg K, Maier S, Cornelison TL, Clayton JA (2017) Considering sex as a biological variable in preclinical research. FASEB J 31:29–34. CrossRefPubMedGoogle Scholar
  169. Mink JW (1996) A model for waste processing ? Pergamorr Prog Neurobiol 50:26. CrossRefGoogle Scholar
  170. Mitchell P, Cumming RG, Attebo K, Panchapakesan J (1997) Prevalence of cataract in Australia: the Blue Mountains Eye Study. Ophthalmology 104:581–588. CrossRefPubMedGoogle Scholar
  171. Mitchell SJ, Madrigal-Matute J, Scheibye-Knudsen M, Fang E, Aon M, Gonzalez-Reyes JA, Cortassa S, Kaushik S, Gonzalez-Freire M, Patel B, Wahl D, Ali A, Calvo-Rubio M, Buron MI, Guiterrez V, Ward TM, Palacios HH, Cai H, Frederick DW, Hine C, Broeskamp F, Habering L, Dawson J, Beasley TM, Wan J, Ikeno Y, Hubbard G, Becker KG, Zhang Y, Bohr VA, Longo DL, Navas P, Ferrucci L, Sinclair DA, Cohen P, Egan JM, Mitchell JR, Baur JA, Allison DB, Anson RM, Villalba JM, Madeo F, Cuervo AM, Pearson KJ, Ingram DK, Bernier M, de Cabo R (2016) Effects of sex, strain, and energy intake on hallmarks of aging in mice. Cell Metab 23:1093–1112. CrossRefPubMedPubMedCentralGoogle Scholar
  172. Miyamura M, Schnell O, Yamashita C, Yoshioka T, Matsumoto C, Mori T, Ukimura A, Kitaura Y, Matsumura Y, Ishizaka N, Hayashi T (2010) Effects of acarbose on the acceleration of postprandial hyperglycemia-induced pathological changes induced by intermittent hypoxia in lean mice. J Pharmacol Sci 114:32–40. CrossRefPubMedGoogle Scholar
  173. Morales JF, Snow ET, Murnane JP (2003) Environmental factors affecting transcription of the human L1 retrotransposon. II. Stressors. Mutagenesis 18:151–158. CrossRefPubMedGoogle Scholar
  174. Moran LJ, Misso ML, Wild RA, Norman RJ (2010) Impaired glucose tolerance, type 2 diabetes and metabolic syndrome in polycystic ovary syndrome: a systematic review and meta-analysis. Hum Reprod Update 16:347–363. CrossRefPubMedGoogle Scholar
  175. Moreira APB, Texeira TFS, Ferreira AB, do Carmo Gouveia Peluzio M, de Cássia Gonçalves Alfenas R (2012) Influence of a high-fat diet on gut microbiota, intestinal permeability and metabolic endotoxaemia. Br J Nutr 108:801–809. CrossRefGoogle Scholar
  176. Morgan CL, Jenkins-Jones S, Currie CJ, Rees DA (2012) Evaluation of adverse outcome in young women with polycystic ovary syndrome versus matched, reference controls: a retrospective, observational study. J Clin Endocrinol Metab 97:3251–3260. CrossRefPubMedGoogle Scholar
  177. Nagpal R, Mainali R, Ahmadi S, Wang S, Singh R, Kavanagh K, Kitzman DW, Kushugulova A, Marotta F, Yadav H (2018) Gut microbiome and aging: physiological and mechanistic insights. Nutr Healthy Aging 4:267–285. CrossRefPubMedPubMedCentralGoogle Scholar
  178. Nakada D, Oguro H, Levi BP, Ryan N, Kitano A, Saitoh Y, Takeichi M, Wendt GR, Morrison SJ (2014) Oestrogen increases haematopoietic stem-cell self-renewal in females and during pregnancy. Nature 505:555–558. CrossRefPubMedPubMedCentralGoogle Scholar
  179. Naqvi S, Godfrey AK, Hughes JF, Goodheart ML, Mitchell RN, Page DC (2019) Conservation, acquisition, and functional impact of sex-biased gene expression in mammals. Science. CrossRefPubMedGoogle Scholar
  180. Nelson JF, Strong R, Bokov A, Diaz V, Ward W (2012) Probing the relationship between insulin sensitivity and longevity using genetically modified mice. J Gerontol A Biol Sci Med Sci 67:1332–1338. CrossRefPubMedPubMedCentralGoogle Scholar
  181. Newman-Casey PA, Talwar N, Nan B, Musch DC, Pasquale LR, Stein JD (2014) The potential association between postmenopausal hormone use and primary open-angle glaucoma. JAMA Ophthalmol 132:298–303. CrossRefPubMedPubMedCentralGoogle Scholar
  182. Nolen GA (1972) Effect of various restricted dietary regimens on growth, health and longevity of albino-rats. J Nutr 102:1477CrossRefPubMedGoogle Scholar
  183. Ossewaarde ME, Bots ML, Verbeek AL, Peeters PH, van der Graaf Y, Grobbee DE, van der Schouw YT (2005) Age at menopause, cause-specific mortality and total life expectancy. Epidemiology 16:556–562CrossRefPubMedGoogle Scholar
  184. Ostan R, Monti D, Gueresi P, Bussolotto M, Franceschi C, Baggio G (2016) Gender, aging and longevity in humans: an update of an intriguing/neglected scenario paving the way to a gender-specific medicine. Clin Sci (London, England: 1979) 130:1711–1725. CrossRefGoogle Scholar
  185. Pal S, Tyler JK (2016) Epigenetics and aging. Sci Adv 2:e1600584. CrossRefPubMedPubMedCentralGoogle Scholar
  186. Parker SC, Stitzel ML, Taylor DL, Orozco JM, Erdos MR, Akiyama JA, van Bueren KL, Chines PS, Narisu N, Black BL, Visel A, Pennacchio LA, Collins FS (2013) Chromatin stretch enhancer states drive cell-specific gene regulation and harbor human disease risk variants. Proc Natl Acad Sci USA 110:17921–17926. CrossRefGoogle Scholar
  187. Pasquale LR, Kang JH (2011) Female reproductive factors and primary open-angle glaucoma in the Nurses Health Study. Eye 25:633–641. CrossRefPubMedPubMedCentralGoogle Scholar
  188. Paterni I, Granchi C, Katzenellenbogen JA, Minutolo F (2014) Estrogen receptors alpha (ERα) and beta (ERβ): subtype-selective ligands and clinical potential. Steroids 90:13–29. CrossRefPubMedGoogle Scholar
  189. Pattabiraman PP, Toris CB (2016) The exit strategy: pharmacological modulation of extracellular matrix production and deposition for better aqueous humor drainage. Eur J Pharmacol 787:32–42. CrossRefPubMedGoogle Scholar
  190. Pawluski JL, Brummelte S, Barha CK, Crozier TM, Galea LAM (2009) Effects of steroid hormones on neurogenesis in the hippocampus of the adult female rodent during the estrous cycle, pregnancy, lactation and aging. Front Neuroendocrinol 30:343–357. CrossRefPubMedGoogle Scholar
  191. Phillips CI, Gore SM (1985) Ocular hypotensive effect of late pregnancy with and without high blood pressure. Br J Ophthalmol 69:117–119. CrossRefPubMedPubMedCentralGoogle Scholar
  192. Pike CJ (2017) Sex and the development of Alzheimer’s disease. J Neurosci Res 95:671–680. CrossRefPubMedPubMedCentralGoogle Scholar
  193. Plottel Claudia S, Blaser Martin J (2011) Microbiome and malignancy. Cell Host Microbe 10:324–335. CrossRefPubMedPubMedCentralGoogle Scholar
  194. Podcasy JL, Epperson CN (2016) Considering sex and gender in Alzheimer disease and other dementias. Dialogues Clin Neurosci 18:437–446PubMedPubMedCentralGoogle Scholar
  195. Poirier J, Davignon J, Bouthillier D, Kogan S, Bertrand P, Gauthier S (1993) Polymorphism and Alzheimer’ s disease. Lancet 342:697–699CrossRefPubMedGoogle Scholar
  196. Pomatto LC, Carney C, Shen B, Wong S, Halaszynski K, Salomon MP, Davies KJ, Tower J (2017) The mitochondrial lon protease is required for age-specific and sex-specific adaptation to oxidative stress. Curr Biol 27:1–15. CrossRefPubMedGoogle Scholar
  197. Qu K, Zaba LC, Giresi PG, Li R, Longmire M, Kim YH, Greenleaf WJ, Chang HY (2015) Individuality and variation of personal regulomes in primary human T cells. Cell Syst 1:51–61. CrossRefPubMedPubMedCentralGoogle Scholar
  198. Quigley H, Broman AT (2006) The number of people with glaucoma worldwide in 2010 and 2020. Br J Ophthalmol 90:262–267. CrossRefPubMedPubMedCentralGoogle Scholar
  199. Quintana-Murci L, Fellous M (2001) The human Y chromosome: the biological role of a “functional wasteland”. J Biomed Biotechnol 2001:18–24. CrossRefGoogle Scholar
  200. Qureshi IA, Mehler MF (2010) Genetic and epigenetic underpinnings of sex differences in the brain and in neurological and psychiatric disease susceptibility. Prog Brain Res 186:77–95. CrossRefPubMedPubMedCentralGoogle Scholar
  201. Reed BG, Carr BR (2000) The normal menstrual cycle and the control of ovulation. In: Feingold KR, Anawalt B, Boyce A, Chrousos G, Dungan K, Grossman A, Hershman JM, Kaltsas G, Koch C, Kopp P, Korbonits M, McLachlan R, Morley JE, New M, Perreault L, Purnell J, Rebar R, Singer F, Trence DL, Vinik A, Wilson DP (eds) Endotext., Inc., South DartmouthGoogle Scholar
  202. Regan JC, Khericha M, Dobson AJ, Bolukbasi E, Rattanavirotkul N, Partridge L (2016) Sex difference in pathology of the ageing gut mediates the greater response of female lifespan to dietary restriction. Elife 5:e10956. CrossRefPubMedPubMedCentralGoogle Scholar
  203. Regitz-Zagrosek V, Kararigas G (2017) Mechanistic pathways of sex differences in cardiovascular disease. Physiol Rev 97:1–37. CrossRefPubMedGoogle Scholar
  204. Regitz-Zagrosek V, Lehmkuhl E, Mahmoodzadeh S (2007) Gender aspects of the role of the metabolic syndrome as a risk factor for cardiovascular disease. Gend Med 4(Suppl B):S162–S177CrossRefPubMedGoogle Scholar
  205. Regitz-Zagrosek V, Jaguszewska K, Preis K (2015) Pregnancy-related spontaneous coronary artery dissection. Eur Heart J 36:2273–2274PubMedGoogle Scholar
  206. Rera M, Clark RI, Walker DW (2012) Intestinal barrier dysfunction links metabolic and inflammatory markers of aging to death in Drosophila. Proc Natl Acad Sci USA 109:21528–21533. CrossRefGoogle Scholar
  207. Rochelle TL, Yeung DKY, Bond MH, Li LMW (2015) Predictors of the gender gap in life expectancy across 54 nations. Psychol Health Med 20:129–138. CrossRefPubMedGoogle Scholar
  208. Sadagurski M, Cady G, Miller RA (2017) Anti-aging drugs reduce hypothalamic inflammation in a sex-specific manner. Aging Cell 16:652–660. CrossRefPubMedPubMedCentralGoogle Scholar
  209. Savage DC (1977) Microbial ecology of the gastrointestinal tract. Annu Rev Microbiol 31:107–133. CrossRefPubMedGoogle Scholar
  210. Schachter AS, Davis KL (2000) Alzheimer’s disease. Dialogues Clin Neurosci 2:91–100PubMedPubMedCentralGoogle Scholar
  211. Schurz H, Salie M, Tromp G, Hoal EG, Kinnear CJ, Möller M (2019) The X chromosome and sex-specific effects in infectious disease susceptibility. Hum Genom 13:2. CrossRefGoogle Scholar
  212. Schwabe RF, Jobin C (2013) The microbiome and cancer. Nat Rev Cancer 13:800–812. CrossRefPubMedPubMedCentralGoogle Scholar
  213. Selman C, Lingard S, Choudhury AI, Batterham RL, Claret M, Clements M, Ramadani F, Okkenhaug K, Schuster E, Blanc E, Piper MD, Al-Qassab H, Speakman JR, Carmignac D, Robinson IC, Thornton JM, Gems D, Partridge L, Withers DJ (2008) Evidence for lifespan extension and delayed age-related biomarkers in insulin receptor substrate 1 null mice. FASEB J 22:807–818. CrossRefPubMedGoogle Scholar
  214. Selman C, Tullet JM, Wieser D, Irvine E, Lingard SJ, Choudhury AI, Claret M, Al-Qassab H, Carmignac D, Ramadani F, Woods A, Robinson IC, Schuster E, Batterham RL, Kozma SC, Thomas G, Carling D, Okkenhaug K, Thornton JM, Partridge L, Gems D, Withers DJ (2009) Ribosomal protein S6 kinase 1 signaling regulates mammalian life span. Science 326:140–144. CrossRefPubMedPubMedCentralGoogle Scholar
  215. Sender R, Fuchs S, Milo R (2016a) Are we really vastly outnumbered? Revisiting the ratio of bacterial to host cells in humans. Cell 164:337–340. CrossRefGoogle Scholar
  216. Sender R, Fuchs S, Milo R (2016b) Revised estimates for the number of human and bacteria cells in the body. PLoS Biol 14:e1002533. CrossRefPubMedPubMedCentralGoogle Scholar
  217. Shadyab AH, Macera CA, Shaffer RA, Jain S, Gallo LC, Gass ML, Waring ME, Stefanick ML, LaCroix AZ (2017) Ages at menarche and menopause and reproductive lifespan as predictors of exceptional longevity in women: the Women’s Health Initiative. Menopause 24:35–44. CrossRefPubMedPubMedCentralGoogle Scholar
  218. Shulman LM, Bhat V (2006) Gender disparities in Parkinson’s disease. Expert Rev Neurother 6:407–416. CrossRefPubMedGoogle Scholar
  219. Simon M, Van Meter M, Ablaeva J, Ke Z, Gonzalez RS, Taguchi T, De Cecco M, Leonova KI, Kogan V, Helfand SL, Neretti N, Roichman A, Cohen HY, Meer MV, Gladyshev VN, Antoch MP, Gudkov AV, Sedivy JM, Seluanov A, Gorbunova V (2019) LINE1 derepression in aged wild-type and SIRT6-deficient mice drives inflammation. Cell Metab 29:871–885.e5. CrossRefPubMedGoogle Scholar
  220. Skaletsky H, Kuroda-Kawaguchi T, Minx PJ, Cordum HS, Hillier L, Brown LG, Repping S, Pyntikova T, Ali J, Bieri T, Chinwalla A, Delehaunty A, Delehaunty K, Du H, Fewell G, Fulton L, Fulton R, Graves T, Hou SF, Latrielle P, Leonard S, Mardis E, Maupin R, McPherson J, Miner T, Nash W, Nguyen C, Ozersky P, Pepin K, Rock S, Rohlfing T, Scott K, Schultz B, Strong C, Tin-Wollam A, Yang SP, Waterston RH, Wilson RK, Rozen S, Page DC (2003) The male-specific region of the human Y chromosome is a mosaic of discrete sequence classes. Nature 423:825–837. CrossRefPubMedGoogle Scholar
  221. Skuse D, Printzlau F, Wolstencroft J (2018) Sex chromosome aneuploidies. Handb Clin Neurol 147:355–376. CrossRefPubMedGoogle Scholar
  222. Smith AD (2002) Imaging the progression of Alzheimer pathology through the brain. Proc Natl Acad Sci USA 99:4135–4137. CrossRefPubMedGoogle Scholar
  223. Smith KD, Young KE, Talbot CC, Schmeckpeper BJ (1987) Repeated DNA of the human Y chromosome. Development 101:77–92PubMedGoogle Scholar
  224. Snow KK, Cote J, Yang W, Davis NJ, Seddon JM (2002) Association between reproductive and hormonal factors and age-related maculopathy in postmenopausal women. Am J Ophthalmol 134:842–848. CrossRefPubMedGoogle Scholar
  225. Sommer A, Tielsch JM (1996) Risk factors for open-angle glaucoma: the Barbados Eye Study. Arch Ophthalmol 114:235. CrossRefPubMedGoogle Scholar
  226. Steegenga WT, Mischke M, Lute C, Boekschoten MV, Pruis MGM, Lendvai A, Verkade HJ, Boekhorst J, Timmerman HM, Plösch T, Müller M (2014) Sexually dimorphic characteristics of the small intestine and colon of prepubescent C57BL/6 mice. Biol Sex Differ 5:11. CrossRefPubMedPubMedCentralGoogle Scholar
  227. Stegeman R, Weake VM (2017) Transcriptional signatures of aging. J Mol Biol 429:2427–2437. CrossRefPubMedPubMedCentralGoogle Scholar
  228. 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. Aging Cell 7:641–650. CrossRefPubMedPubMedCentralGoogle Scholar
  229. Sudhir K, Chou TM, Chatterjee K, Smith EP, Williams TC, Kane JP, Malloy MJ, Korach KS (1997) Premature coronary artery disease associated with a disruptive mutation in the estrogen receptor gene in a man. Circulation 96:3774–3777. CrossRefPubMedGoogle Scholar
  230. Sun LY, Spong A, Swindell WR, Fang Y, Hill C, Huber JA, Boehm JD, Westbrook R, Salvatori R, Bartke A (2013) Growth hormone-releasing hormone disruption extends lifespan and regulates response to caloric restriction in mice. eLife 2013:1–24. CrossRefGoogle Scholar
  231. Tanaka M, Nakayama J (2017) Development of the gut microbiota in infancy and its impact on health in later life. Allergol Int 66:515–522. CrossRefPubMedGoogle Scholar
  232. Tchkonia T, Morbeck DE (2010) Fat tissue, aging, and cellular senescence. Aging Cell 9:667–684. CrossRefPubMedPubMedCentralGoogle Scholar
  233. Teipel SJ, Bayer W, Alexander GE, Zebuhr Y, Teichberg D, Kulic L, Schapiro MB, Möller HJ, Rapoport SI, Hampel H (2002) Progression of corpus callosum atrophy in Alzheimer disease. Arch Neurol 59:243–248. CrossRefPubMedGoogle Scholar
  234. Testori A, Caizzi L, Cutrupi S, Friard O, De Bortoli M, Cora D, Caselle M (2012) The role of transposable elements in shaping the combinatorial interaction of transcription factors. BMC Genom 13:400. CrossRefGoogle Scholar
  235. Thevaranjan N, Puchta A, Schulz C, Naidoo A, Szamosi JC, Verschoor CP, Loukov D, Schenck LP, Jury J, Foley KP, Schertzer JD, Larché MJ, Davidson DJ, Verdú EF, Surette MG, Bowdish DME (2017) Age-associated microbial dysbiosis promotes intestinal permeability, systemic inflammation, and macrophage dysfunction. Cell Host Microbe 21:455–466.e4. CrossRefPubMedPubMedCentralGoogle Scholar
  236. Toth MJ, Tchernof A, Sites CK, Poehlman ET (2000) Effect of menopausal status on body composition and abdominal fat distribution. Int J Obes 24:226–231. CrossRefGoogle Scholar
  237. Tsai MS, Tangalos EG, Petersen RC, Smith GE, Schaid DJ, Kokmen E, Ivnik RJ, Thibodeau SN (1994) Apolipoprotein E: risk factor for Alzheimer disease. Am J Hum Genet 54:643–649PubMedPubMedCentralGoogle Scholar
  238. Tsukamoto I, Kojo S (1990) The sex difference in the regulation of liver regeneration after partial hepatectomy in the rat. Biochim Biophys Acta 1033:287–290. CrossRefPubMedGoogle Scholar
  239. Turnbaugh PJ, Ley RE, Mahowald MA, Magrini V, Mardis ER, Gordon JI (2006) An obesity-associated gut microbiome with increased capacity for energy harvest. Nature 444:1027–1031. CrossRefGoogle Scholar
  240. Ucar D, Benayoun BA (2018) Chapter 1—aging epigenetics: changes and challenges. In: Moskalev A, Vaiserman AM (eds) Epigenetics of aging and longevity, vol 4. Academic Press, Boston, pp 3–32CrossRefGoogle Scholar
  241. Uhlenhaut NH, Jakob S, Anlag K, Eisenberger T, Sekido R, Kress J, Treier AC, Klugmann C, Klasen C, Holter NI, Riethmacher D, Schutz G, Cooney AJ, Lovell-Badge R, Treier M (2009) Somatic sex reprogramming of adult ovaries to testes by FOXL2 ablation. Cell 139:1130–1142. CrossRefGoogle Scholar
  242. Vajaranant TS, Pasquale LR (2012) Estrogen deficiency accelerates aging of the optic nerve. Menopause 19:942–947. CrossRefPubMedPubMedCentralGoogle Scholar
  243. Valle A, Guevara R, García-Palmer FJ, Roca P, Oliver J (2007) Sexual dimorphism in liver mitochondrial oxidative capacity is conserved under caloric restriction conditions. Am J Physiol Cell Physiol 293:1302–1308. CrossRefGoogle Scholar
  244. Vemuri R, Sylvia KE, Klein SL, Forster SC, Plebanski M, Eri R, Flanagan KL (2019) The microgenderome revealed: sex differences in bidirectional interactions between the microbiota, hormones, immunity and disease susceptibility. Semin Immunopathol 41:265–275. CrossRefPubMedGoogle Scholar
  245. Vigen R, Maddox TM, Allen LA (2012) Aging of the United States population: impact on heart failure. Curr Heart Fail Rep 9:369–374. CrossRefPubMedPubMedCentralGoogle Scholar
  246. Villa A, Gelosa P, Castiglioni L, Cimino M, Rizzi N, Pepe G, Lolli F, Marcello E, Sironi L, Vegeto E, Maggi A (2018) Sex-specific features of microglia from adult mice. Cell Rep 23:3501–3511. CrossRefPubMedPubMedCentralGoogle Scholar
  247. Viña J, Lloret A (2010) Why women have more Alzheimer’s disease than men: gender and mitochondrial toxicity of amyloid-β peptide. J Alzheimer’s Dis 20:527–533. CrossRefGoogle Scholar
  248. Wang X, Simpkins JW, Dykens JA, Cammarata PR (2003) Oxidative damage to human lens epithelial cells in culture: estrogen protection of mitochondrial potential, ATP, and cell viability. Investig Ophthalmol Vis Sci 44:2067–2075. CrossRefGoogle Scholar
  249. Wang YE, Kakigi C, Barbosa D, Porco T, Chen R, Wang S, Li Y, Singh K, Pasquale LR, Lin SC (2016) Oral contraceptive use and prevalence of self-reported glaucoma or ocular hypertension in the United States. Ophthalmology 123:729–736. CrossRefPubMedPubMedCentralGoogle Scholar
  250. Whyte WA, Orlando DA, Hnisz D, Abraham BJ, Lin CY, Kagey MH, Rahl PB, Lee TI, Young RA (2013) Master transcription factors and mediator establish super-enhancers at key cell identity genes. Cell 153:307–319. CrossRefPubMedPubMedCentralGoogle Scholar
  251. Wilkinson JE, Burmeister L, Brooks SV, Chan CC, Friedline S, Harrison DE, Hejtmancik JF, Nadon N, Strong R, Wood LK, Woodward MA, Miller RA (2012) Rapamycin slows aging in mice. Aging Cell 11:675–682. CrossRefPubMedPubMedCentralGoogle Scholar
  252. Wilson MR, Hertzmark E, Walker AM, Childs Shaw K, Epstein DL (1987) A case-control study of risk factors in open angle glaucoma. Arch Ophthalmol 105:1066–1071. CrossRefPubMedGoogle Scholar
  253. Wood JG, Jones BC, Jiang N, Chang C, Hosier S, Wickremesinghe P, Garcia M, Hartnett DA, Burhenn L, Neretti N, Helfand SL (2016) Chromatin-modifying genetic interventions suppress age-associated transposable element activation and extend life span in Drosophila. Proc Natl Acad Sci USA 113:11277–11282. CrossRefPubMedGoogle Scholar
  254. Wood-Kaczmar A, Gandhi S, Wood NW (2006) Understanding the molecular causes of Parkinson’s disease. Trends Mol Med 12:521–528. CrossRefPubMedGoogle Scholar
  255. Xiao L, Sonne SB, Feng Q, Chen N, Xia Z, Li X, Fang Z, Zhang D, Fjære E, Midtbø LK, Derrien M, Hugenholtz F, Tang L, Li J, Zhang J, Liu C, Hao Q, Vogel UB, Mortensen A, Kleerebezem M, Licht TR, Yang H, Wang J, Li Y, Arumugam M, Wang J, Madsen L, Kristiansen K (2017) High-fat feeding rather than obesity drives taxonomical and functional changes in the gut microbiota in mice. Microbiome 5:43. CrossRefPubMedPubMedCentralGoogle Scholar
  256. Xu J, Gontier G, Chaker Z, Lacube P, Dupont J, Holzenberger M (2014) Longevity effect of IGF-1R ± mutation depends on genetic background-specific receptor activation. Aging Cell 13:19–28. CrossRefPubMedGoogle Scholar
  257. Xu J, Murphy SL, Kochanek KD, Bastian BA (2016) Deaths: final data for 2013. Natl Vital Stat Rep 64:1–119PubMedGoogle Scholar
  258. Yang X, Schadt EE, Wang S, Wang H, Arnold AP, Ingram-Drake L, Drake TA, Lusis AJ (2006) Tissue-specific expression and regulation of sexually dimorphic genes in mice. Genome Res 16:995–1004. CrossRefPubMedPubMedCentralGoogle Scholar
  259. Yao W, Lay YE, Kot A, Liu R, Zhang H, Chen H, Lam K, Lane NE (2016) Improved mobilization of exogenous mesenchymal stem cells to bone for fracture healing and sex difference. Stem Cells 34:2587–2600. CrossRefPubMedPubMedCentralGoogle Scholar
  260. Yatsunenko T, Rey FE, Manary MJ, Trehan I, Dominguez-Bello MG, Contreras M, Magris M, Hidalgo G, Baldassano RN, Anokhin AP, Heath AC, Warner B, Reeder J, Kuczynski J, Caporaso JG, Lozupone CA, Lauber C, Clemente JC, Knights D, Knight R, Gordon JI (2012) Human gut microbiome viewed across age and geography. Nature 486:222–227. CrossRefPubMedPubMedCentralGoogle Scholar
  261. Yen A, Kellis M (2015) Systematic chromatin state comparison of epigenomes associated with diverse properties including sex and tissue type. Nat Commun 6:7973. CrossRefPubMedPubMedCentralGoogle Scholar
  262. Younan C, Mitchell P, Cumming RG, Panchapakesan J, Rochtchina E, Hales AM (2002) Hormone replacement therapy, reproductive factors, and the incidence of cataract and cataract surgery: the Blue Mountains Eye Study. Am J Epidemiol 155:997–1006. CrossRefPubMedGoogle Scholar
  263. Yu D, Yang SE, Miller BR, Wisinski JA, Sherman DS, Brinkman JA, Tomasiewicz JL, Cummings NE, Kimple ME, Cryns VL, Lamming DW (2018) Short-Term methionine deprivation improves metabolic health via sexually dimorphic, mTORC1-independent mechanisms. FASEB J 32:3471–3482. CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Nirmal K. Sampathkumar
    • 1
    • 2
  • Juan I. Bravo
    • 1
    • 3
  • Yilin Chen
    • 1
    • 4
  • Prakroothi S. Danthi
    • 1
  • Erin K. Donahue
    • 1
    • 5
  • Rochelle W. Lai
    • 1
  • Ryan Lu
    • 1
    • 3
  • Lewis T. Randall
    • 1
    • 3
  • Nika Vinson
    • 6
  • Bérénice A. Benayoun
    • 1
    • 7
    • 8
    Email author
  1. 1.Leonard Davis School of GerontologyUniversity of Southern CaliforniaLos AngelesUSA
  2. 2.Maurice Wohl Clinical Neuroscience Institute, King’s College LondonLondonUK
  3. 3.Graduate Program in the Biology of AgingUniversity of Southern CaliforniaLos AngelesUSA
  4. 4.Masters Program in Nutrition, Healthspan, and LongevityUniversity of Southern CaliforniaLos AngelesUSA
  5. 5.Neuroscience Graduate ProgramUniversity of Southern CaliforniaLos AngelesUSA
  6. 6.Department of Urology, Pelvic Medicine and Reconstructive SurgeryUCLA David Geffen School of MedicineLos AngelesUSA
  7. 7.USC Norris Comprehensive Cancer Center, Epigenetics and Gene RegulationLos AngelesUSA
  8. 8.USC Stem Cell InitiativeLos AngelesUSA

Personalised recommendations