Giới tính, lão hóa và tuổi thọ ở người: Cập nhật về một kịch bản thú vị/bị bỏ qua mở đường cho y học theo giới tính
Tóm tắt
Dữ liệu cho thấy sự khác biệt giới tính đáng kể trong tuổi thọ và tỷ lệ tử vong, bao gồm khả năng sống đến tuổi cao, được tổng hợp từ các dữ liệu lâm sàng và nhân khẩu học, nhấn mạnh tầm quan trọng của một góc nhìn lịch sử toàn diện cũng như sự tương tác giữa gen - môi trường/lối sống. Sự khác biệt giới tính về tỷ lệ mắc và tỷ lệ mới mắc của những bệnh liên quan đến tuổi tác quan trọng nhất, chẳng hạn như bệnh tim mạch và bệnh thoái hóa thần kinh, ung thư, tiểu đường loại 2, tàn tật, tự miễn dịch và nhiễm trùng, được tổng hợp và cập nhật với sự chú ý đặc biệt đến vai trò của hệ miễn dịch và hiện tượng lão hóa miễn dịch. Nhìn chung, sự khác biệt giới tính dường như phổ biến và vẫn ít được xem xét và điều tra mặc dù có tầm quan trọng sinh học của chúng. Các cơ chế sinh học cơ bản chịu trách nhiệm cho sự khác biệt giới tính trong lão hóa và tuổi thọ là khá phức tạp và vẫn chưa được hiểu rõ. Bài tổng quan này tập trung vào những người sống đến trăm tuổi và con cái của họ như một mô hình của lão hóa khỏe mạnh và tóm tắt kiến thức sẵn có về ba hiện tượng sinh học cơ bản, tức là sự thiên lệch trong việc in hoạt động của nhiễm sắc thể X liên quan đến tuổi tác, sự thay đổi vi khuẩn đường ruột và các biến thể di truyền DNA ty thể di truyền từ mẹ. Kết luận, cần thiết một cách tiếp cận y học theo giới tính thích hợp và nên được theo đuổi một cách hệ thống trong các nghiên cứu về lão hóa khỏe mạnh, tuổi thọ và các bệnh liên quan đến tuổi tác, trong một thế giới toàn cầu hóa đặc trưng bởi những khác biệt giới tính lớn có ảnh hưởng cao đến sức khỏe và bệnh tật.
Từ khóa
Tài liệu tham khảo
Ostan, 2015, Gender and longevity, Ital. J. Gender-Specific Med., 1, 10
Cevenini, 2010, Systems biology and longevity: an emerging approach to identify innovative anti-aging targets and Strategies, Curr. Pharm. Des., 16, 802, 10.2174/138161210790883660
Regitz-Zagrosek, 2012, Sex and gender differences in health, EMBO Rep., 13, 596, 10.1038/embor.2012.87
Franceschi, 2000, Do men and women follow different trajectories to reach extreme longevity? Italian Multicenter Study on Centenarians (IMUSCE), Aging (Milano), 12, 77
Passarino, 2002, Male/female ratio in centenarians: a possible role played by population genetic structure, Exp. Gerontol., 37, 1283, 10.1016/S0531-5565(02)00140-7
Barford, 2006, Life expectancy: women now on top everywhere, BMJ, 332, 808, 10.1136/bmj.332.7545.808
Livi Bacci, 2015, La differenza di genere nella longevità: si attenua il vantaggio delle donne, Longevità, Vecchiaia, Salute, 34
Wisser, 2014, The sex differential in mortality: a historical comparison of the adult-age pattern of the ratio and the difference, MPIDR Working Paper WP 2014-005
Beltrán-Sánchez, 2015, Twentieth century surge of excess adult male mortality, Proc. Natl. Acad. Sci. U.S.A., 112, 8993, 10.1073/pnas.1421942112
OECD, 2014, Life expectancy and healthy life expectancy at birth, 16
Van Oyen, 2013, Gender differences in healthy life years within the EU: an exploration of the “health-survival” paradox, Int. J. Public Health, 58, 143, 10.1007/s00038-012-0361-1
Austad, 2015, Sex differences in longevity and in responses to anti-aging interventions: a mini-review, Gerontology, 62, 40, 10.1159/000381472
Heron, 2016, Deaths: leading causes for 2013, Natl. Vital. Stat. Rep., 65, 1
Jagger, 2008, Inequalities in healthy life years in the 25 countries of the European Union in 2005: a cross-national meta-regression analysis, Lancet, 372, 2124, 10.1016/S0140-6736(08)61594-9
Fouweather, 2015, Comparison of socio-economic indicators explaining inequalities in Healthy Life Years at age 50 in Europe: 2005 and 2010, Eur. J. Public Health, 25, 978, 10.1093/eurpub/ckv070
Regitz-Zagrosek, 2016, Gender in cardiovascular diseases: impact on clinical manifestations, management, and outcomes, Eur. Heart. J., 37, 24, 10.1093/eurheartj/ehv598
Baggio, 2013, Gender medicine: a task for the third millennium, Clin. Chem. Lab. Med., 51, 713, 10.1515/cclm-2012-0849
Ambrosy, 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, 10.1016/j.jacc.2013.11.053
Levy, 2002, Long-term trends in the incidence of and survival with heart failure, N. Engl. J. Med., 347, 1397, 10.1056/NEJMoa020265
Kenchaiah, 2015, Heart failure in women: insights from the Framingham Heart Study, Cardiovasc. Drugs Ther., 29, 377, 10.1007/s10557-015-6599-0
Barton, 2009, Postmenopausal hypertension: mechanisms and therapy, Hypertension, 54, 11, 10.1161/HYPERTENSIONAHA.108.120022
Barrett-Connor, 1991, Why is diabetes mellitus a stronger risk factor for fatal ischemic heart disease in women than in men? The Rancho Bernardo Study, JAMA, 265, 627, 10.1001/jama.1991.03460050081025
Leslie, 2016, Preeclampsia and the risk of future vascular disease and mortality: a review, J. Midwifery Womens Health, 61, 315, 10.1111/jmwh.12469
Guariguata, 2014, Determinants of gender differences in the prevalence of diabetes, Diabetes Res. Clin. Pract., 106, e14, 10.1016/j.diabres.2014.08.008
Wild, 2004, Global prevalence of diabetes: estimates for the year 2000 and projections for 2030, Diabetes Care, 27, 1047e53, 10.2337/diacare.27.5.1047
Huxley, 2006, Excess risk of fatal coronary heart disease associated with diabetes in men and women: meta-analysis of 37 prospective cohort studies, BMJ, 332, 73, 10.1136/bmj.38678.389583.7C
Cull, 2004, Changing aspirin use in patients with Type 2 diabetes in the UKPDS, Diabet Med., 21, 1368, 10.1111/j.1464-5491.2004.01328.x
Wexler, 2005, Sex disparities in treatment of cardiac risk factors in patients with type 2 diabetes, Diabetes Care, 28, 514, 10.2337/diacare.28.3.514
Persell, 2004, Aspirin use among adults with diabetes: recent trends and emerging sex disparities, Arch. Intern. Med., 164, 2492, 10.1001/archinte.164.22.2492
Maggi, 2006, Metabolic syndrome, diabetes, and cardiovascular disease in an elderly Caucasian cohort: the Italian Longitudinal Study on Aging, J. Gerontol. A Biol. Sci. Med. Sci., 61, 505, 10.1093/gerona/61.5.505
Mottillo, 2010, The metabolic syndrome and cardiovascular risk a systematic review and meta-analysis, J. Am. Coll. Cardiol., 56, 1113, 10.1016/j.jacc.2010.05.034
Donington, 2011, Sex and gender differences in non-small cell lung cancer, Semin. Thorac. Cardiovasc. Surg., 23, 137, 10.1053/j.semtcvs.2011.07.001
Nelson, 2007, The relation of age, race, and gender to the subside location of colorectal carcinoma, Cancer, 80, 103
Strimpakos, 2009, Pharmacogenetics and biomarkers in colorectal cancer, Pharmacogenomics J., 9, 147, 10.1038/tpj.2009.8
Ferlay, 2013, Cancer incidence and mortality patterns in Europe: estimates for 40 countries in 2012, Eur. J. Cancer, 49, 1374, 10.1016/j.ejca.2012.12.027
Alzheimer Europe, 2013, Dementia in Europe Yearbook 2013
Gabelli, 2015, Gender differences in cognitive decline and Alzheimer's disease, Ital. J. Gender-Specific Med., 1, 21
Bachman, 1992, Prevalence of dementia and probable senile dementia of the Alzheimer type in the Framingham Study, Neurology, 42, 115, 10.1212/WNL.42.1.115
Bretsky, 1999, Evidence for an interaction between apolipoprotein E genotype, gender, and Alzheimer disease, Alzheimer Dis. Assoc. Disord., 13, 216, 10.1097/00002093-199910000-00007
Farrer, 1997, Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease: a meta-analysis, JAMA, 278, 1349, 10.1001/jama.1997.03550160069041
Sampedro, 2015, Alzheimer's Disease Neuroimaging Initiative: APOE-by-sex interactions on brain structure and metabolism in healthy elderly controls, Oncotarget, 6, 26663, 10.18632/oncotarget.5185
Santoro, 2010, Evidence for sub-haplogroup H5 of mitochondrial DNA as a risk factor for late onset Alzheimer's disease, PLoS One, 5, e12037, 10.1371/journal.pone.0012037
Jaffe, 1994, Estrogen regulates metabolism of Alzheimer amyloid β precursor protein, J. Biol. Chem., 269, 13065, 10.1016/S0021-9258(17)36796-0
Wang, 1999, Estrogen provides neuroprotection in transient forebrain ischemia through perfusion-independent mechanisms in rats, Stroke, 30, 630, 10.1161/01.STR.30.3.630
Aenlle, 2009, Estrogen effects on cognition and hippocampal transcription in middle-aged mice, Neurobiol. Aging, 30, 932, 10.1016/j.neurobiolaging.2007.09.004
Rocca, 2010, Oophorectomy, menopause, estrogen, and cognitive aging: the timing hypothesis, Neurodegener. Dis., 7, 163, 10.1159/000289229
Litim, 2015, Neuroactive gonadal drugs for neuroprotection in male and female models of Parkinson's disease, Neurosci. Biobehav. Rev., 10.1016/j.neubiorev.2015.09.024
Pringsheim, 2014, The prevalence of Parkinson's disease: a systematic review and meta-analysis, Mov. Disord., 29, 1583, 10.1002/mds.25945
Nitkowska, 2014, Reproductive life characteristics in females affected with Parkinson's disease and in healthy control subjects: a comparative study on Polish population, Neurol. Neurochir. Pol., 48, 322, 10.1016/j.pjnns.2014.08.004
Ragonese, 2004, Risk of Parkinson disease in women: effect of reproductive characteristics, Neurology, 62, 2010, 10.1212/WNL.62.11.2010
Rocca, 2008, Increased risk of parkinsonism in women who underwent oophorectomy before menopause, Neurology, 70, 200, 10.1212/01.wnl.0000280573.30975.6a
Christensen, 2009, Ageing populations: the challenges ahead, Lancet, 374, 1196, 10.1016/S0140-6736(09)61460-4
Corrao, 2014, Gender-differences in disease distribution and outcome in hospitalized elderly: data from the REPOSI study, Eur. J. Intern. Med., 25, 617, 10.1016/j.ejim.2014.06.027
Santalucia, 2015, Gender difference in drug use in hospitalized elderly patients, Eur. J. Intern. Med., 26, 483, 10.1016/j.ejim.2015.07.006
Johnson, 2014, The epidemiology of osteoarthritis, Best Pract. Res. Clin. Rheumatol., 28, 5, 10.1016/j.berh.2014.01.004
Srikanth, 2005, A meta-analysis of sex differences prevalence, incidence and severity of osteoarthritis, Osteoarthritis Cartilage, 13, 769, 10.1016/j.joca.2005.04.014
Sundström, 2014, The relationship between marital and parental status and the risk of dementia, Int. Psychogeriatr., 26, 749, 10.1017/S1041610213002652
Heuberger, 2014, The association between depression and widowhood and nutritional status in older adults, Geriatr. Nurs., 35, 428, 10.1016/j.gerinurse.2014.06.011
Cole, 2003, Risk factors for depression among elderly community subjects: a systematic review and meta-analysis, Am. J. Psychiatry, 160, 1147, 10.1176/appi.ajp.160.6.1147
Dahlberg, 2015, Predictors of loneliness among older women and men in Sweden: a national longitudinal study, Aging Ment. Health, 19, 409, 10.1080/13607863.2014.944091
Dykstra, 2007, Social and emotional loneliness among divorced and married men and women: comparing the deficit and cognitive perspectives, Basic Appl. Social Psychol., 29, 112, 10.1080/01973530701330843
Lennartsson, 2007, ‘What's marital status got to do with it?’ Gender inequalities in economic resources, health and functional abilities among older adults, Health Inequalities and Welfare Resources: Continuity and Change in Sweden, 179
Moon, 2011, Widowhood and mortality: a meta-analysis, PLoS One, 6, e23465, 10.1371/journal.pone.0023465
Clouston, 2014, The role of partnership status on late-life physical function, Can. J. Aging, 33, 413, 10.1017/S0714980814000282
Vina, 2005, Why females live longer than males: control of longevity by sex hormones, Sci. Aging Knowledge Environ., 23, pe17
Bouman, 2005, Sex hormones and the immune response in humans, Hum. Reprod. Update, 11, 411, 10.1093/humupd/dmi008
Giefing-Kröll, 2015, How sex and age affect immune responses, susceptibility to infections, and response to vaccination, Aging Cell, 14, 309, 10.1111/acel.12326
Hao, 2007, Modulation of 17β-estradiol on the number and cytotoxicity of NK cells in vivo related to MCM and activating receptors, Int. Immunopharmacol., 7, 1765, 10.1016/j.intimp.2007.09.017
Ashcroft, 1999, Topical estrogen accelerates cutaneous wound healing in aged humans associated with an altered inflammatory response, Am. J. Pathol., 155, 1137, 10.1016/S0002-9440(10)65217-0
Kramer, 2004, 17β-Estradiol regulates cytokine release through modulation of CD16 expression in monocytes and monocyte-derived macrophages, Arthritis Rheum., 50, 1967, 10.1002/art.20309
Olsen, 2011, Evidence that androgens modulate human thymic T cell output, J. Investig. Med., 59, 32, 10.2310/JIM.0b013e318200dc98
Klein, 2010, The Xs and Y of immune responses to viral vaccines, Lancet Infect. Dis., 10, 338, 10.1016/S1473-3099(10)70049-9
Sakiani, 2013, Gonadal steroids and humoral immunity, Nat. Rev. Endocrinol., 9, 56, 10.1038/nrendo.2012.206
Gomez, 2015, The gut microbiome in autoimmunity: sex matters, Clin. Immunol., 159, 154, 10.1016/j.clim.2015.04.016
Fish, 2008, The X-files in immunity: sex-based differences predispose immune responses, Nat. Rev. Immunol., 8, 737, 10.1038/nri2394
Zandman-Goddard, 2007, Gender and autoimmunity, Autoimmun. Rev., 6, 366, 10.1016/j.autrev.2006.10.001
Vrachnis, 2014, Probing the impact of sex steroids and menopause-related sex steroid deprivation on modulation of immune senescence, Maturitas, 78, 174, 10.1016/j.maturitas.2014.04.014
Ossewaarde, 2005, Age at menopause, cause-specific mortality and total life expectancy, Epidemiology, 4, 556, 10.1097/01.ede.0000165392.35273.d4
Gagnon, 2009, Is there a trade-off between fertility and longevity? A comparative study of women from three large historical databases accounting for mortality selection Am, J. Hum. Biol., 4, 533, 10.1002/ajhb.20893
Weinberger, 2012, Vaccines for the elderly, Clin. Microbiol. Infect., 18, 100, 10.1111/j.1469-0691.2012.03944.x
Scholz, 2013, A comparative review of aging and B cell function in mice and humans, Curr. Opin. Immunol., 25, 504, 10.1016/j.coi.2013.07.006
Solana, 2012, Innate immunosenescence: effect of aging on cells and receptors of the innate immune system in humans, Semin. Immunol., 24, 331, 10.1016/j.smim.2012.04.008
Shaw, 2011, Dysregulation of human Toll-like receptor function in aging, Ageing Res. Rev., 10, 346, 10.1016/j.arr.2010.10.007
Salminen, 2012, Mitochondrial dysfunction and oxidative stress activate inflammasomes: impact on the aging process and age-related diseases, Cell. Mol. Life Sci., 69, 2999, 10.1007/s00018-012-0962-0
Sansoni, 2008, The immune system in extreme longevity, Exp. Gerontol., 43, 61, 10.1016/j.exger.2007.06.008
Franceschi, 2000, Inflamm-aging: an evolutionary perspective on immunosenescence, Ann. N.Y. Acad. Sci., 908, 244, 10.1111/j.1749-6632.2000.tb06651.x
Cevenini, 2013, Inflamm-ageing, Curr. Opin. Clin. Nutr. Metab. Care, 16, 14, 10.1097/MCO.0b013e32835ada13
Franceschi, 2014, Chronic inflammation (inflammaging) and its potential contribution to age-associated diseases, J. Gerontol. A Biol. Sci. Med. Sci., 69, S4, 10.1093/gerona/glu057
Hirokawa, 2013, Slower immune system aging in women versus men in the Japanese population, Immun Ageing, 15, 10
Giglio, 1994, Immune cell circulating subsets are affected by gonadal function, Life Sci, 54, 1305, 10.1016/0024-3205(94)00508-7
Deguchi, 2001, Postmenopausal changes in production of type 1 and type 2 cytokines and the effects of hormone replacement therapy, Menopause, 8, 266, 10.1097/00042192-200107000-00008
Kamada, 2001, Postmenopausal changes in serum cytokine levels and hormone replacement therapy, Am. J. Obstet. Gynecol., 184, 309, 10.1067/mob.2001.109940
Vural, 2006, Effects of hormone replacement therapy on plasma pro-inflammatory and anti-inflammatory cytokines and some bone turnover markers in postmenopausal women, Pharmacol. Res., 54, 298, 10.1016/j.phrs.2006.06.006
Yasui, 2007, Changes in serum cytokine concentrations during the menopausal transition, Maturitas, 56, 396, 10.1016/j.maturitas.2006.11.002
Goetzl, 2010, Gender specificity of altered human immune cytokine profiles in aging, FASEB J., 24, 3580, 10.1096/fj.10-160911
Ostan, 2008, Immunosenescence and immunogenetics of human longevity, Neuroimmunomodulation, 15, 224, 10.1159/000156466
Fontana, 2015, Promoting health and longevity through diet: from model organisms to humans, Cell, 161, 106, 10.1016/j.cell.2015.02.020
Fontana, 2010, Extending healthy lifespan: from yeast to humans, Science, 328, 321, 10.1126/science.1172539
Longo, 2015, Interventions to slow aging in humans: are we ready?, Aging Cell, 14, 497, 10.1111/acel.12338
Regan, 2013, Gender and longevity: why do men die earlier than women? Comparative and experimental evidence, Best Pract. Res. Clin. Endocrinol. Metab., 27, 467, 10.1016/j.beem.2013.05.016
Clancy, 2001, Extension of life-span by loss of CHICO, a Drosophila insulin receptor substrate protein, Science, 292, 104, 10.1126/science.1057991
Tatar, 2001, A mutant Drosophila insulin receptor homolog that extends life-span and impairs neuroendocrine function, Science, 292, 107, 10.1126/science.1057987
Holzenberger, 2003, IGF-1 receptor regulates lifespan and resistance to oxidative stress in mice, Nature, 421, 182, 10.1038/nature01298
Selman, 2009, Ribosomal protein S6 kinase 1 signaling regulates mammalian life span, Science, 326, 140, 10.1126/science.1177221
Miller, 2014, Rapamycin-mediated lifespan increase in mice is dose and sex dependent and metabolically distinct from dietary restriction, Aging Cell, 13, 468, 10.1111/acel.12194
Passtoors, 2013, Gene expression analysis of mTOR pathway: association with human longevity, Aging Cell, 12, 24, 10.1111/acel.12015
van Heemst, 2005, Reduced insulin/IGF-1 signalling and human longevity, Aging Cell, 4, 79, 10.1111/j.1474-9728.2005.00148.x
Leung, 2004, Estrogen regulation of growth hormone action, Endocr. Rev., 25, 693, 10.1210/er.2003-0035
Bondanelli, 2003, Activation of the somatotropic axis by testosterone in adult men: evidence for a role of hypothalamic growth hormone-releasing hormone, Neuroendocrinology, 77, 380, 10.1159/000071310
Xu, 2006, Androgens induce prostate cancer cell proliferation through mammalian target of rapamycin activation and post-transcriptional increases in cyclin D proteins, Cancer Res., 66, 7783, 10.1158/0008-5472.CAN-05-4472
Altamirano, 2009, Testosterone induces cardiomyocyte hypertrophy through mammalian target of rapamycin complex 1 pathway, J. Endocrinol., 202, 299, 10.1677/JOE-09-0044
Harvie, 2011, The effects of intermittent or continuous energy restriction on weight loss and metabolic disease risk markers: a randomized trial in young overweight women, Int. J. Obes. (Lond.), 35, 714, 10.1038/ijo.2010.171
Jakubowicz, 2013, Effects of caloric intake timing on insulin resistance and hyperandrogenism in lean women with polycystic ovary syndrome, Clin. Sci. (Lond.), 125, 423, 10.1042/CS20130071
Bédard, 2015, Sex differences in the impact of the Mediterranean diet on systemic inflammation, Nutr. J., 14, 46, 10.1186/s12937-015-0035-y
Bédard, 2012, Sex differences in the impact of the Mediterranean diet on cardiovascular risk profile, Br. J. Nutr., 108, 1428, 10.1017/S0007114511006969
Bédard, 2014, Sex-related differences in the effects of the Mediterranean diet on glucose and insulin homeostasis, J. Nutr. Metab., 2014, 424130, 10.1155/2014/424130
Bédard, 2015, Sex differences in the impact of the Mediterranean diet on LDL particle size distribution and oxidation, Nutrients, 7, 3705, 10.3390/nu7053705
Bédard, 2014, Effects of the traditional Mediterranean diet on adiponectin and leptin concentrations in men and premenopausal women: do sex differences exist?, Eur. J. Clin. Nutr., 68, 561, 10.1038/ejcn.2014.27
Leblanc, 2015, Differences between men and women in dietary intakes and metabolic profile in response to a 12-week nutritional intervention promoting the Mediterranean diet, J. Nutr. Sci., 4, e13, 10.1017/jns.2015.2
Franceschi, 2008, The extreme longevity: the state of the art in Italy, Exp. Gerontol., 43, 45, 10.1016/j.exger.2007.06.006
Salvioli, 2009, Why do centenarians escape or postpone cancer? The role of IGF-1, inflammation and p53, Cancer Immunol. Immunother., 58, 1909, 10.1007/s00262-008-0639-6
Paolisso, 1996, Glucose tolerance and insulin action in healthy centenarians, Am. J. Physiol., 270, E890
Barbi, 2009, Più longevi e meno diversi: recente evoluzione della sopravvivenza, Rapporto Sulla Popolazione: Salute e Sopravvivenza, 11
Livi Bacci, 2015, Vivere a lungo, ma quanto a lungo?, 14
Robine, 2005, An unprecedented increase in the number of centenarians, Genus, 61, 57
Prati, 2011, Sopravvivenza e salute: l'evoluzione della sopravvivenza, Rapporto Sulla Popolazione. L'Italia a 150 Anni dall'Unità, 79
Caselli, 1991, A new insight into morbidity and mortality transition in Italy, Genus, 47, 1
di Fraia, 2011, Il recupero dello svantaggio maschile nella sopravvivenza, Rapporto Sulla Popolazione. L'Italia a 150 Anni dall'Unità, 88
Poulain, 2004, Identification of a geographic area characterized by extreme longevity in the Sardinia island: the AKEA study, Exp. Gerontol., 39, 1423, 10.1016/j.exger.2004.06.016
Lipsi, 2002, Evoluzione della Geografia della Mortalità in Italia: Tavole Provinciali e Probabilità di Morte per Causa, Anni: 1971–1973, 1981–1983, 1991–1993
Caselli, 2006, Family clustering in Sardinian longevity: a genealogical approach, Exp. Gerontol., 41, 727, 10.1016/j.exger.2006.05.009
Gueresi, 2013, Does the longevity of one or both parents influence the health status of their offspring?, Exp. Gerontol, 48, 395, 10.1016/j.exger.2013.02.004
Bucci, 2016, Centenarians' offspring as a model of healthy aging: a reappraisal of the data on Italian subjects and a comprehensive overview, Aging (Albany NY), 8, 510, 10.18632/aging.100912
Horvath, 2015, Decreased epigenetic age of PBMCs from Italian semi-supercentenarians and their offspring, Aging (Albany NY), 7, 1159, 10.18632/aging.100861
Garagnani, 2014, The three genetics (nuclear DNA, mitochondrial DNA, and gut microbiome) of longevity in humans considered as metaorganisms, Biomed. Res. Int., 2014, 560340, 10.1155/2014/560340
Austad, 2006, Why women live longer than men: sex differences in longevity, Gend. Med., 3, 79, 10.1016/S1550-8579(06)80198-1
Bittel, 2008, Comparison of X-chromosome inactivation patterns in multiple tissues from human females, J. Med. Genet., 45, 309, 10.1136/jmg.2007.055244
Deng, 2014, X chromosome regulation: diverse patterns in development, tissues and disease, Nat. Rev. Genet., 15, 367, 10.1038/nrg3687
Ozcelik, 2008, X chromosome inactivation and female predisposition to autoimmunity, Clin. Rev. Allergy Immunol., 34, 348, 10.1007/s12016-007-8051-0
Gentilini, 2012, Age-dependent skewing of X chromosome inactivation appears delayed in centenarians’ offspring: is there a role for allelic imbalance in healthy aging and longevity?, Aging Cell, 11, 277, 10.1111/j.1474-9726.2012.00790.x
Gentilini, 2015, Stochastic epigenetic mutations (DNA methylation) increase exponentially in human aging and correlate with X chromosome inactivation skewing in females, Aging (Albany NY), 7, 568, 10.18632/aging.100792
Sgarbi, 2014, Mitochondria hyperfusion and elevated autophagic activity are key mechanisms for cellular bioenergetic preservation in centenarians, Aging (Albany NY), 6, 296, 10.18632/aging.100654
Raule, 2014, The co-occurrence of mtDNA mutations on different oxidative phosphorylation subunits, not detected by haplogroup analysis, affects human longevity and is population specific, Aging Cell, 13, 401, 10.1111/acel.12186
Rose, 2007, The mitochondrial DNA control region shows genetically correlated levels of heteroplasmy in leukocytes of centenarians and their offspring, BMC Genomics, 8, 293, 10.1186/1471-2164-8-293
Rose, 2010, Somatic point mutations in mtDNA control region are influenced by genetic background and associated with healthy aging: a GEHA study, PLoS One, 5, e13395, 10.1371/journal.pone.0013395
Giuliani, 2014, Transmission from centenarians to their offspring of mtDNA heteroplasmy revealed by ultra-deep sequencing, Aging (Albany NY), 6, 454, 10.18632/aging.100661
Achilli, 2011, Mitochondrial DNA backgrounds might modulate diabetes complications rather than T2DM as a whole, PLoS One, 6, e21029, 10.1371/journal.pone.0021029
Chinnery, 2010, Mitochondrial DNA haplogroups and risk of transient ischaemic attack and ischaemic stroke: a genetic association study, Lancet. Neurol., 9, 498, 10.1016/S1474-4422(10)70083-1
Gaweda-Walerych, 2008, Mitochondrial DNA haplogroups and subhaplogroups are associated with Parkinson's disease risk in a Polish PD cohort, J. Neural. Transm., 115, 1521, 10.1007/s00702-008-0121-9
Lee, 2010, Has the microbiota played a critical role in the evolution of the adaptive immune system?, Science, 330, 1768, 10.1126/science.1195568
Mueller, 2006, Differences in fecal microbiota in different European study populations in relation to age, gender, and country: a cross-sectional study, Appl. Environ. Microbiol., 72, 1027, 10.1128/AEM.72.2.1027-1033.2006
Biagi, 2010, Through ageing, and beyond: gut microbiota and inflammatory status in seniors and centenarians, PLoS One, 5, e10667, 10.1371/journal.pone.0010667