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Inflammation, But Not Telomere Length, Predicts Successful Ageing at Extreme Old Age: A Longitudinal Study of Semi-supercentenarians Yasumichi Arai^ 1 , Carmen M Martin-Ruiz^ 2 , Michiyo Takayama^ 3 , Yukiko Abe^ 1 , Toru Takebayashi^ 4 , Shigeo Koyasu^ 5 , Makoto Suematsu^ 6 , Nobuyoshi Hirose^ 1 , Thomas von Zglinicki^ 2 Affiliations Expand Affiliations * ^1 Centre for Supercentenarian Research, Keio University School of Medicine, Tokyo, Japan. * ^2 Newcastle University Institute for Ageing, Campus for Ageing and Vitality, Newcastle University, UK. * ^3 Centre for Preventive Medicine, Keio University School of Medicine, Tokyo, Japan. * ^4 Department of Preventive Medicine and Public Health, Keio University School of Medicine, Tokyo, Japan. * ^5 Laboratory for Immune Cell Systems, RIKEN Centre for Integrative Medical Sciences (IMS), Yokohama, Kanagawa, Japan ; Department of Microbiology and Immunology, Keio University School of Medicine, Tokyo, Japan. * ^6 Centre for Supercentenarian Research, Keio University School of Medicine, Tokyo, Japan ; Department of Biochemistry, Keio University School of Medicine, and JST, ERATO, Suematsu Gas Biology Project, Tokyo, Japan. * PMID: 26629551 * PMCID: PMC4634197 * DOI: 10.1016/j.ebiom.2015.07.029 Free PMC article Item in Clipboard Inflammation, But Not Telomere Length, Predicts Successful Ageing at Extreme Old Age: A Longitudinal Study of Semi-supercentenarians Yasumichi Arai et al. EBioMedicine. 2015. Free PMC article Show details Display options Display options Format [Abstract] EBioMedicine Actions * Search in PubMed * Search in NLM Catalog * Add to Search . 2015 Jul 29;2(10):1549-58. doi: 10.1016/j.ebiom.2015.07.029. eCollection 2015 Oct. Authors Yasumichi Arai^ 1 , Carmen M Martin-Ruiz^ 2 , Michiyo Takayama^ 3 , Yukiko Abe^ 1 , Toru Takebayashi^ 4 , Shigeo Koyasu^ 5 , Makoto Suematsu^ 6 , Nobuyoshi Hirose^ 1 , Thomas von Zglinicki^ 2 Affiliations * ^1 Centre for Supercentenarian Research, Keio University School of Medicine, Tokyo, Japan. * ^2 Newcastle University Institute for Ageing, Campus for Ageing and Vitality, Newcastle University, UK. * ^3 Centre for Preventive Medicine, Keio University School of Medicine, Tokyo, Japan. * ^4 Department of Preventive Medicine and Public Health, Keio University School of Medicine, Tokyo, Japan. * ^5 Laboratory for Immune Cell Systems, RIKEN Centre for Integrative Medical Sciences (IMS), Yokohama, Kanagawa, Japan ; Department of Microbiology and Immunology, Keio University School of Medicine, Tokyo, Japan. * ^6 Centre for Supercentenarian Research, Keio University School of Medicine, Tokyo, Japan ; Department of Biochemistry, Keio University School of Medicine, and JST, ERATO, Suematsu Gas Biology Project, Tokyo, Japan. * PMID: 26629551 * PMCID: PMC4634197 * DOI: 10.1016/j.ebiom.2015.07.029 Item in Clipboard Full text links Cite Display options Display options Format [Abstract] Abstract To determine the most important drivers of successful ageing at extreme old age, we combined community-based prospective cohorts: Tokyo Oldest Old Survey on Total Health (TOOTH), Tokyo Centenarians Study (TCS) and Japanese Semi-Supercentenarians Study (JSS) comprising 1554 individuals including 684 centenarians and (semi-) supercentenarians, 167 pairs of centenarian offspring and spouses, and 536 community-living very old (85 to 99 years). We combined z scores from multiple biomarkers to describe haematopoiesis, inflammation, lipid and glucose metabolism, liver function, renal function, and cellular senescence domains. In Cox proportional hazard models, inflammation predicted all-cause mortality with hazard ratios (95% CI) 1.89 (1.21 to 2.95) and 1.36 (1.05 to 1.78) in the very old and (semi-)supercentenarians, respectively. In linear forward stepwise models, inflammation predicted capability (10.8% variance explained) and cognition (8(.)6% variance explained) in (semi-) supercentenarians better than chronologic age or gender. The inflammation score was also lower in centenarian offspring compared to age-matched controls with D (95% CI) = - 0.795 (- 1.436 to - 0.154). Centenarians and their offspring were able to maintain long telomeres, but telomere length was not a predictor of successful ageing in centenarians and semi-supercentenarians. We conclude that inflammation is an important malleable driver of ageing up to extreme old age in humans. Keywords: ALT, alanine aminotransferase or alanine transaminase; ANOVA, analysis of variance; AST, aspartate aminotransferase or aspartate transaminase; Ageing; CD, cluster of differentiation; CMV, cytomegalovirus; CRP, C-reactive protein; CVD, cardiovascular disease; Centenarian; ELISA, enzyme-linked immunosorbent assay; GGTP, gamma-glutamyl-transpeptidase; IL-6, interleukin 6; IQR, inter-quartile range; Inflammation; JSS, Japanese Semi-Supercentenarians Study; LTL, leukocyte telomere length; MMSE, Mini-Mental State Examination; NK cells, natural killer cells; PCR, polymerase chain reaction; SD, standard deviation; TCS, Tokyo Centenarians Study; TNF-alpha, tumour necrosis factor-alpha (TNF-alpha); TOOTH, Tokyo Oldest Old Survey on Total Health; Telomere; eGFR, estimated glomerular filtration rate. Figures Fig. 1 Fig. 1 Telomere length in study participants... Fig. 1 Telomere length in study participants up to 115 years of age. Leukocyte telomere... Fig. 1 Telomere length in study participants up to 115 years of age. Leukocyte telomere length vs age is shown for males (blue or cyan) and females (green or red). Centenarians, (semi-)supercentenarians, and centenarian offspring are shown in blue (males) or red (females), respectively. Unrelated participants younger than 100 years are indicated in cyan (males) or green (females). Regression lines belonging to these groups are indicated by the same colour. Fig. 2 Fig. 2 Kaplan-Meier survival curves for tertiles... Fig. 2 Kaplan-Meier survival curves for tertiles of biomarker domains and telomere length in the... Fig. 2 Kaplan-Meier survival curves for tertiles of biomarker domains and telomere length in the very old, centenarian, and (semi-) supercentenarian group. For each age group, the domains were independently organized into tertiles and assessed as independent predictors of survival. The p-value indicates the significance of the log-rank Mantel-Cox test of equality of survival distributions. Fig. 3 Fig. 3 Predictors of capability (a), cognition... Fig. 3 Predictors of capability (a), cognition (b), and multi-morbidity (c). Forward stepwise model selection... Fig. 3 Predictors of capability (a), cognition (b), and multi-morbidity (c). Forward stepwise model selection was performed with age, gender, and all domain scores as predictors. Models were run separately for all unrelated participants and for each of the indicated age groups. Bars indicate the percentage of target variance explained by each predictor. All significant predictors (p < 0.05) in each group are shown. The total variance explained by each model is given (as %) on top. See this image and copyright information in PMC Comment in * Cellular Senescence and Inflammatory Burden as Determinants of Mortality in Elderly People Until the Extreme old age. Giacconi R, Malavolta M, Costarelli L, Provinciali M. Giacconi R, et al. EBioMedicine. 2015 Sep 11;2(10):1316-7. doi: 10.1016/ j.ebiom.2015.09.015. eCollection 2015 Oct. EBioMedicine. 2015. PMID: 26629526 Free PMC article. No abstract available. Similar articles * Demographic, phenotypic, and genetic characteristics of centenarians in Okinawa and Honshu, Japan: Part 2 Honshu, Japan. Arai Y, Sasaki T, Hirose N. Arai Y, et al. Mech Ageing Dev. 2017 Jul;165(Pt B):80-85. doi: 10.1016/j.mad.2017.02.005. Epub 2017 Feb 16. Mech Ageing Dev. 2017. PMID: 28214534 Review. * Leukocyte telomere length and prevalence of age-related diseases in semisupercentenarians, centenarians and centenarians' offspring. Tedone E, Arosio B, Gussago C, Casati M, Ferri E, Ogliari G, Ronchetti F, Porta A, Massariello F, Nicolini P, Mari D. Tedone E, et al. Exp Gerontol. 2014 Oct;58:90-5. doi: 10.1016/ j.exger.2014.06.018. Epub 2014 Jun 27. Exp Gerontol. 2014. PMID: 24975295 * Decreased epigenetic age of PBMCs from Italian semi-supercentenarians and their offspring. 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Slawinska N, Krupa R. Slawinska N, et al. Int J Mol Sci. 2021 Jan 8;22(2):590. doi: 10.3390/ijms22020590. Int J Mol Sci. 2021. PMID: 33435578 Free PMC article. Review. See all "Cited by" articles References 1. 1. Akbaraly T.N., Hamer M., Ferrie J.E., Lowe G., Batty G.D., Hagger-Johnson G. Chronic inflammation as a determinant of future aging phenotypes. CMAJ. 2013;185:E763-E770. - PMC - PubMed 2. 1. Andersen S.L., Sebastiani P., Dworkis D.A., Feldman L., Perls T.T. Health span approximates life span among many supercentenarians: compression of morbidity at the approximate limit of life span. J. Gerontol. A Biol. Sci. Med. Sci. 2012;67:395-405. - PMC - PubMed 3. 1. Arai Y., Iinuma T., Takayama M., Takayama M., Abe Y., Fukuda R. The Tokyo Oldest Old survey on Total Health (TOOTH): a longitudinal cohort study of multidimensional components of health and well-being. BMC Geriatr. 2010;10:35. - PMC - PubMed 4. 1. Arai Y., Inagaki H., Takayama M., Abe Y., Saito Y., Takebayashi T. Physical independence and mortality at the extreme limit of life span: supercentenarians study in Japan. J. Gerontol. A Biol. Sci. Med. Sci. 2014;69:486-494. - PubMed 5. 1. Atzmon G., Cho M., Cawthon R.M., Budagov T., Katz M., Yang X. Evolution in health and medicine Sackler colloquium: genetic variation in human telomerase is associated with telomere length in Ashkenazi centenarians. Proc. Natl. Acad. Sci. U. S. 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