Experimental Gerontology 58 (2014) 250–255

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Frailty and telomere length: Cross-sectional analysis in 3537 older adults from the ESTHER cohort Kai-Uwe Saum a,⁎,1, Aida Karina Dieffenbach a,b,1, Aysel Müezzinler a,c, Heiko Müller a, Bernd Holleczek d, Christa Stegmaier d, Katja Butterbach a, Matthias Schick h, Federico Canzian e, Hermann Stammer f, Petra Boukamp f, Klaus Hauer g, Hermann Brenner a,b,c,⁎ a

Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 581, 69120 Heidelberg, Germany German Cancer Consortium (DKTK), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany c Network Aging Research (NAR), University of Heidelberg, Bergheimer Straße 20, 69115 Heidelberg, Germany d Epidemiological Cancer Registry of Saarland, Präsident-Baltz-Straße 5, 66119 Saarbrücken, Germany e Genomic Epidemiology Group, German Cancer Research Center, Im Neuenheimer Feld 580, 69120 Heidelberg, Germany f Division of Genetics of Skin Carcinogenesis, German Cancer Research Center, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany g Department of Geriatric Research, Bethanien-Hospital and Geriatric Centre, University of Heidelberg, Rohrbacher Str. 149, 69126 Heidelberg, Germany h Genomics and Proteomics Core Facility, German Cancer Research Center, Im Neuenheimer Feld 580, 69120 Heidelberg, Germany b

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Article history: Received 26 March 2014 Received in revised form 17 July 2014 Accepted 20 August 2014 Available online 21 August 2014 Section Editor: Diana Van Heemst Keywords: Frailty index Frailty Elderly Telomere length Telomeres

a b s t r a c t Both telomere length and frailty were observed to be associated with aging. Whether and to what extent telomere length is related to frailty is essentially unknown. In this cross-sectional analysis of baseline data of 3537 community-dwelling adults aged 50 to 75 years of a large German cohort study, we assessed the hypothesis that shorter telomere length might be a biological marker for frailty. Using whole blood DNA we examined mean telomere repeat copy to single gene copy number (T/S ratio) using quantitative PCR. Construction of a frailty index (FI) was based on a deficit accumulation approach, which quantifies frailty as ratio of the deficits present divided by the total number of deficits considered. Mean FI was determined according to age by tertiles of T/S ratio. Furthermore, we used correlation analyses stratified for gender and age groups to examine the association of the T/S ratio with frailty. Mean FI value was similar across tertiles of the T/S ratio (0.24 ± 0.14, 0.24 ± 0.14 and 0.23 ± 0.14, respectively (p = 0.09)), and FI and the T/S ratio were uncorrelated in gender- and age-specific analyses. In conclusion, T/S ratio and frailty were unrelated in this large sample of older adults. T/S ratio may therefore not be a meaningful biological marker for frailty. © 2014 Elsevier Inc. All rights reserved.

1. Introduction Telomeres are repetitive DNA sequences at the ends of the chromosomes that protect the DNA against degradation and maintain chromosomal stability (Charames and Bapat, 2003). By investigating peripheral blood lymphocytes (or hematopoietic cells) it was shown that telomere length varies among individuals, and shortens 30 to 150 base pairs (bp) with each cell division (Huffman et al., 2000). Shortened telomeres were shown to be correlated with age ⁎ Corresponding authors at: German Cancer Research Center, Division of Clinical Epidemiology and Aging Research, Im Neuenheimer Feld 581, 69120 Heidelberg, Germany. E-mail addresses: [email protected] (K.-U. Saum), [email protected] (A.K. Dieffenbach), [email protected] (A. Müezzinler), [email protected] (H. Müller), [email protected] (B. Holleczek), [email protected] (C. Stegmaier), [email protected] (K. Butterbach), [email protected] (F. Canzian), [email protected] (H. Stammer), [email protected] (P. Boukamp), [email protected] (K. Hauer), [email protected] (H. Brenner). 1 First two authors contributed equally to this work.

http://dx.doi.org/10.1016/j.exger.2014.08.009 0531-5565/© 2014 Elsevier Inc. All rights reserved.

and several age-related pathologies such as cardiovascular diseases, diabetes, Alzheimer's disease, schizophrenia and osteoporosis (Ballon et al., 2001; Bekaert et al., 2007; Fyhrquist et al., 2013; Jeyapalan and Sedivy, 2008; Kao et al., 2008; Muezzinler et al., 2013; Valdes et al., 2007). Moreover, an inverse association between telomere length and mortality has been shown (Bakaysa et al., 2007; Cawthon et al., 2003; Fitzpatrick et al., 2011; Sanders and Newman, 2013). The observed telomere shortening with age and age-related diseases led to the hypothesis that telomere length might represent a biological marker for the aging process (Butt et al., 2010; Oeseburg et al., 2010; Vaziri et al., 1993; von Zglinicki, 2012). Frailty, a multidimensional syndrome characterized by loss of physiological reserves and increased vulnerability to age-related diseases and functional impairment, has received rapidly increasing attention in aging research in the past 10 years (Bergman et al., 2007; Fried et al., 2001; Mitnitski et al., 2005). Several biomarkers in the peripheral blood were shown to be related to the frailty phenotype, such as high levels of C-reactive protein, as well as higher levels of the inflammatory cytokine interleukin-6 (Cesari et al., 2004; Cohen et al., 2003; Hubbard

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et al., 2009). Whether and to what extent telomere length is related to frailty is essentially unknown. So far, only one study assessed this association. This study was conducted in a Chinese population aged 65 years and older and reported no significant correlation between telomeres and frailty (Woo et al., 2008). In this study, we aim to assess the association between mean telomere repeat copy to single gene copy number (T/S ratio) and frailty in a large cohort study of adults from Germany aged between 50 and 75 years. 2. Methods 2.1. Study Design and Data Collection This investigation is based on the baseline data from the ESTHER cohort study (“Epidemiologische Studie zu Chancen der Verhütung, Früherkennung und optimierten Therapie chronischer Erkrankungen in der älteren Bevölkerung”) conducted in Saarland, Germany. Detailed information about the study design and study population has been reported elsewhere (Schöttker et al., 2013). Briefly, 9949 study participants, aged 50 to 75 years, were recruited between July 2000 and December 2002 during a general health check-up by their general practitioners in Saarland, Germany. The ESTHER study was approved by the ethics committees of the medical faculty of the University of Heidelberg and of the medical board of the state of Saarland. A standardized questionnaire on sociodemographic, medical, and lifestyle factors was completed by each participant. Genomic DNA was extracted from whole blood samples using a salting out procedure (Miller et al., 1988) and stored at − 20 °C. Telomere measurements were carried out in baseline samples from a randomly selected subsample of 3572 out of 4190 participants known to be still alive and providing another blood sample at 8-year follow-up. 2.2. Frailty Index The frailty index (FI) is an approach to measure frailty by an accumulation of deficits (Mitnitski et al., 2001). The FI counts individuals' deficits in health which can be: symptoms, signs, blood markers, disabilities and diseases. The index is expressed as ratio of the deficits present divided by the total number of deficits considered. Construction of the FI followed a standard procedure (Searle et al., 2008). A detailed description of the FI used in this analysis has recently been reported elsewhere (Saum et al., 2014). Briefly, 34 out of 50 potential variables from the participants' baseline questionnaire were included in the FI which cover diseases, general health, difficulties in activities of daily living (ADL), and symptoms (see Appendix A, Supplementary Table A.1). We excluded 16 variables, as they were not related to age, or their related health problem or disability was already covered by other variables. All variables were self-reported. Variables were included either as binary, three-level or five-level categorical variables (see Appendix A, Supplementary Table A.1). We recoded all variables using the convention that ‘0’ indicates the absence of a deficit, and ‘1’ indicates the (full) presence of a deficit. For scaled variables we used additional intermediate values. We validated the FI by conducting bivariate and multivariate Cox regression analyses with the FI as predictor variable and age, sex and smoking as covariates. The FI was significantly related to a 10-year mortality in both analyses (Saum et al., 2014). 2.3. Telomere Measurement 2.3.1. Quantitative PCR Method DNA concentration was quantified using PicoGreen®. Subsequent standardizations of concentrations were performed to ensure accurate and uniform DNA concentrations. Relative telomere lengths (RTL) were measured by quantitative PCR (qPCR) (Cawthon, 2002). This

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method assesses the ratio of telomere repeat copy number to number of single copy gene (T/S ratio) in experimental samples relative to a reference sample. T/S ratio is proportional to average TL as amplification is proportional to the number of primer binding sites in the first cycle of the PCR reaction (Cawthon, 2002). The formula used to calculate T/S is presented in Appendix A. In this study 36B4 was used as the single copy gene, which is a house-keeping gene on chromosome 12. Two quality-control samples were inserted into each PCR plate in order to assess the coefficients of inter- and intra-plate variability. The inter-assay variability for the telomeres was 4%, and 8% for single copy gene. The coefficients of variations (CV) of two quality-control samples were 7% and 5%. All samples were measured in triplicates and the mean of the three measurements was used. Calculation of RTL was based on comparison of the distinct cycle number determined by threshold values (Ct) at a constant fluorescence level. PCRs were performed on the Lightcycler® 480 (Roche Diagnostics GmbH, Mannheim, Germany). 2.3.2. Southern Blot Telomere restriction fragment length (TRFL) analysis was additionally performed in a sub-sample of our population (N = 20) to validate our results from the qPCR measurements and obtain absolute telomere length in base pairs. Briefly, 3.5 μg of genomic DNA was digested overnight at 37 °C with restriction enzymes HphI and Mnl I (Thermo Scientific GmbH, Schwerte, Germany) and loaded onto 0.7% agarose gel with Diglabeled marker VII (Roche Diagnostics GmbH, Mannheim, Germany). Then, DNA was processed as previously described (Figueroa et al., 2000). Detection of Dig-labeled probe and marker was performed using Anti-Digoxigenin-AP, Fab fragments and CPD Star (Roche Diagnostics GmbH, Mannheim, Germany). Image analysis was done with ImageJ Analysis Software (Version 1.44). For quantification of TRFL values chemiluminescence image exposures were digitized and these data were used for calculating the mean TRFL with TRFL = ∑(ODi * Li) / ∑(ODi) with ODi being the integrated signal intensity at position i, and Li — the length of DNA fragment in position i in the range between 2 and 23 kb.

Table 1 Study sample characteristics by T/S ratio tertiles. Characteristic

1st T/S tertile (n = 1178)

2nd T/S tertile (n = 1188)

3rd T/S tertile (n = 1171)

T/S ratioa (Mean ± SD) Frailty index (mean ± SD) Womena, n (%) Agea (mean ± SD) Married, n (%) BMIb, n (%) Normal range Overweight Obese Smoking, n (%) Never smoker Former smoker Current smoker Alcohol, n (%) Abstainer Low Mid High Physical activity, n (%) Inactive Insufficient Sufficient Education, n (%) ≤9 years 10 to 11 years ≥12 years

0.79 ± 0.12 0.24 ± 0.14 606 (51.4) 62.3 ± 6.6 899 (77.2)

1.07 ± 0.07 0.24 ± 0.14 650 (54.7) 62.4 ± 6.5 922 (78.7)

1.43 ± 0.21 0.23 ± 0.14 707 (60.4) 61.0 ± 6.5 877 (76.1)

293 (24.9) 571 (48.6) 312 (26.5)

339 (28.6) 557 (46.9) 291 (24.5)

340 (29.2) 536 (45.9) 291 (24.9)

526 (45.9) 410 (35.8) 211 (18.4)

588 (51.0) 366 (31.7) 200 (17.3)

568 (49.8) 357 (31.3) 216 (18.9)

332 (30.8) 644 (59.8) 77 (7.2) 24 (2.2)

362 (33.8) 644 (60.2) 51 (4.8) 13 (1.2)

344 (32.2) 655 (61.3) 56 (5.2) 14 (1.3)

224 (19.1) 564 (48.0) 388 (33.0)

255 (21.5) 542 (45.8) 387 (32.7)

235 (20.1) 525 (45.0) 408 (34.9)

849 (73.9) 174 (15.1) 126 (11.0)

874 (75.5) 158 (13.7) 125 (10.8)

829 (72.4) 199 (17.4) 117 (10.2)

Note: 1st tertile cut-point of T/S ratio = 0.94, 2nd tertile cut-point of T/S ratio = 1.19. Mean and standard deviation of the frailty index were derived from 20 imputated data sets. a Kruskal–Wallis test or Chi2 test was statistically significant (P b 0.05). b Normal range (BMI b 25), overweight (25 ≤ BMI b 30), obese (BMI ≥ 30).

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2.4. Statistical Analyses In order to construct the FI for the entire study sample, we employed a multiple imputation procedure to deal with missing values of variables included in the FI. Twenty imputed data sets were created. The maximum number of iterations for imputed values was set to 300. Age, sex, mortality status after 10 years and all selected variables for construction of the FI (Appendix A, Supplementary Table A.1) were included in the imputation model. Scaled variables were dichotomized for each scale level and after multiple imputation the imputed values were rounded to their nearest scale level. All further analyses were performed in the twenty imputed data sets and results of the individual data sets were combined by the SAS procedure PROC MIANALYZE. We used standard descriptive methods to describe demographic characteristics at baseline, stratified by tertiles of the T/S ratio. Differences between the tertiles were analyzed using Kruskal–Wallis test or Chi2 test. To estimate the baseline average slope of the increase of the deficit accumulation with age we plotted the FI versus age stratified for tertiles of T/S ratio, separately for both sexes. The correlation between FI and T/S ratio was analyzed using Spearman correlation coefficients. Correlation

analyses were performed with and without stratification or adjustment by age and sex. An alpha level of 0.05 was used to determine statistical significance. Analyses were performed using SAS, version 9.2 (SAS Institute, Inc., Cary, NC). 3. Results Overall telomere length measurements by the T/S ratio were successful in 3537 of the 3572 subjects and were highly correlated with absolute telomere length measured by Southern blot in the validation sample of 20 participants (r = 0.68, p = 0.002). Sociodemographic characteristics of the study sample stratified by tertiles of the T/S ratio (1st tertile: b0.94; 2nd tertile: 0.94–1.19; 3rd tertile: N 1.19) are described in Table 1. The 3537 subjects with valid T/S measurements were on average 61.9 ± 6.6 years old and 55.5% of them were women. The mean T/S ratio increased from 0.79 in the 1st tertile to 1.43 in the 3rd tertile. The gender distribution differed in T/S ratio tertiles with a higher proportion of women in the 3rd tertile than in the other tertiles (p b .005). The distribution of other sociodemographic or life style variables (BMI, smoking status, alcohol consumption, physical activity,

T/S ratio 1st Tertile 2nd Tertile 3rd Tertile

T/S ratio 1st Tertile 2nd Tertile 3rd Tertile

Fig. 1. Average frailty index according to age and T/S ratio tertiles. Panel A: Women. Panel B: Men.

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marital status, education) were not statistically different between the T/S ratio tertiles. No statistically significant difference of the FI between the T/S ratio tertiles was observed (1st tertile: 0.24 ± 0.14; 2nd tertile: 0.24 ± 0.14; 3rd tertile: 0.23 ± 0.14). However, the FI increased with age in all T/S ratio tertiles (Fig. 1). Correlation coefficients very close to zero were found between FI and T/S ratio in both women and men (Fig. 2), and in all 5-year age groups (even though some of the correlations were statistically significant due to the very large sample size) (Fig. 3).

4. Discussion 4.1. Main Findings To our knowledge, this is the first study to assess the correlation between telomere length and frailty in a Western population with a relatively broad age range. In this large cross-sectional study telomere

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length was inversely related to age but essentially uncorrelated with frailty. In addition, women more often had larger telomeres than men. Our findings of longer telomeres in women than in men and of a decrease of telomere length with age are consistent with previous observations. At birth telomere length in men and women is similar, but by adulthood telomeres are longer in women (Cherif et al., 2003). A less pronounced decrease of telomere length with age among women could be explained by the possible influence of endogenous hormones on telomerase, an enzyme which adds telomeric repeats to the ends of chromosomes (Blackburn and Collins, 2011; Cohen et al., 2007; Holt et al., 1996; Kelland, 2005). It has been suggested that estrogens protect telomeres against oxidative stress, which has been related to telomere shortening (Aviv, 2002; Vasa et al., 2000; von Zglinicki, 2012). In our study population women were postmenopausal, and over 60% reported taking hormone therapy at the time of recruitment, hence both endogenous and exogenous hormone supply during the life course might have contributed to the observed sex differences in telomere length. The fact that women were more frail but had longer telomeres compared to men is in line with and complements the results of a recent

Fig. 2. Correlation graph for frailty index and T/S ratio in (A) Women and (B) Men.

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Fig. 3. Correlation graph for frailty index and T/S ratio for overall study sample stratified in 5-year age groups.

study of Woo et al. in a Chinese population (Woo et al., 2008). Taken together, both studies support suggestions that telomere length is not a meaningful biomarker for frailty, neither in Asian nor in Caucasian populations. In the interpretation of our data it should be kept in mind that frailty was measured using the deficit accumulation approach. This approach is a broad summary measure of health status and therefore less specific than e.g. the frailty phenotype by Fried et al. (2001), which mainly focuses on physical functioning and in turn better reflects reduction in muscle strength and muscle mass. Although several studies have hypothesized an association between telomere length and indicators of physical function (e.g. grip strength) in elderly, none of them has found a significant relation between telomeres and physical performance measures (Bekaert et al., 2005; Harris et al., 2006; Mather et al., 2010). However, these studies had relatively small sample sizes and included narrow age ranges. Possible associations between telomere length and frailty phenotype defined by Fried et al. and others have not been analyzed yet and should be addressed in future research.

4.2. Strengths and Limitations There are several strengths and limitations of our study. The main strengths of the study lie in the large sample size for both men and women from a general population sample of non-institutionalized older adults, for whom a detailed assessment of the FI was available.

The telomere measurements were validated using Southern blot, and results from the two methods were highly correlated (r = 0.68), with correlation coefficients comparable to those reported by other studies (Brouilette et al., 2007; Cawthon, 2002; Willeit et al., 2010). The remaining disagreement between both methods can be explained by measurement errors of both measurement types. Additionally, TL measured using Southern blot includes the subtelomeric regions as well, and hence does not provide the actual length of telomeres (Lin and Yan, 2005; Saldanha et al., 2003). For this analysis, we used single TL measurements rather than serial TL measurements over time for each individual; therefore, we could not examine intra-individual TL variability. Variables of the FI relied on selfreports and are therefore subject to potential recall or reporting bias.

4.3. Conclusion In summary, this cross-sectional analysis from a large populationbased study in a Western population did not find any relevant correlations between relative TL measured by the T/S ratio and frailty measured by a deficit accumulation approach, neither overall nor in different subgroups defined by sex and age. Even though both TL and frailty have been shown to be associated with age and age-related diseases, our findings suggest that TL is not a meaningful biological marker of frailty. However, existing evidence is limited by exclusive measurement of frailty by the FI and by the cross-sectional nature of only two studies that reported

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on the correlation between TL and frailty to date. Future studies should investigate this relationship in a longitudinal manner, with measurements of TL and frailty at multiple time points, and by using alternative, more specific measures of frailty, such as the Fried frailty index. Acknowledgment This work was supported in part by the Baden-Württemberg State Ministry of Science, Research and Arts; by the German Federal Ministry of Education and Research (grant number 01ET0717); and by the CHANCES project funded in the Seventh Framework Programme of the Directorate-General for Research and Innovation in the European Commission (grant number 242244). PB is funded by the German Federal Ministry of Education and Research-GerontoSys-Stromal Aging (031.5576B). The funding sources had no role in design, methods, subject recruitment, data collection, statistical analysis and preparation of the paper. The authors declare that they have no conflict of interest. Appendix A. Supplementary data Supplementary data to this article can be found online at http://dx. doi.org/10.1016/j.exger.2014.08.009. References Aviv, A., 2002. Telomeres, sex, reactive oxygen species, and human cardiovascular aging. J. Mol. Med. (Berl.) 80, 689–695. Bakaysa, S.L., Mucci, L.A., Slagboom, P.E., et al., 2007. Telomere length predicts survival independent of genetic influences. Aging Cell 6 (6), 769–774. Ballon, G., Ometto, L., Righetti, E., et al., 2001. Human immunodeficiency virus type 1 modulates telomerase activity in peripheral blood lymphocytes. J. Infect. Dis. 183, 417–424. Bekaert, S., Van Pottelbergh, I., De Meyer, T., et al., 2005. Telomere length versus hormonal and bone mineral status in healthy elderly men. Mech. Ageing Dev. 126, 1115–1122. Bekaert, S., De Meyer, T., Rietzschel, E.R., et al., 2007. Telomere length and cardiovascular risk factors in a middle-aged population free of overt cardiovascular disease. Aging Cell 6, 639–647. Bergman, H., Ferrucci, L., Guralnik, J., et al., 2007. Frailty: an emerging research and clinical paradigm—issues and controversies. J. Gerontol. A Biol. Sci. Med. Sci. 62, 731–737. Blackburn, E.H., Collins, K., 2011. Telomerase: an RNP enzyme synthesizes DNA. Cold Spring Harb. Perspect. Biol. 3. Brouilette, S.W., Moore, J.S., McMahon, A.D., et al., 2007. Telomere length, risk of coronary heart disease, and statin treatment in the West of Scotland Primary Prevention Study: a nested case–control study. Lancet 369, 107–114. Butt, H.Z., Atturu, G., London, N.J., Sayers, R.D., Bown, M.J., 2010. Telomere length dynamics in vascular disease: a review. Eur. J. Vasc. Endovasc. Surg. 40, 17–26. Cawthon, R.M., 2002. Telomere measurement by quantitative PCR. Nucleic Acids Res. 30, e47. Cawthon, R.M., Smith, K.R., O'Brien, E., Sivatchenko, A., Kerber, R.A., 2003. Association between telomere length in blood and mortality in people aged 60 years or older. Lancet 361, 393–395. Cesari, M., Penninx, B.W., Pahor, M., et al., 2004. Inflammatory markers and physical performance in older persons: the InCHIANTI study. J. Gerontol. A Biol. Sci. Med. Sci. 59, 242–248. Charames, G.S., Bapat, B., 2003. Genomic instability and cancer. Curr. Mol. Med. 3, 589–596. Cherif, H., Tarry, J.L., Ozanne, S.E., Hales, C.N., 2003. Ageing and telomeres: a study into organ- and gender-specific telomere shortening. Nucleic Acids Res. 31, 1576–1583. Cohen, H.J., Harris, T., Pieper, C.F., 2003. Coagulation and activation of inflammatory pathways in the development of functional decline and mortality in the elderly. Am. J. Med. 114, 180–187.

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Frailty and telomere length: cross-sectional analysis in 3537 older adults from the ESTHER cohort.

Both telomere length and frailty were observed to be associated with aging. Whether and to what extent telomere length is related to frailty is essent...
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