Original Article

International Journal of Obesity (2016) 40, 773–778; doi:10.1038/ijo.2015.238; published online 22 December 2015

Integrative Biology

Telomere length increase after weight loss induced by bariatric surgery: results from a 10 year prospective study

M Laimer1,2,6, A Melmer1,6, C Lamina3, J Raschenberger3, P Adamovski1, J Engl1, C Ress1, A Tschoner1, C Gelsinger1, L Mair1, S Kiechl4, J Willeit4, P Willeit5, C Stettler2, H Tilg1, F Kronenberg5 and C Ebenbichler1

  1. 1Department of Internal Medicine I, Medical University of Innsbruck, Innsbruck, Austria
  2. 2Division of Endocrinology, Diabetes and Clinical Nutrition, University Hospital Bern, Bern, Switzerland
  3. 3Department of Medical Genetics, Molecular and Clinical Pharmacology, Division of Genetic Epidemiology, Medical University of Innsbruck, Innsbruck, Austria
  4. 4Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria
  5. 5Department of Public Health and Primary Care, School of Clinical Medicine, University of Cambridge, Cambridge, UK

Correspondence: Dr M Laimer, Department of Internal Medicine I, University Hospital Innsbruck, Medical University of Innsbruck, Anichstraße 35, Innsbruck 6020, Austria. E-mail: markus.laimer@me.com

6These authors contributed equally to this work.

Received 17 February 2015; Revised 22 October 2015; Accepted 1 November 2015
Accepted article preview online 26 November 2015; Advance online publication 22 December 2015

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Abstract

Background/Objectives:

 

Obesity contributes to telomere attrition. Studies focusing on short-term effects of weight loss have been unable to identify protection of telomere length. This study investigates long-term effects of pronounced weight loss induced by bariatric surgery on telomere length.

Subjects/Methods:

 

One hundred forty-two patients were recruited in a prospective, controlled intervention study, follow-up investigations were done after 10.46±1.48 years. A control group of normal weight participants was recruited and followed from 1995 to 2005 in the Bruneck Study. A total of 110 participants from each study was matched by age and sex to compare changes in telomere length. Quantitative PCR was used to determine telomere length.

Results:

 

Telomere length increased significantly by 0.024±0.14 (P=0.047) in 142 bariatric patients within 10 years after surgery. The increase was different from telomere attrition in an age- and sex-matched cohort population of the Bruneck Study (−0.057±0.18; β=0.08; P=0.003). Significant changes in telomere length disappeared after adjusting for baseline body mass index (BMI) because of general differences in BMI and telomere length between the two study populations (β=0.07; P=0.06). Age was proportional to telomere length in matched bariatric patients (r=0.188; P=0.049) but inversely correlated with telomere length in participants of the Bruneck Study (r=−0.197; P=0.039). There was no association between percent BMI/excess weight loss and telomere attrition in bariatric patients. Baseline telomere length in bariatric patients was inversely associated with baseline plasma cholesterol and triglyceride concentrations. Telomere shortening was associated with lower high-density lipoprotein cholesterol and higher fasting glucose concentration at baseline in bariatric patients.

Conclusions:

 

Increases in relative telomere length were found after bariatric surgery in the long term, presumably due to amelioration of metabolic traits. This may overrule the influence of age and baseline telomere length and facilitate telomere protection in patients experiencing pronounced weight loss.

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Introduction

Telomere length is considered to be a surrogate marker of biological aging. Short telomeres are associated with obesity-related co-morbidities including diabetes mellitus, hypertension, cardiovascular disease and cancer.1, 2 Telomeres provide a number of specific functions, including stabilization of the chromosome, prevention of aberrant recombination and protection against end-degrading enzymes.3 Telomere length decreases during cell division, leading to shorter telomeres with increasing age.4, 5, 6 When telomere length reaches a critically low threshold in one or more chromosomes, the cell is signaled to stop replication with eventual apoptosis.7

Lee et al. found an inverse association between telomere length and body mass index (BMI) in a cross-sectional study in 309 study participants. These effects were independent of sex, age, fasting glucose, serum insulin, blood lipid and lipoprotein concentrations, habitual physical activity, smoking status and other cardiometabolic risk factors.8 A population-based cohort study conducted by Njajou et al. suggested that shorter telomere length is a risk factor for increased adiposity.9 A recent meta-analysis of cross-sectional and longitudinal studies performed by Muezzinler et al. reported an inverse relationship of BMI to telomere length in a majority but not all of the cross-sectional studies.10 Moreover, the authors reported considerable limitations regarding data from longitudinal studies that investigate BMI and telomere length.

Although numerous beneficial effects accompany weight loss, studies focused on either short-term effects of weight loss due to bariatric surgery or long-term effects of lifestyle intervention, have been unable to identify changes in telomere length.11, 12 The aim of this prospective study was to investigate long-term effects of pronounced and sustained weight loss induced by bariatric surgery on telomere length compared with the natural changes in a normal weight control group from the general population.

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Patients and methods

The department of surgery determined eligibility for surgical intervention for the treatment of obesity. A total of 142 patients (121 women and 21 men) with a BMI >35kgm2 and at least one obesity-related co-morbidity or a BMI>40kgm2 were examined within a 2-months period pre-operatively and 10 years after bariatric surgery. All bariatric patients were Caucasian and originated from the region of North Tyrol, Western Austria.

Exclusion criteria at baseline were diabetes mellitus, uncontrolled hypertension, a history of cardiovascular disease, secondary cause of obesity, pregnancy, medication influencing coagulation, lipid-lowering or antipsychotic medication and alcohol consumption of more than 20-g alcohol per day. Acute infectious disease and inflammation was excluded by medical history, physical and laboratory examinations. Written informed consent was obtained from all patients.

Participants (BMI 25.51±3.95) from the Bruneck Study served as controls. The Bruneck Study is a prospective, population-based study without specific exclusion criteria that aims to investigate the epidemiology and pathogenesis of atherosclerosis and related traits.13 Participants from the Bruneck Study inhabit the eponymous city in South Tyrol, an area very similar to North Tyrol according to socio-economic status, food availability, epidemiology and lifestyle-options. At study baseline in 1990, a random sample of 1000 subjects was recruited from the entire population of Bruneck. Stratified according to sex and age, 125 subjects of each sex for each decade of age between 40 and 79 (mean 58±11) years were invited to participate. Follow-up examinations were performed every 5 years.

After exclusion of 32 bariatric patients who could not have been matched to participants of the Bruneck Study because of age differences, 110 participants from each study were successfully matched by age and sex (93 women and 17 men). EDTA blood samples were taken after fasting and abstaining from smoking for at least 12h. After centrifugation, plasma was stored at −70°C.

Surgical procedure

The surgical procedures were performed at the Department of Thoracic and Transplant Surgery, Innsbruck Medical University, as described previously.14 Bariatric surgical intervention was performed in 142 patients between 1998 and 2004. In brief, 128 patients received Swedish adjustable Gastric Banding and 14 patients received Roux-Y-Gastric bypass.

Anthropometric measures

Body height was measured to the nearest 0.1cm and body weight was measured to the nearest 0.1kg using an electronic scale. BMI was calculated by dividing body weight by body height in m2. Excess weight loss was defined as: (difference in BMI between baseline and follow-up) divided by ((BMI at baseline-25) in percent).

Measurements of fasting blood lipids included total cholesterol, high-density lipoprotein cholesterol (HDL-C) and triglycerides (TG). Total cholesterol, HDL-C and TG were quantified using a commercially available enzymatic kit (Roche Diagnostic Systems, Basel, Switzerland) on a Hitachi 902 auto-analyzer (Roche Diagnostic Systems). Low-density lipoprotein cholesterol was calculated according to the Friedewald formula.15 Fasting glucose was determined using an automated analyzer within the central clinical laboratory at the University Hospital Innsbruck.

Measurement of relative telomere length

In the bariatric patients’ cohort, DNA was isolated using Qiagen EZ1 DNA Blood 350μl Kit (Qiagen Instruments, Hilden, Germany), whereas in the Bruneck study the INVISORB Blood Universal Kit (Stratec Biomedical, Beringen, Switzerland) was used. In both samples, telomere length was determined using quantitative PCR assay for measuring signals of a telomere (T) and a reference single-copy gene (S) in singleplex reactions. The calculated T/S ratios are proportional to individual relative telomere length. Relative quantities of the target and reference genes were determined using the efficiency correction method.16 This method calculates the relative expression ratio from the real-time PCR efficiencies and the crossing point deviation of an unknown sample versus a control. Relative telomere length was then determined as the ratio between the corrected efficiency of the T in comparison with a single-copy reference gene (S=36B4). The reference gene 36B4 has been validated as being suitable for this method in previous studies.17, 18 Two aspects render this model beneficial: first, no calibration curve is needed, and secondly, control levels are included in the model to standardize each reaction run with respect to DNA integrity, sample loading and inter-PCR variations.18, 19 All samples were run in quadruplicates. The mean of the intra-assay correlation of variability of the threshold cycle-values for the telomere was 0.39 and 0.23% for the reference single-copy gene. For the inter-assay correlation of variabilitythe same control sample was run on each plate. The correlation of variability of the T/S ratio between the plates was 6.2%.

Statistical analyses

A priori power calculations determined a minimum of 44 subjects to sufficiently identify a difference of 0.1 in relative telomere length, based on a two-tailed α-error of 5%, a power of 90% and an s.d. of 0.15 in telomere length after the intervention.

Our study included 142 subjects from whom genomic DNA samples were available at baseline and 10 years after bariatric surgery. The dependent Student's t-test for paired samples was used to compare relative telomere length, anthropometric and metabolic parameters before and after surgery. For non-normally distributed parameters, the paired Wilcoxon test was used. The partial Spearman rank correlation coefficient (r), adjusted for age, was calculated to identify correlations between baseline telomere length as well as between differences in relative telomere length and longitudinal changes in anthropometric or metabolic parameters. Differences in relative telomere length cannot be correlated with baseline values readily without accounting for mathematical coupling or regression to the mean.19 In this analysis, Oldham’s method was used to evaluate whether higher baseline values lead to higher attrition, which tests the correlation between the average of baseline and follow-up values of with the difference in relative telomere length.

Bariatric patients were matched with subjects in the general population of the Bruneck Study. Matching criteria were age and sex. Differences in relative telomere length over 10 years between the matched bariatric patients group (n=110) and the matched participants from the Bruneck Study (n=110) were compared using a linear regression model with change in relative telomere length as the outcome variable. In a second step, the model was adjusted for age, sex and baseline BMI.

All analyses were performed using IBM SPSS 21 (IBM, Armonk, New York, NY, USA) or R 3.0.1. Package 'optmatch' version 09-1 was used for matching37 (R Development Core Team, R Foundation, Vienna, Austria; Hansen and Klopfer). A P-value of <0.05 was considered statistically significant.

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Results

Baseline and follow-up characteristics and differences in relative telomere length, anthropometric and metabolic parameters are shown in Table 1 for the bariatric surgery study and Table 2 for the Bruneck Study. Correlations between baseline relative telomere length, relative telomere attrition, anthropometric and metabolic parameters are shown in Table 3. Figure 1 illustrates matching between bariatric surgery patients and participants of the Bruneck Study.

Figure 1.
Figure 1 - Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, please contact help@nature.com or the author

Description of the matching of bariatric patients with participants from the general population over an investigation/observation period of 10 years. Gray bars indicate the number of measures at a specific telomere length, red line indicates either gain or loss in telomere length after an investigation/observation period of 10 years. Abbreviation: RTL, relative telomere length.

Full figure and legend (77K)




Telomere length

During 10 years of pronounced and sustained weight loss, relative telomere length increased by 0.024±0.14 (P=0.047) in bariatric patients (aged 29–79 years). Telomere length increased significantly in female (0.023±0.14; P=0.044; n=121) but not in male patients (0.025±0.13; P=0.454; n=21; see Table 1). Baseline telomere length did not differ significantly between female and male patients (P=0.415). Baseline relative telomere length was significantly associated with baseline cholesterol (r=−0.194; P=0.043) and TG (r=−0.248; P=0.013). The increase in telomere length was negatively correlated with baseline glucose concentration (r=−0.277; P=0.005) and positively with HDL-C (r=0.256; P=0.006; see Table 3). There was no correlation between the average of baseline and follow-up relative telomere length values and the difference (Spearman r=−0.04, P=0.64), which corresponds to Oldham’s method to test, if the telomere attrition depends on the baseline values.

Matched cohort

In total, 110 bariatric patients and 110 participants of the Bruneck Study were matched for age (aged 45–79 years) and sex (93 women and 17 men). In the Bruneck Study cohort, relative telomere length shortened by −0.057±0.18 (P=0.001) over a follow-up period of 10 years, while in the matched subsample of the bariatric patients, relative telomere length increased by 0.0229±0.15 (P=0.103; see Figure 1). In the matched Bruneck Study cohort, telomere length decreased significantly in female (−0.049±0.19; P=0.004; n=93) and male participants (−0.101±0.13; P=0.019; n=17; see Table 2). Baseline telomere length differed significantly between sex categories with women having longer telomeres compared with men (P=0.016). Both groups were compared using linear regression on relative telomere length increase. The unadjusted model revealed that bariatric patients had a higher increase of relative telomere length compared with participants of the Bruneck Study (β=0.08; P=0.003). This result did not change when the model was adjusted for age and sex (β=0.08; P=0.003). Additional adjustment for BMI did not change the effect estimate; however, the model was not significant anymore (β=0.07; P=0.06). Age correlated inversely to telomere length in the matched Bruneck Study cohort (r=−0.197; P=0.039) but proportional to telomere length in bariatric patients (r=0.188; P=0.049). Increases in relative telomere length was found in 86 patients in the total bariatric cohort (0.11±1.00), 60 bariatric patients from the matched cohort (0.12±0.11) and in 39 matched participants of the Bruneck Study (0.12±0.10).

Anthropometric parameters

Mean body weight loss during 10 years after bariatric surgery was 24.65±22.57kg (P<0.001). Mean BMI decreased by 8.75±7.97kgm2 (P<0.001). Fasting glucose concentrations (−5.19±24.83mgdl1; P<0.001), HDL-C (mean increase 11.35±15.83mgdl1; P<0.001) and TG (−33.84±113.65mgdl1; P<0.001) significantly changed within 10 years after bariatric surgery.

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Discussion

Relative telomere length increased after 10 years of bariatric surgery. In comparison, we found significant telomere attrition in a reference population matched on sex and age.

An inverse relationship between BMI, systemic inflammation and telomere length was found in a recent investigation.20 An earlier study showed that intensive lifestyle intervention was capable of restoring relative telomere length in overweight and obese adolescents within a follow-up period of 2 months.21 Increases in relative telomere length were also documented in previous studies after follow-up periods of several years.22, 23 Summarizing the effects of numerous influencing factors, telomere length most likely appears to oscillate in length, levelling out over time.24 To identify a major trend for changes in telomere length and to measure the net effect of a long-term intervention like bariatric surgery, a considerable follow-up period is crucial to overcome oscillating variations in relative telomere length.

Baseline telomere length is a widely accepted determinant of telomere attrition corresponding to results of numerous, previous studies.21, 22, 25 Data of the present study revealed a significant correlation (r=−0.422; P<0.001) between baseline and difference in telomere length following a simple correlation analysis, thereby corresponding to the hypothesis that telomere maintenance is more active at shorter telomeres.21, 25 Nevertheless, such simple analysis may not overcome a possible regression to the mean effect, which—in the present study—reveals the correlation between shorter baseline TL and TL elongation to be a mathematical artifact. Regression to the mean can frequently be observed when measurements are performed in the same subject repeatedly. Relatively high and low observations are likely to be followed by less extreme measurements, which is caused by a non-systematic variation (that is, random error) in observed values, deriving from, for example, random measurement error or fluctuations in a subject. Statistically, meeting the assumption that variances of baseline (x) and follow-up (y) telomere length are the same, the correlation between x and xy will always be positive. Oldham method tries to overcome this effect by testing the correlation between the difference and the mean of baseline and follow-up measurements. For detailed statistical explanations, please refer to the articles of Tu et al.26 and Barnett et al.27 Following this controlled approach, there was no significant association between baseline telomere length and telomere elongation in the present study.

A previous study by Nordfjall et al. illustrated that baseline telomere length accounts for ~57% of telomere attrition. The remaining variation may be due to epigenetic and other unidentified influencing factors.25 Previous studies revealed a connection between active smoking, features of the metabolic syndrome and telomere attrition.28, 29 Another study identified a measurable influence of vascular dysfunction and oxidative stress on relative telomere length in patients diagnosed with the metabolic syndrome. It was found that markers of oxidative stress were pronounced in patients with shorter telomeres.30 These findings are reproduced by results of the present study, as baseline telomere length was shorter in patients with higher cholesterol and TG. The increase in relative telomere length correlated to baseline concentrations of fasting plasma glucose and HDL-C. Patients were more likely to experience an increase in relative telomere length if, for instance, they had higher HDL-C values at baseline. Presumably, metabolically healthier patients were also more likely to experience a stronger absolute amelioration of metabolic traits after surgery, in turn facilitating increases in relative telomere length. However, mean differences in HDL-C or fasting plasma glucose did not correlate to changes in relative telomere length, which limits the significance of the present results. This may be caused by the relatively small sample size of bariatric patients. As some metabolic parameters changed in both directions, a small sample size may reduce statistical power and distort correlations between changes in telomere length and metabolic parameters. In conclusion, we hypothesize that the effect of metabolic traits related to obesity may be a possible determining factor for telomere elongation patients undergoing bariatric surgery, which is was shown in studies performed by Huzen et al.28 and Zhao et al.29

The missing correlation between baseline telomere length and its elongation may arise from the variations in metabolic traits at follow-up, which are present by some but not all bariatric patients.

We found a significant, proportional association between age and telomere length in bariatric patients and an inverse relationship in the general population cohort. Telomere length is a proposed marker of biological aging, and several cross-sectional and epidemiological studies support this hypothesis.31, 32, 33 This hypothesis corresponds to our findings. Telomere length of both cohorts was associated with age. In the Bruneck Study cohort, age and telomere length were inversely correlated, while it was correlated proportionally in bariatric patients over 10 years. In a recent study by Garcia-Calzon et al., telomere length was independent of age. Thus, the study was performed in adolescent subjects with a follow-up period of 6 month, whereas age-related changes in telomere length were not expected.21 Several other studies illustrated an inverse relationship between age and telomere length.12, 18, 28 One possible explanation for the adverse effect of age on telomere length between both cohorts is the amelioration of metabolic traits in bariatric patients. Amelioration of obesity-related traits induced by weight loss due to bariatric surgery was found to sustain over 25 years, as results from the Program on the Surgical Control of the Hyperlipidemias trial illustrate.34 A recent study by Huzen et al.28 illustrates that telomere length depended inversely on features of the metabolic syndrome, namely waist–hip ratio, blood glucose level and HDL-C. We found a significant correlation between fasting plasma glucose, HDL-C and the difference in telomere length. Even though one would expect a significant reduction of telomere length within 10 years, bariatric intervention and its associated amelioration of metabolic traits in some but not all patients may have overruled factors promoting telomere attrition, including age. When including the whole cohort of bariatric patients (n=142) in the analysis, the correlation between age and telomere length vanished (r=0.068, P=0.421). This finding may derive from the greater variation in metabolic disturbances compared with the age and sex-matched bariatric cohort. Another population-based study reported an inverse correlation between baseline and follow-up telomere length within 6 months, which vanished over time period of 10 years.24 Although this study did not report on metabolic features of the individuals, it can be presumed that several factors including the metabolic profile may overrule the effect of ageing on telomere length.

Changes in BMI were not correlated with baseline or difference in telomere length. This is in contrast to several former studies that illustrated an inverse relationship between telomere length and BMI. Weight loss has been shown to significantly diminish metabolic traits and to increase telomere length, although with a considerable delay of ~5 post-operative years.35 Nevertheless, the impact of body weight on telomere attrition is not clarified. A recent meta-analysis by Muezzinler et al. is consistent with the hypothesis that increased body weight accelerates telomere shortening, whereas there are still studies illustrating associations in opposite directions. Muezzinler et al. conclude that on the one hand increased body weight most likely promotes telomere attrition, but on the other hand heterogeneity of and the small number in relevant studies limits the understanding of adiposity in telomere dynamics. Another population-based study reported that body weight was associated with telomere length cross-sectional but not with telomere attrition over 10 years.12 Comparing these results with our study, it is noteworthy that BMI did not associate with baseline telomere length. Nevertheless, as we included patients with BMIgreater than or equal to35kgm2, the effect of obesity on telomere length may be capped, leaving the rest of variation to other factors including metabolic traits.

Actual weight loss itself seems less important than the metabolic amelioration after bariatric surgery. In the long-term, bariatric patients benefit from weight loss facilitating telomere length protective mechanisms, which are then able to maintain or even restore telomere length.

After adjustment for baseline BMI, significant differences in telomere length between bariatric patients and participants of the Bruneck Study vanished. Adjusting for BMI is a crucial approach in prospective studies on telomere length, as can be read above. Nevertheless, as the range of BMI hardly overlaps between bariatric patients and participants of the Bruneck Study, BMI is the critical parameter that defines the case and control cohort. It is, in our opinion, inexpedient to adjust for BMI in the present case–control study, as this approach removes the crucial distinction between bariatric patients and participants of the Bruneck Study. It was furthermore not possible to match the control group by BMI, since the Bruneck Study is a population-based sample cohort with a minority of participants with BMIgreater than or equal to35kgm2 (three out of the 110 matched participants). Therefore, it cannot be ruled out that difference in telomere length changes result from differences in baseline BMI and/or baseline telomere length.

The present study has several limitations: the recruitment of a sufficient control cohort is desperately needed in prospective studies investigating the effect of bariatric surgery. However, withholding surgery from patients with a medical indication for bariatric intervention for years goes against the ethical standards of the institutional research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. It is notable that baseline telomere length differed between bariatric patients and participants of the Bruneck Study. One possible explanation could be that bariatric patients had higher baseline BMI compared with participants of the Bruneck Study. Nevertheless, we cannot rule out that the DNA isolation method influences relative telomere length measurement, as indicated in a previous study.36 Since we compared differences between baseline and follow-up values within each group based on the same isolation methods, we do not expect a major influence of DNA isolation methods on our conclusions. Also, telomere length attrition presumably differed in both cohorts dependent on baseline relative telomere length but independent of whether participants received bariatric surgery or not. This may have reduced the main effect over time in the comparison of both cohorts. Also, statistical power may be limited due to the small number of patients. Nevertheless, Bruneck participants’ relative telomere length diminished over time, while an increase was measurable in the bariatric cohort.

In conclusion, relative telomere length increased after 10 years of pronounced and sustained weight loss because of bariatric surgery. In contrast, relative telomere length was found to decrease in an age- and sex-matched general population cohort over 10 years. A possible explanation is the amelioration of metabolic traits, which are associated with weight loss and may compensate for the influence of both, age and baseline telomere length on telomere attrition. Because of numerous confounding factors, future prospective intervention studies with both, a considerable sample size and follow-up period are required to identify the main contributors to changes in telomere length after bariatric surgery.

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Conflict of interest

The authors declare no conflict of interest.

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Acknowledgements

This study was supported by the Austrian Science Fund (FWF) ZFP 266730 and by the Austrian Science Fund (FWF) KLI 348. The expert technical assistance of Dr Karin Salzmann is gratefully acknowledged. CL, Department of Medical Genetics, Molecular and Clinical Pharmacology, Division of Genetic Epidemiology, Medical University Innsbruck, Austria, performed the data analysis of the present study. Informed consent was obtained from all individual participants included in the study. All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

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