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Biological Clocks and Physical Functioning in Monozygotic Female Twins Elina Sillanpää1,2* , Eija K

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Biological Clocks and Physical Functioning in Monozygotic Female Twins Elina Sillanpää1,2* , Eija K Sillanpää et al. BMC Geriatrics (2018) 18:83 https://doi.org/10.1186/s12877-018-0775-6 RESEARCH ARTICLE Open Access Biological clocks and physical functioning in monozygotic female twins Elina Sillanpää1,2* , Eija K. Laakkonen1, Elina Vaara3, Taina Rantanen1, Vuokko Kovanen1, Sarianna Sipilä1, Jaakko Kaprio2,4 and Miina Ollikainen2,4 Abstract Background: Biomarkers of biological aging – DNA methylation age (DNAm age) and leukocyte telomere length (LTL)– correlate strongly with chronological age across the life course. It is, however, unclear how these measures of cellular wear and tear are associated with muscle strength and functional capacity, which are known to decline with older age and are associated with mortality. We investigated if DNAm age and LTL were associated with body composition and physical functioning by examining 48 monozygotic twin sisters. Methods: White blood cell DNAm age (predicted years) was calculated from Illumina 450 k BeadChip methylation data using an online calculator. DNAm age acceleration was defined from the residuals derived from a linear regression model of DNAm age on chronological age. LTL was measured by qPCR. Total body percentage of fat and lean mass were estimated using bioimpedance. Physical functioning was measured by grip strength, knee extension strength and by 10 m maximal walking speed test. Results: In all participants, DNAm age (58.4 ± 6.6) was lower than chronological age (61.3 ± 5.9 years). Pairwise correlations of monozygotic co-twins were high for DNAm age (0.88, 95% CI 0.79, 0.97), age acceleration (0.68, 95% CI 0.30, 0.85) and LTL (0.77, 95% CI 0.60, 0.94). Increased age acceleration i.e. faster epigenetic aging compared to chronological age was associated with lower grip strength (β = − 5.3 SE 1.9 p = 0.011), but not with other measures of physical functioning or body composition. LTL was not associated with body composition or physical functioning. Conclusions: To conclude, accelerated DNAm age is associated with lower grip strength, a biomarker known to be associated with physiological aging, and which predicts decline in physical functioning and mortality. Further studies may clarify whether epigenetic aging explains the decline in muscle strength with aging or whether DNAm age just illustrates the progress of aging. Keywords: Epigenetic clock, Telomeres, Methylation, Twin design, Post-menopausal, Physical function Background measured characteristics and exposure. Biological clocks Many theories have emerged to explain the processes or may increase our understanding on human aging [2]. mechanisms driving aging. It is well known that aging DNA methylation (DNAm) age [3] and telomere length and especially longevity has a genetic component [1], [4] are timely and interesting biological clocks, which and some environmental factors such as infections, diet, may provide insights into the mechanisms behind why alcohol use, smoking and work exposures predispose to some individuals age faster than others and are more age-related diseases and increase probability of death. prone to age-related diseases and accelerated decline in However, only a small fraction of individual variation to physical functioning (Fig. 1). life expectancy can be accounted for using known and Epigenetic changes affect the function of DNA without altering the genetic code itself. Epigenetic regulation * Correspondence: [email protected] modifies the function of genetic information by control- 1Gerontology Research Center, Faculty of Sport and Health Sciences, ling when specific genes are switched on or off, for ex- University of Jyväskylä, P.O. Box 35 (VIV), FIN-40014 Jyväskylä, Finland 2Institute for Molecular Medicine Finland (FIMM), University of Helsinki, ample during development or aging. DNAm is one type Helsinki, Finland of epigenetic modification, which changes over time. Full list of author information is available at the end of the article © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Sillanpää et al. BMC Geriatrics (2018) 18:83 Page 2 of 7 up till old age, while others suffer from accelerated decline during aging. The purpose of the present study was to in- vestigate if novel biological clocks (DNAm age and LTL) can explain interindividual variation in body composition and physical functioning in 54 to 72 year-old women. Methods Participants and study design The participants originate from two studies: 1) “Sarcopenia - Skeletal Muscle Adaptation to Postmenopausal Hypogonad- ism and Effects of Hormone Replacement Therapy and Physical Activity in Older Women: a Genetic and Molecular Biological Study on Estrogen-related Pathways” (SAWEs, n =15pairs)andtheFinnishTwinStudyon Aging (FITSA, n = 9 pairs). Participants of both these Fig. 1 Association between grip strength and DNA methylation age acceleration in the total group of subjects (n = 48) studies were recruited from the Older Finnish Twin Cohort [14, 15] and the recruitment process has been described in detail elsewhere [16, 17]. Briefly, SAWEs The most promising estimate for biological age devel- twins were recruited for laboratory visit based on oped from DNAm data is Steve Horvath’s DNAm age, discordance for long term hormone replacement ther- also known as “Epigenetic clock” [3]. DNAm age is an apy (HRT), while FITSA participants participated on age estimate based on DNA methylation at 353 specific laboratory visit within study investigating the role of CpG sites. DNAm age increases over chronological age, genetic and environmental factors in the disablement but it is not yet clear if it is only a marker of biological process in old age and HRT discordant pairs were se- aging or has an effect on aging per se [3]. lected from larger population afterwards. Altogether Telomeres are short DNA sequences located at the 24 monozygotic Caucasian twin pairs discordant for end of the eukaryotic chromosomes protecting func- long term HRT were investigated. HRT users and tional DNA. In most somatic cells, such as in leukocytes, their co-twins did not differ in regards to biological telomerase activity is low and telomeres shorten with clocks, body composition or physical functioning every cell cycle. This is due to the inability of DNA poly- (Additional file 1: Table S1). Twins were similar in merase to fully replicate chromosome ends leading to their physical activity habits, daily energy intake, use replicative senescence and apoptosis [5]. Oxidative stress of medication, and smoking behavior [17, 18]. enhances telomere erosion with cell replication [6], whereas inflammation entails an increase turnover of DNA methylation age and age acceleration leucocytes [7]. Telomere length can be used as an indi- High molecular weight white blood cell DNA was ex- cator of cells replicative history and regenerative poten- tracted using QIAamp DNA Mini Kit (QIAGEN, Nordic, tial and, therefore, it might serve as an indicator of Sollentuna, Sweden). Bisulfite conversion of DNA was biological age [8]. completed using EZ-96 DNA methylation-Gold Kit Both DNAm age and telomere length are highly herit- (Zymo Research, Irvine, CA, USA) according to the able [3, 9]. Few studies done so far have suggested that manufacturer’s instructions, and the co-twins were al- these biological age estimates are uncorrelated and ways converted on the same plate to minimize potential therefore appear to be tagging different aspects of the batch effects. Genome-wide DNAm was measured using aging process [2]. Faster running clock i.e. shorter telo- Illumina’s Infinium HumanMethylation450 BeadChip ac- meres or higher DNAm age compared to chronological cording to the manufacturer’s instructions. The Illumina age are associated with declining physical function with BeadChips measure single-CpG resolution DNAm levels aging [10–12], and predict higher mortality risk [2, 13]. at 485577 CpG sites across the human genome. DNAm Of several age-related physiological changes, decline in age was calculated from 353 specific CpG-sites known muscle mass and strength are the most important factors to be associated with aging based on their methylation in regards to physical functioning and quality of life. using validated algorithm and online tool [3]. Age accel- Muscle strength loss with aging together with adverse eration, which describes the difference between chrono- changes in body composition predispose to several age- logical age and DNAm age (“faster or slower biological related diseases and to decline in physical functioning, aging”) was calculated for all subjects as the residuals mobility and loss of independence. However, muscle from a linear regression model of DNAm age on strength and mass are well-preserved in some individuals chronological age. Sillanpää et al. BMC Geriatrics (2018) 18:83 Page 3 of 7 Telomere length measurements into account using the cluster option in the analyses. HRT Quantitative real-time polymerase chain reaction (qPCR) was also considered as a potential confounder, but it had based method was used determine
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