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Physical activity in midlife and telomere length measured in old age
Experimental Gerontology 48 (2013) 81–84
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Experimental Gerontology journal homepage: www.elsevier.com/locate/expgero
Physical activity in midlife and telomere length measured in old age Salla Savela a,⁎, Outi Saijonmaa b, Timo E. Strandberg c, Pentti Koistinen a, Arto Y. Strandberg d, Reijo S. Tilvis d, Kaisu H. Pitkälä e, Tatu A. Miettinen e, 1, Frej Fyhrquist b a
Oulu City Hospital, Box 77, 90015 City of Oulu, Finland Minerva Institute for Medical Research and University of Helsinki, Box 20, 00014 Helsinki, Finland Institute of Health Sciences/Geriatrics, University of Oulu and University Hospital, Unit of General Practice, Box 5000, 90014 University of Oulu, Finland d Clinics of General Internal Medicine and Geriatrics, Helsinki University Hospital, Box 340, 00290 Helsinki, Finland e Unit of General Practice, Helsinki University Hospital, and Department of General Practice, Helsinki University, Box 20, 00014 Helsinki, Finland b c
a r t i c l e
i n f o
Article history: Received 15 November 2011 Received in revised form 27 January 2012 Accepted 7 February 2012 Available online 22 February 2012 Section Editor: A. Simm Keywords: Physical activity Leukocyte telomere length Proportion of short telomeres Biological aging Midlife activity
a b s t r a c t Physical activity has been associated with alterations in telomere length, a potential indicator of biological aging, but several inconsistencies exist. Our aim was to investigate the associations between physical activity in midlife and leukocyte telomere length (LTL) measured in old age in the Helsinki Businessmen Study, Finland. At entry, in 1974, 782 men (mean age 47) completed a questionnaire about their physical activity and this was collapsed into 3 categories: low (n = 148), moderate (n = 398) and high physical activity (n = 236, 7 of whom had a competitive activity level). After 29-year follow-up in 2003, mean LTL and the proportion of short (b 5 kB) telomeres were measured from DNA samples of a random subcohort of survivors (n = 204, mean age 76) using the Southern blot technique. Adjusted for age, body mass index (BMI), cholesterol and smoking in 1974, the moderate physical activity group had longer mean LTL (8.27 kB, SE 0.05) than the low (8.10 kB, SE 0.07), or high (8.10 kB, SE 0.05) physical activity groups (P = 0.03 between groups). Conversely, the proportion of short telomeres was lowest in the moderate physical activity group (11.35%, SE 0.25), and higher in the high (12.39%, SE 0.29), and the low physical activity (12.21%, SE 0.39) groups (P = 0.02 between groups). We conclude that the results of this observational cohort study give support to the idea that both low and high physical activity is in the long-term associated with factors shortening LTL. © 2012 Elsevier Inc. All rights reserved.
1. Introduction Physical activity is associated with longevity, better function and quality of life in old age and it has been considered as an effective approach to prevent chronic diseases as diabetes, hypertension, osteoporosis and especially cardiovascular diseases (Blair et al., 1989; Boone-Heinonen et al., 2009; Heaney et al., 2000; Warburton et al., 2006). A graded linear relation has been found between the level of physical activity and health status (Warburton et al., 2006). Telomeres are nucleoprotein structures located at the ends of chromosomes, preserving chromosome stability and integrity. Telomeres shorten with increasing age and their length has been taken as a potential indicator of biological aging, although more evidence supporting that is needed (Mather et al., 2011) and not all aging researchers support this concept (Macieira-Coelho, 2011). The range of factors that influence telomere dynamics is not fully established. Some studies have found significant inverse relationship between
Abbreviations: kB, Kilobase; BMI, Body Mass Index; LTL, Leukocyte telomere length; SE, Standard error; SD, Standard deviation; IQ, Interquartile range. ⁎ Corresponding author. Tel.: + 358 505527429; fax: + 358 855845639. E-mail address: salla.savela@fimnet.fi (S. Savela). 1 Deceased. 0531-5565/$ – see front matter © 2012 Elsevier Inc. All rights reserved. doi:10.1016/j.exger.2012.02.003
LTL and mortality (Fitzpatrick et al., 2011; Kimura et al., 2008), whereas others have not (Martin-Ruiz et al., 2005; Njajou et al., 2009; Strandberg et al., 2011b). In several studies significant relation has been found between LTL and several aging-related conditions and diseases such as cardiovascular diseases (Fitzpatrick et al., 2007; Willeit et al., 2010a), diabetes (Sampson et al., 2006) and cancer (Willeit et al., 2010b). The association between physical activity and telomere length is not unequivocal. Increasing levels of physical activity have been shown to have positive correlation to LTL (Cherkas et al., 2008), but the linear association has not been confirmed in all studies (Collins et al., 2003; Ludlow et al., 2008) and one study found no association between physical activity and LTL (Cassidy et al., 2010). The previous surveys of the subcohorts of the Helsinki Businessmen study have shown that smoking and overweight in midlife (Strandberg et al., 2011b), as well as lifelong low cholesterol level (Strandberg et al., 2011a) were related to shorter LTL in old age, while LTL in old age did not predict mortality possibly because telomere attrition is affected by clustering of various mortality predictors in later life (Strandberg et al., 2011b). In the present study we investigated the association between midlife physical activity level and LTL measured in old age among 204 men, whose physical activity information and the results of LTL measurements were available. Because
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the midlife activity was sustained in old age in our cohort (Savela et al., 2010), the results may reflect long-term effect of exercise on telomeres. 2. Material and methods
al., 2010; Hemann et al., 2001) and therefore both mean LTL and the proportion of short telomeres (b5 kB) were measured as previously described (Fyhrquist et al., 2010); (Strandberg et al., 2011b) using the Southern blot technique with TeloTAGGG Telomere length assay kits (Roche Moleculas Biochemicals, Basel Switzerland).
2.1. Study population 2.4. Statistical analyses A cohort of initially healthy men with high socioeconomic status has been prospectively followed from the 1960s in the Helsinki Businessmen Study. The cohort and the examinations have been described earlier (Miettinen et al., 1985; Savela et al., 2010; Strandberg et al., 2009). In brief, initially healthy men, mostly business executives, born in 1919–1934, had participated in structured health check-ups during the 1960s and early 1970s at the Institute of Occupational Health in Helsinki, Finland. They were evaluated with questionnaires and clinical and laboratory examinations in 1974, whereupon 1815 men were found to be actively working and healthy without diabetes, clinical cardiovascular disease or regular medications. Of the 1815 men, a structured questionnaire covering details of their physical activity is available for 782 men (mean age 47) in 1974. The majority (90.7%, n = 709) of these men were assessed to be at high cardiovascular risk according to their risk factor profile. The age distribution as well as long-term mortality among the men with detailed physical activity was not statistically different from the rest of the cohort. The study procedures including genetic testing have been approved by the Ethics Committee of the Department of Medicine, University of Helsinki. All participants provided written informed consent. 2.2. Baseline examinations in 1974 and evaluation of physical activity Lifestyle variables, including smoking and alcohol consumption were assessed with questionnaires, blood pressure, weight and height were measured and BMI was calculated as weight (kg) divided by height (m) squared. Laboratory examinations included serum lipids and blood glucose. Both work-related and leisure-time physical activities were assessed with detailed questionnaires, including global description of their leisure-time physical activity on a 4-step scale: 1) Activity mainly reading, watching television, going to the cinema or other sedentary activity. 2) Walking, cycling, skiing, gardening, bowling, fishing or other light exercise weekly. 3) Jogging, running, skiing, swimming, tennis, badminton, heavy gardening or similar exercise weekly on a regular basis. 4) Regular vigorous/competitive exercise several times a week on a regular basis. Because only 7 men reported competitive activity, groups 3 and 4 were combined in the analyses. Men answering yes to question 1 were categorized as low activity; 2 as moderate; and 3 and 4 as high activity group. 2.3. Laboratory examinations in 2002–2003 and telomere measurements After 29-year follow-up (mean age 76), a random subcohort of survivors was invited to laboratory tests whereupon venous blood samples were taken for genetic analyses. In this subcohort, physical activity of 1974 was available for 204 men and they form the population of the present study. Extraction of DNA of peripheral blood leukocytes was performed with standard procedures using PureGene, Gentra method (Gentra systems, Minneapolis, MN, USA). There is increasing evidence suggesting that regardless of mean LTL, one critically short telomere may cause a cell to enter senescence (Bendix et
Statistical analyses were performed with NCSS 2004 software (NCSS, Kaysville, Utah). Continuous variables are shown as means with SDs, or medians with IQ ranges. Leisure-time physical activity was categorized as described above. Age, body-mass index and serum cholesterol level were used as continuous variables. Smoking at baseline was categorized as current or non-smoker. Spearman rank correlation and analysis of covariance (ANCOVA) were used to study the relationship between physical activity, mean LTL and proportion of short telomeres. Fisher's multiple-comparison test was used to compare groups. P values of less than 0.05 (two-sided) were considered to indicate statistical significance.
3. Results 3.1. Physical activity at baseline In 1974, as a global description of physical activity, 148 (18.9%), 398 (50.9%), and 236 (30.2%) men reported low (sedentary), moderate, and high leisure-time physical activity, respectively. In the subcohort of 204 men with LTL measurements, 38 (18.6%), 95 (46.6%) and 71 (34.8%) men were included into the low, moderate and high physical activity groups. Baseline characteristics of the subcohort of 204 men and the whole group of 782 men are shown in Table 1. Probably due to the homogeneity of the initial cohort, the subcohort reasonably well represented all 782 men with details of physical activity in 1974.
3.2. Telomere length Mean LTL and the proportion of short telomeres in the 3 activity groups are compared in Fig. 1. The moderate physical activity group had significantly longer mean LTL (8.27 kB, SE 0.05) than the low (8.10 kB, SE 0.07), or high (8.10 kB, SE 0.05) physical activity group after adjusting for age, BMI, cholesterol and smoking in 1974 (P = 0.03 between 3 groups). Proportion of short telomeres was significantly lower in the moderate activity group (11.35%, SE 0.25) than in the high (12.39%, SE 0.29), activity group after adjusting for age, BMI, cholesterol and smoking in 1974 (P = 0.02 between 3 groups), but there was no significant difference between proportion of short telomeres in the moderate activity and low activity (12.21%, SE 0.39) groups.
Table 1 Baseline characteristics of the whole cohort (n = 782) and the subcohort of 204 men. Variable at start of follow up in 1974 Whole cohort N = 782 Subcohort N = 204 Age, mean (SD) years BMI, mean (IQ) Current smokers, percentages Cholestrol, mean (SD) mmol/L Triglyserides, mean (SD) mmol/L 1 h glucose median (IQ) mmol/L Alcohol median (IQ) grams/week RR systolic, mean (SD) mm Hg RR diastolic (SD) mm Hg
47.9 (4.1) 26.3 (2.8) 34.7% 6.4 (1.0) 1.5 (1.2–2.1) 7.0 (5.6–8.7) 126 (56–252) 145.7 (18.7) 94.1 (10.7)
47.0 (4.0) 25.8 (2.8) 31.4% 6.5 (1.0) 1.5 (1.2–2.0) 6.8 (5.4–8.7) 126 (56–252) 144.3 (18.3) 93.3 (10.8)
S. Savela et al. / Experimental Gerontology 48 (2013) 81–84
LTL* P=0.03 between groups
Proportion of Short Telomeres * P=0.02 between groups Percentages
Kilobases
8.5 8.0 7.5 7.0
13.0 12.5 12.0 11.5 11.0 10.5 10.0
Low activity
Moderate activity
High activity
Low activity
Moderate activity
High activity
8.08
8.27
8.12
12.30
11.30
12.60
LTL ** P=0.03 between groups
Proportion of Short Telomeres ** P=0.02 between groups Percentages
8.5
Kilobases
83
8.0 7.5 7.0
13.0 12.5 12.0 11.5 11.0 10.5 10.0
Low activity
Moderate activity
High activity
Low activity
Moderate activity
High activity
8.10
8.26
8.10
12.20
11.40
12.40
Fig. 1. Leukocyte telomere length (kB) and the proportion of short telomeres (b5 kB, %) in the 3 physical activity groups, bars represent means with SE. *Adjusted for age. **Adjusted for age, BMI, cholesterol and smoking in 1974.
4. Discussion The main finding of this study was that long-term moderate level of leisure time physical activity was associated with longer mean LTL than both low and high levels of physical activity. After adjusting for age, BMI, cholesterol and smoking in 1974 the difference between mean LTL of the moderate and low activity groups was 172 base pairs corresponding to a difference of approximately 4 to 6 years in “biological age” assuming an annual mean LTL shortening of 30–40 base pairs (Aviv et al., 2009; Hastie et al., 1990; Slagboom et al., 1994; Valdes et al., 2005). Taking into account the beneficial effects of exercise on health our finding of shorter LTL in the high activity group is surprising. It is also in contrast with a twin study (Cherkas et al., 2008) showing a positive effect to LTL by increasing levels of physical activity. However, our results support the findings of the study of 69 volunteers aged 50–70 years in which moderate levels of physical were associated with longer LTL compared with both the lowest and the highest quartiles of physical activity (Ludlow et al., 2008). Furthermore, in a study of endurance athletes, those participants suffering from fatigued athlete myopathic syndrome had a severe reduction in skeletal muscle DNA telomere length compared with 13 healthy athlete controls (Collins et al., 2003). The various mechanisms by which exercise may affect aging at the cellular level have not been fully understood. Induced mitochondrial biology, lower basal levels of ROS, increased activity of antioxidants and damage repair enzymes (Baar, 2004; Radak et al., 2008a) as well as up-regulation of neurotrophic factors (Dishman et al., 2006) have been proposed to be involved. Telomere length may be one link between physical activity and health (Ludlow and Roth, 2011) and concept is supported by the results of our study. The present results may also be explained by the concept of hormesis (Rattan, in press) (Calabrese and Mattson, 2011), i.e. the response of biological systems to stressors is illustrated by a U-shaped curve. In case of physical activity, the two end-points of the hormesis curve are inactivity and overtraining, and it has been stated that normal and positively adapted function of the organism can be achieved with regular moderate exercise bouts (Radak et al., 2008b). Nevertheless, it is well established in epidemiologic studies that physical activity has a graded dose–response association with reduced mortality also in the higher levels of physical activity (Samitz
et al., 2011) and this was evident also in our previous survey of 782 men from Helsinki Businessmen Study: men in the highest physical activity group had the lowest mortality rate (Savela et al., 2010). It is therefore conceivable, that high levels of physical activity being associated with longevity may not be related to leukocyte telomere length. Thus, high levels of physical activity may promote longevity by mechanisms which do not affect telomere length. The strengths of our study include long follow-up time and the socioeconomically homogenous cohort, which reduces confounding. Physical activity at work and leisure time, lifestyle and other stress factors differ in various socioeconomic groups (Kim et al., 2004) and socioeconomic factors have been also associated to LTL, independent of known risk factors influencing the aging process (Cherkas et al., 2006; Woo et al., 2009). It is important that physical activity was sustained from midlife to old age in our cohort (Savela et al., 2010), and therefore the results probably reflect long-term, not cross-sectional, effect of exercise on telomeres. Our study also has limitations. The male cohort of high socioeconomic status limits generalizability to women or other socioeconomic groups. LTL was measured in old age, and thus restricted to survivors. Physical activity was determined in 1974 by self-report, which has been proposed to overestimate actual amounts of physical activity and thus underestimate the benefits of physical activity among older adults (Manini et al., 2006). Also, large variation of physical activity intensity and duration may occur within the three physical activity categories. The number of subjects analyzed was limited, but provided statistical significance. In conclusion, both low and high physical activities were associated with shorter telomeres in older men. The results reflect the multifaceted effects of physical activity on health and underscore the need for caution when interpreting the biological relevance of LTL association with life style.
Funding This work was supported by the Jahnsson Foundation, the University Central Hospitals of Oulu and Helsinki (EVO funding), the Konung Gustaf V:s och Drottning Victorias Frimurarestiftelse, the Wilhelm and Else Stockmann Foundation, the Päivikki and Sakari Sohlberg Foundation and Uulo Arhio Foundation.
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Experimental Gerontology journal homepage: www.elsevier.com/locate/expgero
Physical activity in midlife and telomere length measured in old age Salla Savela a,⁎, Outi Saijonmaa b, Timo E. Strandberg c, Pentti Koistinen a, Arto Y. Strandberg d, Reijo S. Tilvis d, Kaisu H. Pitkälä e, Tatu A. Miettinen e, 1, Frej Fyhrquist b a
Oulu City Hospital, Box 77, 90015 City of Oulu, Finland Minerva Institute for Medical Research and University of Helsinki, Box 20, 00014 Helsinki, Finland Institute of Health Sciences/Geriatrics, University of Oulu and University Hospital, Unit of General Practice, Box 5000, 90014 University of Oulu, Finland d Clinics of General Internal Medicine and Geriatrics, Helsinki University Hospital, Box 340, 00290 Helsinki, Finland e Unit of General Practice, Helsinki University Hospital, and Department of General Practice, Helsinki University, Box 20, 00014 Helsinki, Finland b c
a r t i c l e
i n f o
Article history: Received 15 November 2011 Received in revised form 27 January 2012 Accepted 7 February 2012 Available online 22 February 2012 Section Editor: A. Simm Keywords: Physical activity Leukocyte telomere length Proportion of short telomeres Biological aging Midlife activity
a b s t r a c t Physical activity has been associated with alterations in telomere length, a potential indicator of biological aging, but several inconsistencies exist. Our aim was to investigate the associations between physical activity in midlife and leukocyte telomere length (LTL) measured in old age in the Helsinki Businessmen Study, Finland. At entry, in 1974, 782 men (mean age 47) completed a questionnaire about their physical activity and this was collapsed into 3 categories: low (n = 148), moderate (n = 398) and high physical activity (n = 236, 7 of whom had a competitive activity level). After 29-year follow-up in 2003, mean LTL and the proportion of short (b 5 kB) telomeres were measured from DNA samples of a random subcohort of survivors (n = 204, mean age 76) using the Southern blot technique. Adjusted for age, body mass index (BMI), cholesterol and smoking in 1974, the moderate physical activity group had longer mean LTL (8.27 kB, SE 0.05) than the low (8.10 kB, SE 0.07), or high (8.10 kB, SE 0.05) physical activity groups (P = 0.03 between groups). Conversely, the proportion of short telomeres was lowest in the moderate physical activity group (11.35%, SE 0.25), and higher in the high (12.39%, SE 0.29), and the low physical activity (12.21%, SE 0.39) groups (P = 0.02 between groups). We conclude that the results of this observational cohort study give support to the idea that both low and high physical activity is in the long-term associated with factors shortening LTL. © 2012 Elsevier Inc. All rights reserved.
1. Introduction Physical activity is associated with longevity, better function and quality of life in old age and it has been considered as an effective approach to prevent chronic diseases as diabetes, hypertension, osteoporosis and especially cardiovascular diseases (Blair et al., 1989; Boone-Heinonen et al., 2009; Heaney et al., 2000; Warburton et al., 2006). A graded linear relation has been found between the level of physical activity and health status (Warburton et al., 2006). Telomeres are nucleoprotein structures located at the ends of chromosomes, preserving chromosome stability and integrity. Telomeres shorten with increasing age and their length has been taken as a potential indicator of biological aging, although more evidence supporting that is needed (Mather et al., 2011) and not all aging researchers support this concept (Macieira-Coelho, 2011). The range of factors that influence telomere dynamics is not fully established. Some studies have found significant inverse relationship between
Abbreviations: kB, Kilobase; BMI, Body Mass Index; LTL, Leukocyte telomere length; SE, Standard error; SD, Standard deviation; IQ, Interquartile range. ⁎ Corresponding author. Tel.: + 358 505527429; fax: + 358 855845639. E-mail address: salla.savela@fimnet.fi (S. Savela). 1 Deceased. 0531-5565/$ – see front matter © 2012 Elsevier Inc. All rights reserved. doi:10.1016/j.exger.2012.02.003
LTL and mortality (Fitzpatrick et al., 2011; Kimura et al., 2008), whereas others have not (Martin-Ruiz et al., 2005; Njajou et al., 2009; Strandberg et al., 2011b). In several studies significant relation has been found between LTL and several aging-related conditions and diseases such as cardiovascular diseases (Fitzpatrick et al., 2007; Willeit et al., 2010a), diabetes (Sampson et al., 2006) and cancer (Willeit et al., 2010b). The association between physical activity and telomere length is not unequivocal. Increasing levels of physical activity have been shown to have positive correlation to LTL (Cherkas et al., 2008), but the linear association has not been confirmed in all studies (Collins et al., 2003; Ludlow et al., 2008) and one study found no association between physical activity and LTL (Cassidy et al., 2010). The previous surveys of the subcohorts of the Helsinki Businessmen study have shown that smoking and overweight in midlife (Strandberg et al., 2011b), as well as lifelong low cholesterol level (Strandberg et al., 2011a) were related to shorter LTL in old age, while LTL in old age did not predict mortality possibly because telomere attrition is affected by clustering of various mortality predictors in later life (Strandberg et al., 2011b). In the present study we investigated the association between midlife physical activity level and LTL measured in old age among 204 men, whose physical activity information and the results of LTL measurements were available. Because
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the midlife activity was sustained in old age in our cohort (Savela et al., 2010), the results may reflect long-term effect of exercise on telomeres. 2. Material and methods
al., 2010; Hemann et al., 2001) and therefore both mean LTL and the proportion of short telomeres (b5 kB) were measured as previously described (Fyhrquist et al., 2010); (Strandberg et al., 2011b) using the Southern blot technique with TeloTAGGG Telomere length assay kits (Roche Moleculas Biochemicals, Basel Switzerland).
2.1. Study population 2.4. Statistical analyses A cohort of initially healthy men with high socioeconomic status has been prospectively followed from the 1960s in the Helsinki Businessmen Study. The cohort and the examinations have been described earlier (Miettinen et al., 1985; Savela et al., 2010; Strandberg et al., 2009). In brief, initially healthy men, mostly business executives, born in 1919–1934, had participated in structured health check-ups during the 1960s and early 1970s at the Institute of Occupational Health in Helsinki, Finland. They were evaluated with questionnaires and clinical and laboratory examinations in 1974, whereupon 1815 men were found to be actively working and healthy without diabetes, clinical cardiovascular disease or regular medications. Of the 1815 men, a structured questionnaire covering details of their physical activity is available for 782 men (mean age 47) in 1974. The majority (90.7%, n = 709) of these men were assessed to be at high cardiovascular risk according to their risk factor profile. The age distribution as well as long-term mortality among the men with detailed physical activity was not statistically different from the rest of the cohort. The study procedures including genetic testing have been approved by the Ethics Committee of the Department of Medicine, University of Helsinki. All participants provided written informed consent. 2.2. Baseline examinations in 1974 and evaluation of physical activity Lifestyle variables, including smoking and alcohol consumption were assessed with questionnaires, blood pressure, weight and height were measured and BMI was calculated as weight (kg) divided by height (m) squared. Laboratory examinations included serum lipids and blood glucose. Both work-related and leisure-time physical activities were assessed with detailed questionnaires, including global description of their leisure-time physical activity on a 4-step scale: 1) Activity mainly reading, watching television, going to the cinema or other sedentary activity. 2) Walking, cycling, skiing, gardening, bowling, fishing or other light exercise weekly. 3) Jogging, running, skiing, swimming, tennis, badminton, heavy gardening or similar exercise weekly on a regular basis. 4) Regular vigorous/competitive exercise several times a week on a regular basis. Because only 7 men reported competitive activity, groups 3 and 4 were combined in the analyses. Men answering yes to question 1 were categorized as low activity; 2 as moderate; and 3 and 4 as high activity group. 2.3. Laboratory examinations in 2002–2003 and telomere measurements After 29-year follow-up (mean age 76), a random subcohort of survivors was invited to laboratory tests whereupon venous blood samples were taken for genetic analyses. In this subcohort, physical activity of 1974 was available for 204 men and they form the population of the present study. Extraction of DNA of peripheral blood leukocytes was performed with standard procedures using PureGene, Gentra method (Gentra systems, Minneapolis, MN, USA). There is increasing evidence suggesting that regardless of mean LTL, one critically short telomere may cause a cell to enter senescence (Bendix et
Statistical analyses were performed with NCSS 2004 software (NCSS, Kaysville, Utah). Continuous variables are shown as means with SDs, or medians with IQ ranges. Leisure-time physical activity was categorized as described above. Age, body-mass index and serum cholesterol level were used as continuous variables. Smoking at baseline was categorized as current or non-smoker. Spearman rank correlation and analysis of covariance (ANCOVA) were used to study the relationship between physical activity, mean LTL and proportion of short telomeres. Fisher's multiple-comparison test was used to compare groups. P values of less than 0.05 (two-sided) were considered to indicate statistical significance.
3. Results 3.1. Physical activity at baseline In 1974, as a global description of physical activity, 148 (18.9%), 398 (50.9%), and 236 (30.2%) men reported low (sedentary), moderate, and high leisure-time physical activity, respectively. In the subcohort of 204 men with LTL measurements, 38 (18.6%), 95 (46.6%) and 71 (34.8%) men were included into the low, moderate and high physical activity groups. Baseline characteristics of the subcohort of 204 men and the whole group of 782 men are shown in Table 1. Probably due to the homogeneity of the initial cohort, the subcohort reasonably well represented all 782 men with details of physical activity in 1974.
3.2. Telomere length Mean LTL and the proportion of short telomeres in the 3 activity groups are compared in Fig. 1. The moderate physical activity group had significantly longer mean LTL (8.27 kB, SE 0.05) than the low (8.10 kB, SE 0.07), or high (8.10 kB, SE 0.05) physical activity group after adjusting for age, BMI, cholesterol and smoking in 1974 (P = 0.03 between 3 groups). Proportion of short telomeres was significantly lower in the moderate activity group (11.35%, SE 0.25) than in the high (12.39%, SE 0.29), activity group after adjusting for age, BMI, cholesterol and smoking in 1974 (P = 0.02 between 3 groups), but there was no significant difference between proportion of short telomeres in the moderate activity and low activity (12.21%, SE 0.39) groups.
Table 1 Baseline characteristics of the whole cohort (n = 782) and the subcohort of 204 men. Variable at start of follow up in 1974 Whole cohort N = 782 Subcohort N = 204 Age, mean (SD) years BMI, mean (IQ) Current smokers, percentages Cholestrol, mean (SD) mmol/L Triglyserides, mean (SD) mmol/L 1 h glucose median (IQ) mmol/L Alcohol median (IQ) grams/week RR systolic, mean (SD) mm Hg RR diastolic (SD) mm Hg
47.9 (4.1) 26.3 (2.8) 34.7% 6.4 (1.0) 1.5 (1.2–2.1) 7.0 (5.6–8.7) 126 (56–252) 145.7 (18.7) 94.1 (10.7)
47.0 (4.0) 25.8 (2.8) 31.4% 6.5 (1.0) 1.5 (1.2–2.0) 6.8 (5.4–8.7) 126 (56–252) 144.3 (18.3) 93.3 (10.8)
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LTL* P=0.03 between groups
Proportion of Short Telomeres * P=0.02 between groups Percentages
Kilobases
8.5 8.0 7.5 7.0
13.0 12.5 12.0 11.5 11.0 10.5 10.0
Low activity
Moderate activity
High activity
Low activity
Moderate activity
High activity
8.08
8.27
8.12
12.30
11.30
12.60
LTL ** P=0.03 between groups
Proportion of Short Telomeres ** P=0.02 between groups Percentages
8.5
Kilobases
83
8.0 7.5 7.0
13.0 12.5 12.0 11.5 11.0 10.5 10.0
Low activity
Moderate activity
High activity
Low activity
Moderate activity
High activity
8.10
8.26
8.10
12.20
11.40
12.40
Fig. 1. Leukocyte telomere length (kB) and the proportion of short telomeres (b5 kB, %) in the 3 physical activity groups, bars represent means with SE. *Adjusted for age. **Adjusted for age, BMI, cholesterol and smoking in 1974.
4. Discussion The main finding of this study was that long-term moderate level of leisure time physical activity was associated with longer mean LTL than both low and high levels of physical activity. After adjusting for age, BMI, cholesterol and smoking in 1974 the difference between mean LTL of the moderate and low activity groups was 172 base pairs corresponding to a difference of approximately 4 to 6 years in “biological age” assuming an annual mean LTL shortening of 30–40 base pairs (Aviv et al., 2009; Hastie et al., 1990; Slagboom et al., 1994; Valdes et al., 2005). Taking into account the beneficial effects of exercise on health our finding of shorter LTL in the high activity group is surprising. It is also in contrast with a twin study (Cherkas et al., 2008) showing a positive effect to LTL by increasing levels of physical activity. However, our results support the findings of the study of 69 volunteers aged 50–70 years in which moderate levels of physical were associated with longer LTL compared with both the lowest and the highest quartiles of physical activity (Ludlow et al., 2008). Furthermore, in a study of endurance athletes, those participants suffering from fatigued athlete myopathic syndrome had a severe reduction in skeletal muscle DNA telomere length compared with 13 healthy athlete controls (Collins et al., 2003). The various mechanisms by which exercise may affect aging at the cellular level have not been fully understood. Induced mitochondrial biology, lower basal levels of ROS, increased activity of antioxidants and damage repair enzymes (Baar, 2004; Radak et al., 2008a) as well as up-regulation of neurotrophic factors (Dishman et al., 2006) have been proposed to be involved. Telomere length may be one link between physical activity and health (Ludlow and Roth, 2011) and concept is supported by the results of our study. The present results may also be explained by the concept of hormesis (Rattan, in press) (Calabrese and Mattson, 2011), i.e. the response of biological systems to stressors is illustrated by a U-shaped curve. In case of physical activity, the two end-points of the hormesis curve are inactivity and overtraining, and it has been stated that normal and positively adapted function of the organism can be achieved with regular moderate exercise bouts (Radak et al., 2008b). Nevertheless, it is well established in epidemiologic studies that physical activity has a graded dose–response association with reduced mortality also in the higher levels of physical activity (Samitz
et al., 2011) and this was evident also in our previous survey of 782 men from Helsinki Businessmen Study: men in the highest physical activity group had the lowest mortality rate (Savela et al., 2010). It is therefore conceivable, that high levels of physical activity being associated with longevity may not be related to leukocyte telomere length. Thus, high levels of physical activity may promote longevity by mechanisms which do not affect telomere length. The strengths of our study include long follow-up time and the socioeconomically homogenous cohort, which reduces confounding. Physical activity at work and leisure time, lifestyle and other stress factors differ in various socioeconomic groups (Kim et al., 2004) and socioeconomic factors have been also associated to LTL, independent of known risk factors influencing the aging process (Cherkas et al., 2006; Woo et al., 2009). It is important that physical activity was sustained from midlife to old age in our cohort (Savela et al., 2010), and therefore the results probably reflect long-term, not cross-sectional, effect of exercise on telomeres. Our study also has limitations. The male cohort of high socioeconomic status limits generalizability to women or other socioeconomic groups. LTL was measured in old age, and thus restricted to survivors. Physical activity was determined in 1974 by self-report, which has been proposed to overestimate actual amounts of physical activity and thus underestimate the benefits of physical activity among older adults (Manini et al., 2006). Also, large variation of physical activity intensity and duration may occur within the three physical activity categories. The number of subjects analyzed was limited, but provided statistical significance. In conclusion, both low and high physical activities were associated with shorter telomeres in older men. The results reflect the multifaceted effects of physical activity on health and underscore the need for caution when interpreting the biological relevance of LTL association with life style.
Funding This work was supported by the Jahnsson Foundation, the University Central Hospitals of Oulu and Helsinki (EVO funding), the Konung Gustaf V:s och Drottning Victorias Frimurarestiftelse, the Wilhelm and Else Stockmann Foundation, the Päivikki and Sakari Sohlberg Foundation and Uulo Arhio Foundation.
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