Conceived and designed the experiments: LP MW TVZ JA. Performed the experiments: CMR. Analyzed the data: MSP KDM. Wrote the paper: MSP. Critically reviewed the manuscript and approved the final version: MSP KDM CMR LP MW TVZ JA.
The authors have declared that no competing interests exist.
Telomere length is emerging as a potential factor in the pathogenesis of cardiovascular disease. We investigated whether birth weight, infant growth, childhood cognition and adult height, as well as a range of lifestyle, socio-economic and educational factors, were associated with white blood cell telomere length at age 49–51 years.
The study included 318 members of the Newcastle Thousand Families Study, a prospectively followed birth cohort which includes all individuals born in Newcastle, England in May and June 1947, who attended for clinical examination at age 49–51 years, and had telomere length successfully measured using real-time PCR analyses of DNA extracted from peripheral blood mononuclear cells.
No association was found between birth weight and later telomere length. However, associations were seen with other factors from early life. Education level was the only predictor in males, while telomere length in females was associated with gestational age at birth, childhood growth and childhood IQ.
While these findings may be due to chance, in particular where differing associations were seen between males and females, they do provide evidence of early life associations with telomere length much later in life. Our findings of sex differences in the education association may reflect the sex differences in achieved education levels in this generation where few women went to university regardless of their intelligence. Our findings do not support the concept of telomere length being on the pathway between very early growth and later disease risk.
Telomere length has been reported to be associated with longevity and risk of a number of age-related diseases, including associations with cardiovascular disease
Risk of adverse health in middle age has been proposed to be ‘programmed’ by impaired development in utero
A recent study has suggested a link between education and telomere length in adulthood
The Newcastle Thousand Families birth cohort
The study received ethical approval from the South Durham Lead Research Ethics Committee and the Joint Newcastle Health Authority/University of Newcastle upon Tyne Ethics Committee, and all study members gave their written informed consent.
The Newcastle Thousand Families study began as a prospective study of all 1142 children born in May and June 1947 to mothers resident in Newcastle upon Tyne, UK
The cohort underwent a major follow-up at age 49–51 years
Between October 1996 and December 1998, when study members were aged between 49 and 51 years, height, weight and other markers of size were measured. Waist and hip circumferences were measured according to the protocol of the World Health Organisation Monitoring Trends and Determinants in Cardiovascular Disease project
Telomere length in peripheral blood mononuclear cells was measured using real-time polymerase chain reaction (PCR) analysis
Birth weights, as recorded by the midwife, were standardised for gestational age (as recorded in ante-natal records) and sex
The number of pack-years of cigarettes smoked, current smoking status, physical activity, alcohol consumption and achieved education level were derived from the responses to the self-completion questionnaire data at age 49–51 years
As the distribution of telomere length was skewed, it was log transformed prior to analyses. Linear regression was used to assess potential associations between log transformed telomere length and potential predictors, and relevant assumptions were tested. Regression coefficients (in log base pairs per unit) and corresponding 95% confidence intervals (95% CI) are reported. Sex-specific analyses and tests for interaction between sex and other potential explanatory variables were done within the linear regression framework. The statistical software package Stata, version 10.0, (StataCorp, College Station: TX) was used for all statistical analyses.
Of the original 1142 study members, 832 (86% of the surviving sample of 967 children whose families remained in Newcastle for at least the first year of the study) were traced at age 49–51 years 12. Of these, 574 completed the health and lifestyle questionnaire and telomere length was measured in 318 study members with available DNA samples (120 men, 198 women). There were no differences in early life factors between the study sample and the remainder of the birth cohort, other than for sex, with more women than men included.
Descriptive statistics for all variables are given in
Total | Male | Female | ||||||||||||
Variable | N | Mean (SD) | N | Mean (SD) | N | Mean (SD) | ||||||||
Standardised birth weight (Z score) | 318 | −0.14 | (1.09) | 120 | −0.39 | (0.99) | 198 | 0.01 | (1.13) | |||||
Birth weight (kg) | 318 | 3.37 | (0.51) | 120 | 3.35 | (0.48) | 198 | 3.38 | (0.52) | |||||
Childhood growth (change in z-scores: birth and 9 years) | 275 | −0.01 | (0.49) | 106 | −0.02 | (0.49) | 169 | 0.00 | (0.50) | |||||
Childhood BMI (age 9 years) | 269 | 16.4 | (1.99) | 103 | 16.4 | (1.92) | 166 | 16.4 | (2.04) | |||||
Childhood IQ (age 11 years) | 266 | 101.6 | (13.9) | 103 | 101.8 | (14.3) | 163 | 101.5 | (13.7) | |||||
Height at age 49–51 years (cm) | 314 | 166.1 | (8.44) | 118 | 173.4 | (6.66) | 196 | 161.7 | (5.94) | |||||
BMI at age 49–51 years (kg) | 317 | 26.5 | (4.69) | 120 | 26.79 | (3.54) | 197 | 26.3 | (5.26) | |||||
Waist : Hip ratio | 316 | 0.86 | (0.10) | 120 | 0.95 | (0.06) | 196 | 0.80 | (0.06) | |||||
Percent body fat | 313 | 39.8 | (8.81) | 119 | 36.82 | (7.11) | 194 | 41.58 | (9.27) | |||||
Telomere length at age 49–51 years (log base pairs) | 318 | 8.50 | (0.22) | 120 | 8.59 | (0.22) | 198 | 8.44 | (0.20) | |||||
|
|
|
|
|
|
|||||||||
Gestational Age (weeks) | 317 | 40 | (40,40) | 119 | 40 | (40,40) | 198 | 40 | (40,40) | |||||
Duration Breast Fed (days) | 313 | 61 | (23,219) | 119 | 61 | (28,223) | 194 | 61.5 | (21,219) | |||||
Pack years cigarettes | 316 | 2.25 | (0,22.1) | 119 | 8.3 | (0,29.59) | 197 | 0.7 | (0,17.65) | |||||
Telomere length at age 49–51 years (base pairs) | 318 | 5016 | (1151) | 120 | 5512 | (1210) | 198 | 4716 | (1003) | |||||
|
|
|
|
|
|
|||||||||
Sex | 318 | 100 | 120 | 38 | 198 | 62 | ||||||||
Social class at birth | ||||||||||||||
I,II | 32 | 10 | 14 | 12 | 18 | 9 | ||||||||
III | 200 | 64 | 70 | 60 | 130 | 66 | ||||||||
IV,V | 81 | 26 | 33 | 28 | 48 | 25 | ||||||||
Smoking status age 49–51 years | ||||||||||||||
Never Smoked | 137 | 42 | 41 | 34 | 96 | 48 | ||||||||
Ex Smoker | 92 | 29 | 47 | 40 | 45 | 22 | ||||||||
Current Smoker | 87 | 28 | 31 | 26 | 56 | 28 | ||||||||
Alcohol consumption at age 49–51 years (self reported) | ||||||||||||||
None | 38 | 12 | 10 | 8 | 28 | 14 | ||||||||
Light | 126 | 40 | 49 | 41 | 77 | 39 | ||||||||
Medium | 126 | 40 | 47 | 40 | 79 | 41 | ||||||||
Heavy | 24 | 8 | 13 | 11 | 11 | 6 | ||||||||
Social class at age 49–51 years | ||||||||||||||
I,II | 156 | 52 | 62 | 54 | 94 | 51 | ||||||||
III | 100 | 34 | 39 | 34 | 61 | 33 | ||||||||
IV,V | 42 | 14 | 13 | 12 | 29 | 16 | ||||||||
Physical activity at age 49–51 years | ||||||||||||||
Inactive | 32 | 10 | 11 | 10 | 21 | 11 | ||||||||
Light Activity | 150 | 50 | 61 | 54 | 89 | 48 | ||||||||
Moderate Activity | 68 | 23 | 23 | 20 | 45 | 24 | ||||||||
Heavy Activity | 50 | 17 | 18 | 16 | 32 | 17 | ||||||||
Achieved education level at age 49–51 years | ||||||||||||||
No Qualifications | 104 | 34 | 30 | 26 | 74 | 39 | ||||||||
O Level or equivalent | 105 | 34 | 35 | 30 | 70 | 37 | ||||||||
A level or equivalent | 58 | 19 | 32 | 28 | 26 | 13 | ||||||||
Degree/post graduate | 39 | 13 | 18 | 16 | 21 | 11 |
All | All, adjusted for sex | Male | Female | ||||||
Variable | β (95% CI) | p | β (95% CI) | P | β (95% CI) | p | β (95% CI) | p | |
Sex (male reference category) | −0.15(−0.20, −0.11) | <0.001* | − | – | – | – | – | – | |
Standardised birth weight | −0.01 (−0.02,0.02) | 0.92 | 0.01 (−0.01,0.03) | 0.29 | 0.02 (−0.02,0.06) | 0.30 | 0.01 (−0.02,0.03) | 0.59 | |
Birth weight (kg) | 0.01 (−0.04,0.06) | 0.66 | 0.01 (−0.03,0.06) | 0.53 | 0.06 (−0.02,0.15) | 0.12 | −0.01 (−0.06,0.04) | 0.69 | |
Gestational Age (weeks) | −0.01 (−0.03,0.01) | 0.49 | −0.02 (−0.03,0.01) | 0.31 | 0.02 (−0.02,0.06) | 0.25 | −0.03 (−0.05, −0.03) | 0.03* | |
Duration Breast Fed (weeks) | −0.01 (0.00, 0.01) | 0.46 | −0.00 (0.00, 0.01) | 0.45 | 0.00 (0.00,0.01) | 0.26 | 0.00 (0.00, 0.00) | 0.99 | |
Social class at birth | I,II | −0.01 (−0.09,0.08) | 0.82 | −0.02 (−0.10,0.06) | 0.81 | −0.05 (−0.18,0.08) | 0.74 | 0.00 (−0.09,0.09) | 0.84 |
III | reference | reference | reference | reference | |||||
IV,V | 0.02 (−0.04,0.07) | 0.01 (−0.05,0.06) | −0.01 (−0.01,0.08) | 0.02 (−0.05,0.09) | |||||
Childhood growth | 0.02 (−0.03,0.07) | 0.39 | 0.03 (−0.02,0.08) | 0.31 | −0.03 (−0.12,0.06) | 0.53 | 0.06 (−0.01,0.12) | 0.05 | |
Childhood IQ (age 11) | −0.01 (−0.03,0.00) | 0.13 | 0.00 (−0.01,0.02) | 0.09 | 0.00 (−0.03,0.03) | 0.99 | −0.02 (−0.04, −0.01) | 0.02* | |
Height at age 49–51 years (cm) | 0.01 (0.01,0.01) | 0.002* | 0.00 (−0.01,0.01) | 0.28 | −0.01 (−0.01,0.01) | 0.63 | −0.02 (−0.01,0.02) | 0.30 | |
BMI at age 49–51 years | 0.01(−0.01,0.01) | 0.67 | 0.00 (−0.01,0.01) | 0.88 | 0.01 (−0.01,0.01) | 0.84 | 0.00 (−0.01,0.01) | 0.95 | |
Waist : Hip ratio | 0.57 (0.32,0.82) | <0.001* | −0.13 (−0.53,0.27) | 0.53 | −0.33 (−1.04,0.37) | 0.35 | −0.01 (−0.49,0.47) | 0.97 | |
Percent body fat | −0.01 (−0.01,0.01) | 0.26 | 0.00 (−0.01,0.00) | 0.67 | 0.01 (−0.01,0.01) | 0.86 | 0.01 (−0.02,0.03) | 0.69 | |
Pack years cigarettes | 0.01 (0.00,0.01) | 0.35 | −0.01 (−0.02,0.01) | 0.67 | 0.00 (−0.01,0.01) | 0.48 | 0.00 (−0.02,0.03) | 0.82 | |
\Smoking statusage 49–51 years | Never Smoked | reference | 0.39 | reference | 0.03* | reference | 0.18 | reference | 0.17 |
Ex Smoker | −0.03 (−0.09,0.02) | −0.07 (−0.13, −0.01) | −0.08 (−0.18,0.01) | −0.06 (−0.13,0.01) | |||||
Current Smoker | 0.01 (−0.05,0.07) | −0.02 (−0.06,0.05) | −0.02 (−0.13,0.08) | 0.01 (−0.05,0.07) | |||||
Alcohol consumptionat age 49–51 years | None | reference | 0.98 | reference | 0.87 | reference | 0.72 | reference | 0.45 |
Light | −0.02 (−0.10,0.07) | 0.01 (−0.07,0.08) | −0.08 (−0.23,0.07) | 0.03 (−0.05,0.12) | |||||
Medium | −0.01(−0.06,0.05) | −0.01 (−0.06,0.05) | 0.01 (−0.08,0.10) | −0.01 (−0.08,0.05) | |||||
Heavy | −0.01(−0.11,0.08) | −0.04 (−0.13,0.06) | −0.01 (−0.13,0.14) | −0.08 (−0.21,0.05) | |||||
Social class at age49–51 years | I,II | −0.01 (−0.06,0.05) | 0.96 | −0.01 (−0.06,0.05) | 0.98 | 0.04 (−0.05,0.13) | 0.66 | −0.03 (−0.10,0.03) | 0.61 |
III | reference | reference | reference | reference | |||||
IV,V | −0.01 (−0.09,0.07) | 0.01 (−0.07,0.08) | 0.04 (−0.11, 0.18) | −0.02 (−0.11,0.07) | |||||
Physical activity atage 49–51 years | Inactive | reference | 0.92 | reference | 0.91 | reference | 0.10 | reference | 0.24 |
Light Activity | 0.02(−0.07,0.10) | 0.01 (−0.07,0.09) | −0.12 (−0.26,0.02) | 0.08 (−0.01,0.18) | |||||
Moderate | 0.01(−0.08,0.1) | 0.01 (−0.08,0.10) | −0.02 (−0.17,0.14) | 0.03 (−0.08,0.13) | |||||
Heavy Activity | 0.03 (−0.07,0.05) | 0.03 (−0.02, −0.11) | −0.04 (−0.21,0.12) | 0.07 (−0.4,0.18) | |||||
Achieved education level atage 49–51 years | No Qualifications | reference | 0.04* | reference | 0.01* | reference | 0.01* | reference | 0.16 |
O Level or equivalent | −0.08 (−0.13, −0.02) | −0.08 (−0.14, −0.03) | −0.12 (−0.22, −0.02) | −0.07 (−0.13,0.00) | |||||
A level or equivalent | −0.04 (−0.11,0.03) | −0.08 (−0.15, −0.01) | −0.11 (−0.21, −0.03) | −0.05 (−0.14,0.04) | |||||
Degree/post graduate | 0.01(−0.07,0.09) | −0.01 (−0.09, −0.06) | 0.06 (−0.06,0.18) | −0.08 (−0.18,0.01) |
After adjusting for sex, neither achieved adult height or waist:hip ratio remained associated with telomere length (p = 0.28 and 0.53 respectively). However, the negative association between achieved education level and telomere length remained (p = 0.01). In sex-specific analyses, there were associations between telomere length and gestational age (p = 0.03), childhood growth (p = 0.05) and childhood IQ (p = 0.02) in women. Achieved education level at age 49–51 years in men was associated with telomere length (p<0.01). When compared to the reference category of no qualifications, lesser telomere lengths were seen for those with O and A-levels, but slightly longer telomeres were seen in those with university qualifications. Interactions were seen between sex and both gestational age (p = 0.026) and achieved education level (p = 0.05) on telomere length. Increasing male gestational age was associated with increased telomere length in contrast to an association between decreased length and increasing female gestation. There were decreasing telomere lengths for higher educational achievement in females, but with the longest telomere lengths in the highest achieving males. There was no evidence of interactions between sex and any of the other explanatory variables on telomere length.
Of the associations observed, the highest explanation of variation in the data was seen for sex (r2 = 0.12). Within sex-specific analyses, male achieved education level and female childhood IQ and gestational age accounted for 11%, 4% and 2.4%, respectively, of the variation in log transformed telomere length. After adjustment for sex, the resulting model including education and interactions was found to explain 15% of the variation in log transformed telomere length.
While associations were seen between telomere length and both achieved adult height and contemporary waist:hip ratio, neither association was independent of sex. This is likely to be due to men being both taller and having greater waist:hip ratios and having longer telomeres in this cohort. An association was seen between achieved education level and telomere length, with an interaction with sex. Achieved education level was the only association with telomere length in men, while gestational age, childhood IQ and childhood growth (from birth to age nine years) were associated in women.
The main strength of this study is the ability to analyse prospectively collected data from different stages of life simultaneously. Of 1142 men and women recruited at birth in 1947, 28% participated in the current study. Except for sex, the study sample attending for clinical examination has been shown to be comparable for a wide range of explanatory variables in early life 23. In addition, inclusion of cohort members who had moved out of the study region (18% of those who attended for clinical examination were resident outside the Northern Region of England) increased the representativeness of the population studied. However, the potential for participation bias in terms of later factors remains a possibility and the study may have been underpowered for some variables, particularly for the sex-specific analyses. Despite the small numbers in these analyses, though, a number of associations and interactions were identified and the final model accounted for 15% of the variation in telomere length.
Telomere length is known to vary with age. All cohort members were born within a two-month period and assessed when aged between 49 and 51 years, reducing the potential for bias. Furthermore, they were all born to mothers resident within the city of Newcastle upon Tyne in the north east of England, so should have less genetic and environmental heterogeneity than would be found in a study incorporating a larger geographical area, or one with ethnic diversity
We have previously reported that the men in this cohort had, on average, longer telomeres than the women at age 49–51 years
There were associations between both achieved adult height and contemporary waist:hip ratio and telomere length at age 49–51years in unadjusted analyses, but neither association remained after adjustment for sex or in sex-specific analyses. For waist:hip ratio, this is likely to reflect the larger waist:hip ratio in men compared to women.
Although telomere length is suggested to vary between men and women, such a difference is not apparent at birth, despite the variability in telomere length among newborns
Our finding of an association between childhood growth and telomere length at age 49–51 years was restricted to women, with a higher change in z-score between birth and height at age nine years associated with longer telomeres. Obesity in childhood has been reported to be associated with shorter telomere length, again measured in childhood
Childhood IQ (in females) and achieved education level (in males) were both associated with telomere length. The association with educational attainment for men, in that the longest telomeres were seen in those with the highest achieved education level, is consistent with recent evidence reporting that the associations with telomere length were dependent on educational attainment rather than contemporary socio-economic circumstances
Our findings suggest that, while achieved adult height and waist:hip ratio at age 49–51 years appear to be associated with telomere length at the same age, this is likely to reflect the differences in these measures between men and women and thus be due to confounding. No association was found between birth weight and later telomere length. However, significant associations were seen with other factors from early life. Education level was the only predictor in males, possibly reflecting the higher education levels in males in this generation, while telomere length in females was associated with gestational age, childhood growth and childhood IQ. While these findings may be due to chance, in particular where differing associations were seen between males and females, they do provide evidence of early life associations with telomere length much later in life. However, they do not support the concept of telomere length being on the pathway between very early growth and later disease risk.
We thank all study members for taking part in this study and the study teams and funders past and present.