Association of leucocyte telomere length with frailty: a large-scale cross-sectional analysis in UK Biobank

BackgroundLeucocyte telomere length (LTL), a potential marker of biological age, has been associated with risk of many diseases. We investigated whether LTL is associated with risk of frailty, a multidimensional syndrome of decline that affects multiple systems and predisposes to adverse health outcomes. MethodsIn a cross-sectional analysis, we studied 441,781 UK Biobank participants (aged 40-70 years), with complete data on LTL and frailty indicators. We defined frailty as the presence of at least three of five indicators: weaker grip strength, slower walking pace, weight loss in the past year, lower physical activity, and exhaustion in the past two weeks. We evaluated association of LTL with frailty using adjusted (chronological age, sex, deprivation, smoking, alcohol intake, body mass index, multimorbidity) multinomial and ordinal regression models. We used Mendelian randomisation (MR), using 131 genetic variants associated with LTL, to assess if the association of LTL with frailty was causal. FindingsFrail participants (4{middle dot}6%) were older (median age difference (95% CI): 3 (2{middle dot}5; 3{middle dot}5) years), more likely to be female (61%), and had shorter LTL (-0{middle dot}13SD vs 0{middle dot}03SD) than non-frail. In adjusted analyses, both age and LTL were associated with frailty (OR=1{middle dot}03 (95%CI: 1{middle dot}02-1{middle dot}04) per year of older chronological age; 1{middle dot}10 (1{middle dot}08; 1{middle dot}11) per SD shorter LTL). Within each age group (40-49, 50-59, 60-69 years) the prevalence of frailty was about 33% higher in participants with shorter (-2SD) versus longer telomeres (+2SD). MR analysis showed an association of LTL with frailty that was directionally consistent with the observational association, but not statistically significant. InterpretationInter-individual variation in LTL is associated with the risk of frailty independently of chronological age and other risk factors. Our findings provide evidence for an additional biological determinant of frailty. FundingThe UK Medical Research Council, the Biotechnology and Biological Sciences Research Council and the British Heart Foundation (MRC grant: MR/M012816/1) funded our measurements of LTL in UK Biobank. The funders had no role in study design; the collection, analysis, and interpretation of data; the writing of the report; and the decision to submit the paper for publication. Research in contextO_ST_ABSEvidence before this studyC_ST_ABSTelomere length has been proposed as a biomarker of biological age. Shorter leucocyte telomere length (LTL) is associated with higher incidence of several age-associated diseases, spanning multiple body systems, and with lower life expectancy. However, the association of shorter LTL with frailty, a multidimensional syndrome of decline across multiple systems, is inconclusive. We searched PubMed using the terms "telomere length AND frailty" in the title, abstract, or text with no language restrictions. This search identified 50 papers published before 30 November, 2020. Of these, three systematic reviews and/ or meta-analyses of modest size (five to nine studies, with total n<10,000) and 11 original research articles reported on associations between telomere length and frailty. These small-scale studies, primarily in older individuals, do not support an independent association between shorter LTL and higher risk of frailty. Added value of this studyOur large-scale population-based study, involving over 441,000 participants, provides strong evidence that shorter LTL is associated with higher risk of both pre-frailty and frailty even after adjustment for chronological age and other established determinants of frailty, namely, age, sex, alcohol intake, smoking, obesity, deprivation and multimorbidity. Within each age group (40-49, 50-59, 60-69 years) the prevalence of frailty was about 33% higher in participants with shorter (-2SD) versus longer telomeres (+2SD). Part of the association of shorter LTL with higher risk of frailty may be due to the association in aggregate of LTL with diseases. Findings using genetic variants associated with LTL as instruments were directionally consistent with the observational association, but not statistically significant. Implications of all the available evidenceShorter LTL is associated with frailty independent of chronological age and several other risk factors. The observation that risk of frailty associated with shorter LTL is proportionately similar across the age range of 40-70 years suggests that shorter LTL acts through a mechanism beyond just accelerating the impact of chronological ageing on risk of frailty.