The telomere tumult: meaning and metrics in population studies
Authors: Abraham Aviv
Journal: The Lancet Healthy Longevity (2022)

In The Lancet Healthy Longevity, Vasiliki Bountziouka and collegaues1Bountziouka V Musicha C Allara E et al.Modifiable traits, healthy behaviours, and leukocyte telomere length: a population-based study in UK Biobank.Lancet Healthy Longev. 2022; 3: e321-e331Summary Full Text Full Text PDF PubMed Scopus (1) Google Scholar have authored the latest in a series of communications that leveraged the UK Biobank to transform population-based telomere research. Their paper focuses on associations, in about 400 000 UK Biobank participants, between potentially modifiable traits and leukocyte telomere length (LTL). It shows that behaviours explain less than 0·2% of the inter-individual LTL variation and exert no effect on LTL association with risks of 22 diseases causally linked to it. These findings reinforce a previous meta-analysis by Pepper and colleagues,2Pepper GV Bateson M Nettle D Telomeres as integrative markers of exposure to stress and adversity: a systematic review and meta-analysis.R Soc Open Sci. 2018; 5180744Crossref PubMed Scopus (31) Google Scholar who concluded, based on data from about 400 000 people, that exposures and stress, principally psychological stress, are only weakly associated with LTL. Pepper and colleagues further indicated that such associations might be driven by publication bias and underpowered sample sizes. Jointly, these large studies question the present focus of population studies, reflected in the US National Institutes of Health announcements on Telomeres as sentinels of environmental exposures, psychosocial stress, and disease susceptibility, and on Telomeres in wellness and disease: a biobehavioral approach. The premise driving these announcements is that exposures adversely affecting health also shorten LTL, thereby increasing LTL-related disease risk. However, Bountziouka and colleagues show that common exposures and behaviours are unlikely to exert a consequential influence on LTL during adulthood. Evolution works through gene–environment interaction. Accordingly, contemporary LTL reflects past trade-offs across opposing forces. These included different exposures that resulted in telomere lengthening or shortening to an optimal length for a given geography and evolutionary period.3Hunt SC Hansen MEB Verhulst S et al.Genetics and geography of leukocyte telomere length in sub-Saharan Africans.Hum Mol Genet. 2020; 29: 3014-3020Crossref PubMed Scopus (3) Google Scholar However, the characteristics of these forces were shaped by elements that largely differ from those affecting fitness in present upper-middle-income populations. The nominal effect of exposures and behaviours on LTL is, therefore, hardly surprising. The vast person-to-person LTL variation at any age (SD about 700 bp, range about 3000 bp) is determined before adulthood, principally at birth.4Aubert G Baerlocher GM Vulto I Poon SS Lansdorp PM Collapse of telomere homeostasis in hematopoietic cells caused by heterozygous mutations in telomerase genes.PLoS Genet. 2012; 8e1002696Crossref PubMed Scopus (151) Google Scholar, 5Factor-Litvak P Susser E Kezios K et al.Leukocyte telomere length in newborns: implications for the role of telomeres in human disease.Pediatrics. 2016; 137e20153927Crossref PubMed Scopus (138) Google Scholar This concept draws on LTL measurements by Southern blotting showing that, first, the inter-individual LTL variation among newborns is like that among their parents5Factor-Litvak P Susser E Kezios K et al.Leukocyte telomere length in newborns: implications for the role of telomeres in human disease.Pediatrics. 2016; 137e20153927Crossref PubMed Scopus (138) Google Scholar and, second, the inter-individual differences in LTL shortening after the first decade of life do not offset LTL ranking across individuals, which is established before adulthood.6Benetos A Verhulst S Labat C et al.Telomere length tracking in children and their parents: implications for adult onset diseases.FASEB J. 2019; 33: 14248-14253Crossref PubMed Scopus (26) Google Scholar, 7Benetos A Kark JD Susser E et al.Tracking and fixed ranking of leukocyte telomere length across the adult life course.Aging Cell. 2013; 12: 615-621Crossref PubMed Scopus (147) Google Scholar Thus, LTL tracks with age, meaning that individuals entering adulthood with short (or long) LTL maintain their short (or long) LTL for their remaining lives. Collectively, findings that LTL ranking precedes disease onset by decades4Aubert G Baerlocher GM Vulto I Poon SS Lansdorp PM Collapse of telomere homeostasis in hematopoietic cells caused by heterozygous mutations in telomerase genes.PLoS Genet. 2012; 8e1002696Crossref PubMed Scopus (151) Google Scholar, 5Factor-Litvak P Susser E Kezios K et al.Leukocyte telomere length in newborns: implications for the role of telomeres in human disease.Pediatrics. 2016; 137e20153927Crossref PubMed Scopus (138) Google Scholar and genetic evidence, including Mendelian randomisation analysis,8Codd V Wang Q Allara E et al.Polygenic basis and biomedical consequences of telomere length variation.Nat Genet. 2021; 53: 1425-1433Crossref PubMed Scopus (21) Google Scholar support a causal role of LTL in some human diseases. Bountziouka and colleagues thus propose that population studies pivot away from their focus on behaviours and refocus instead on mechanisms explaining LTL causality in these diseases. This proposition would not be possible were it not for the prescience and perseverance of the UK Biobank investigators, who used a high-throughput quantitative PCR (qPCR) method to generate a massive LTL database that offsets the method's imprecision. By contrast, many investigators used the qPCR method indiscriminately in small studies, including longitudinal investigations optimal for testing causal effects of exposures and behaviours on LTL. Such studies demand precise telomere length measurements because the yearly LTL change among adults is two orders of magnitudes smaller than the absolute LTL, whose measurement error is introduced twice, at baseline and follow-up.9Nettle D Gadalla SM Lai TP Susser E Bateson M Aviv A Measurement of telomere length for longitudinal analysis: implications of assay precision.Am J Epidemiol. 2021; 190: 1406-1413Crossref PubMed Scopus (10) Google Scholar Yet, based on qPCR data, some of these longitudinal studies have claimed that healthy behaviours slow age-related LTL shortening and might even lengthen LTL.10Conklin QA King BG Zanesco AP et al.Insight meditation and telomere biology: the effects of intensive retreat and the moderating role of personality.Brain Behav Immun. 2018; 70: 233-245Crossref PubMed Scopus (26) Google Scholar Predictably, for-profit outfits have stepped in to offer non-expert consumers serial LTL measurements along with advice for maintaining telomere health. Nonetheless, the paper by Bountziouka and colleagues reveals that sample size cannot make up for another major limitation of the qPCR method—ie, its telomere to single-gene ratio metric. This ratio simply indicates that LTL is shorter or longer in group A versus group B. To provide a quantitative context for their findings, the authors transformed their telomere to single-gene ratio into equivalent years of age-related change in LTL. However, the noise of transforming the ratio into this amorphous unit might amplify the qPCR imprecision rather than set a meaningful standard that can be used in clinical settings. To conclude, behaviours and exposures, including psychological stress, exert inconsequential effects on LTL. The UK Biobank is a model for the proper application of the high-throughput qPCR method. By contrast, the wholesale use of the method for smaller studies and longitudinal ones has undermined telomere epidemiology. The method must be reserved for large studies, as major efforts are undertaken to develop precise, high-throughput techniques that generate data in absolute telomere length units. For now, however, investigators embarking on small studies, particularly longitudinal studies, might consider precise gel-based and flow fluorescent in situ hybridisation techniques for LTL measurements. Notwithstanding their labour-intensive nature, these techniques have generated most of our knowledge about the role of telomeres in human health, from the molecular to the population levels. I declare no competing interests. AA telomere research is supported by US National Institutes of Health grants R01 HL134840, U01AG066529 and a grant from the Research Council of Norway through its Centres of Excellence funding 262700. Modifiable traits, healthy behaviours, and leukocyte telomere length: a population-based study in UK BiobankAlthough several potentially modifiable traits and healthy behaviours have a quantifiable association with LTL, at least some of which are likely to be causal, these effects are not of a sufficient magnitude to substantially alter the association between LTL and various diseases or life expectancy. Attempts to change telomere length through lifestyle or behavioural changes might not confer substantial clinical benefit. Full-Text PDF Open Access