Background: Shorter childhood telomere length (TL) and more rapid TL attrition are widely regarded as manifestations of stress. However, the potential effects of health interventions on child TL are unknown. We hypothesized that a water, sanitation, handwashing (WSH), and nutritional intervention would slow TL attrition during the first two years of life. Methods: In a trial in rural Bangladesh (ClinicalTrials.gov, NCT01590095), we randomized geographical clusters of pregnant women into individual water treatment, sanitation, handwashing, nutrition, combined WSH, combined nutrition plus WSH (N + WSH), or control arms. We conducted a substudy enrolling children from the control arm and the N + WSH intervention arm. Participants and outcome assessors were not masked; analyses were masked. Relative TL was measured at 1 and 2 years after intervention, and the change in relative TL was reported. Analysis was intention-to-treat. Findings: Between May 2012 and July 2013, in the overall trial, we randomized 720 geographical clusters of 5551 pregnant women to a control or an intervention arm. In this substudy, after 1 year of intervention, we assessed a total of 662 children (341 intervention and 321 control) and 713 children after 2 years of intervention (383 intervention and 330 control). Children in the intervention arm had significantly shorter relative TL compared with controls after 1 year of intervention (difference −163 base pairs (bp), p=0.001). Between years 1 and 2, TL increased in the intervention arm (+76 bp) and decreased in the controls (−23 bp) (p=0.050). After 2 years, there was no difference between the arms (p=0.305). Interpretation: Our unexpected finding of increased telomere attrition during the first year of life in the intervention group suggests that rapid telomere attrition during this critical period could reflect the improved growth in the intervention group, rather than accumulated stress. Funding: The Bill and Melinda Gates Foundation
Stress negatively affects health by causing changes in cells. As a result, excess stress may predispose people to fall ill more often or age faster. It is difficult to measure stress. Some studies suggest that measuring the ends of chromosomes, known as telomeres, may be one way to measure stress. Like the plastic tips on shoelaces, telomeres protect chromosomes from fraying. All peoples’ telomeres shorten over their lifetime with each cell division. Many studies show that telomeres shorten faster in people who experience more stress. When telomeres become too short, cells die faster without being replaced, and the body ages.
Most studies on telomere length have looked at adults. Few studies have looked at children early in life or asked whether there are ways to intervene to stop or reverse stress-related telomere shortening. The first two years of life are a crucial period for the developing brain and immune system, which could set children on a lifelong course toward health or disease. Young children living in low-resource settings often encounter many sources of stress, like poor nutrition, infectious diseases or violence. Studies are needed to determine if interventions in early childhood aimed at reducing some sources of stress improve telomere length or long-term health.
Now, Lin et al. show that interventions to provide safe water, sanitation, handwashing facilities, and better nutrition to children in rural Bangladesh unexpectedly shortened telomeres. As part of a larger study, pregnant women in rural Bangladesh were divided, at random, into groups. One group received a suite of interventions, which included more sanitary toilets, handwashing facilities, and nutritional supplements for their infants. Another group served as a control and did not receive this extra help. Lin et al. looked at telomere length, growth, and infections in a subset of 713 children whose mothers participated in the study.
Children who got the extra help grew faster and were less likely to get diarrhea or parasitic infections than the children in the control group. Unexpectedly, children in the intervention group had shorter telomeres at 14 months of age than the children in the control group. Lin et al. suggest that the telomere shortening in the intervention group might be a consequence of rapid growth and immune system development in the first year of life rather than resulting from biological stress. More studies are needed to ask whether telomere shortening is indeed linked to faster growth and development early in life. The strong and unexpected findings highlight how little is known about how the length of telomeres can be used to predict future health or disease. Interpreting the length of telomeres over a person’s lifetime could prove more nuanced than originally thought.
Introduction
Children in low-income countries often experience infectious diseases and nutritional deficiencies leading to impaired growth, poor development, and early mortality (Black et al., 2017; GBD 2015 Mortality and Causes of Death Collaborators, 2016; Victora et al., 2008). During early life, children exhibit heightened developmental plasticity and are more sensitive to environmental conditions than later in life (Barker, 2007). The theory of developmental origins of health and disease postulates that multiple, cumulative early life exposures to adverse environmental factors may increase allostatic load (the cumulative biological damage from chronic stress) and susceptibility to adult diseases (Barker, 2007; Juster et al., 2010; Price et al., 2013).
Accumulating evidence implicates telomere length (TL) attrition as a potentially important underlying mechanism that links early life insults with adverse health outcomes later in life (Price et al., 2013). Telomeres, the repetitive DNA sequences and protein complexes protecting the ends of linear chromosomes, gradually shorten during normal cell division. Progressive telomere shortening leads to chromosome instability and cell senescence (Blackburn, 2001). Shorter TL has been linked to several age-related conditions including diabetes, heart disease, and early mortality (Cawthon et al., 2003; Fitzpatrick et al., 2007; Salpea et al., 2010). It remains an open debate whether TL serves as a ‘molecular clock’ that gauges cumulative stress exposures over a lifespan or plays a role in the etiology of various diseases (Blackburn et al., 2015; Hamad et al., 2016; Zhan et al., 2015).
Acute or chronic infections may contribute to childhood TL attrition, and inflammation and oxidative stress may be potential mediators (Houben et al., 2008). Infections may induce T-cell proliferation and accelerated telomere attrition (Aviv, 2004). Although no studies have directly investigated the relationship between infection and childhood TL, related studies in adults and animals support the plausibility of an association. Animal models have demonstrated that repeated exposures to Salmonella enterica cause telomere attrition (Ilmonen et al., 2008), and prenatal chronic malaria infections shorten offspring TL (Asghar et al., 2015). In adult humans, Helicobacter pylori infection, hepatitis C virus, HIV, and experimentally induced respiratory infection have been associated with shorter TL (Cohen et al., 2013; Gianesin et al., 2016; Hou et al., 2009; Zanet et al., 2014). Furthermore, caregiver-reported diarrhea in the first two years of life predicted shorter adult TL (Eisenberg et al., 2017). Early life water, sanitation, and handwashing (WSH) interventions could potentially prevent or reduce infections and slow telomere attrition. A systematic review and meta-analysis of WSH interventions reported a reduction in diarrheal illness (pooled estimate of relative risk 0.67, 95% CI 0.59–0.76) (Fewtrell et al., 2005), and a randomized controlled trial in Pakistan showed that promotion of handwashing decreased acute respiratory infections in children (Luby et al., 2005). To our knowledge, no studies have examined the impact of WSH interventions on TL.
Early life nutrition may affect childhood TL. Breast milk could potentially reduce telomere attrition by protecting against inflammation and oxidative stress (Cacho and Lawrence, 2017; Matos et al., 2015) – exposures associated with telomere attrition (Houben et al., 2008). Studies have found an association between exclusive breastfeeding and preschool TL (Wojcicki et al., 2016a), but no association with adult TL (Eisenberg et al., 2017). Improved intake of micronutrients (vitamins and minerals) may promote telomere maintenance (Bull and Fenech, 2008). Studies in adult populations have found mixed evidence for associations between TL, multivitamin usage, and various micronutrients (Cassidy et al., 2010; Liu et al., 2013; Paul et al., 2015; Richards et al., 2007; Xu et al., 2009). To our knowledge, no randomized controlled trials have assessed the effect of nutritional interventions on child TL.
Telomeres shorten fourfold faster in infants compared to adults (Zeichner et al., 1999); however, only a few studies have assessed the potential associations between environmental factors and TL in early childhood, a sensitive window of growth and development (Entringer et al., 2013; Marchetto et al., 2016; Theall et al., 2013a; Theall et al., 2013b; Wojcicki et al., 2016a). The trajectories of infant TL in low-income countries and the potential impact of early life health-improvement interventions on TL are unknown. We conducted a substudy within a randomized trial in rural Bangladesh to evaluate if an intensive, early life nutrition, water, sanitation, and handwashing intervention would slow telomere attrition among children in their first two years of life (Arnold et al., 2013).
