Association of Short-term Change in Leukocyte Telomere Length With Cortical Thickness and Outcomes of Mental Training Among Healthy Adults: A Randomized Clinical Trial

Abstract

Importance: Telomere length is associated with the development of age-related diseases and structural differences in multiple brain regions. It remains unclear, however, whether change in telomere length is linked to brain structure change, and to what extent telomere length can be influenced through mental training.

Objectives: To assess the dynamic associations between leukocyte telomere length (LTL) and cortical thickness (CT), and to determine whether LTL is affected by a longitudinal contemplative mental training intervention.

Design, setting, and participants: An open-label efficacy trial of three 3-month mental training modules with healthy, meditation-naive adults was conducted. Data on LTL and CT were collected 4 times over 9 months between April 22, 2013, and March 31, 2015, as part of the ReSource Project. Data analysis was performed between September 23, 2016, and June 21, 2019. Of 1582 eligible individuals, 943 declined to participate; 362 were randomly selected for participation and assigned to training or retest control cohorts, with demographic characteristics matched. The retest control cohorts underwent all testing but no training. Intention-to-treat analysis was performed.

Interventions: Training cohort participants completed 3 modules cultivating interoception and attention (Presence), compassion (Affect), or perspective taking (Perspective).

Main outcomes and measures: Change in LTL and CT.

Results: Of the 362 individuals randomized, 30 participants dropped out before study initiation (initial sample, 332). Data were available for analysis of the training intervention in 298 participants (n = 222 training; n = 76 retest control) (175 women [58.7%]; mean [SD] age, 40.5 [9.3] years). The training modules had no effect on LTL. In 699 observations from all 298 participants, mean estimated changes in the relative ratios of telomere repeat copy number to single-copy gene (T/S) were for no training, 0.004 (95% CI, -0.010 to 0.018); Presence, -0.007 (95% CI, -0.025 to 0.011); Affect, -0.005 (95% CI, -0.019 to 0.010); and Perspective, -0.001 (95% CI, -0.017 to 0.016). Cortical thickness change data were analyzed in 167 observations from 67 retest control participants (37 women [55.2%], mean [SD] age, 39.6 [9.0] years). In this retest control cohort subsample, naturally occurring LTL change was related to CT change in the left precuneus extending to the posterior cingulate cortex (mean t161 = 3.22; P < .001; r = 0.246). At the individual participant level, leukocyte telomere shortening as well as lengthening were observed. Leukocyte telomere shortening was related to cortical thinning (t77 = 2.38; P = .01; r = 0.262), and leukocyte telomere lengthening was related to cortical thickening (t77 = 2.42; P = .009; r = 0.266). All analyses controlled for age, sex, and body mass index.

Conclusions and relevance: The findings of this trial indicate an association between short-term change in LTL and concomitant change in plasticity of the left precuneus extending to the posterior cingulate cortex. This result contributes to the evidence that LTL changes more dynamically on the individual level than previously thought. Further studies are needed to determine potential long-term implications of such change in relation to cellular aging and the development of neurodegenerative disorders. No effect of contemplative mental training was noted in what may be, to date, the longest intervention with healthy adults.

Trial registration: ClinicalTrials.gov identifier: NCT01833104.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Lin is a paid consultant to Telomere Diagnostics Inc, formerly Telome Health, and owns stock in the company; the company had no role in this research. Dr Singer reported receiving grants from the European Research Council during the conduct of the study. No other disclosures were reported.

Figures

Figure 1.. Study Design of the ReSource Project

A, Key concepts and core exercises taught during the modules Presence (yellow), Affect (red), and Perspective (green). B, Timeline of the ReSource Project and training sequence per cohort. Retest control participants were recruited in 2 cohorts for logistic reasons but were analyzed jointly. We therefore refer to a single retest control cohort in the text. The displayed study timeline was adapted to most accurately reflect the time points of blood sampling. Test phases for other variables may differ slightly. Samples of retest control cohort I were collected after approximately 2 months of no training before T1 and T2; however, given the smaller sample size of this cohort compared with retest control cohort II, combined RCC sampling occurred approximately every 3 months on average; the same is true for magnetic resonance imaging scans. The full ReSource Project design also included follow-up assessments (T4), but these were not included in the present investigation. Adapted from Singer et al.,

Figure 2.. Study Flow Diagram

Combined numbers from 2 recruitment periods in 2012-2013 and 2013-2014 are shown. BMI indicates body mass index; CT, cortical thickness; fMRI, functional magnetic resonance imaging; MRI, magnetic resonance imaging; ΔLTL, change in leukocyte telomere length (uncorrected); RCC, retest control cohort; SCID, Structural Clinical Interview for DSM-IV Disorders (Axis I and Axis II),; and TC, training cohort. Adapted from Singer et al.

Figure 3.. Association Between Leukocyte Telomere Length Change (DLTL) and Cortical Thickness Change (∆CT)

A, DLTL was positively associated with ∆CT in the left precuneus/posterior cingulate cortex (PCC). Automated Anatomical Labeling atlas: 61% (59%) overlap with precuneus (primary region); 24% [26%] overlap with PCC (secondary region); percentages in brackets indicate results from analysis without age, body mass index, and sex. B, Association between DLTL and ∆CT at each change interval. C, Association of leukocyte telomere lengthening and shortening with ∆CT. For visual display through scatterplots, ∆CT in the cingulate/PCC region was averaged and plotted against DLTL. Each dot represents 1 observation rather than 1 participant. Up to 3 measures of DLTL were available from the same participant, each from a different change interval and controlled for by the linear mixed-model analysis. Displayed regression lines in panels B and C were derived from linear models fit independently for each subsample (B: 1 sample per time interval; C: separate samples for leukocyte telomere lengthening/shortening). Shaded areas represent 95% CIs. CDT indicates cluster-determining threshold; FWE, familywise error correction.

Figure 4.. Raw and Estimated Change in Leukocyte Telomere Length (DLTL) per Training Module

Estimated mean change derived from the linear mixed-model analyses detailed in the Methods section and eAppendix 1 in Supplement 2, with all covariates held constant at their mean. A, Estimates from training model 1, examining the interaction between module and time point of training. B, Estimates from training model 2, examining the mean effects of each module. C, Estimates from an exploratory analysis, examining change over the whole 9-month period. Each circle represents a raw LTL difference score, but the models were fit on LTL scores corrected for regression to the mean (DLTL). Error bars represent 95% CIs. Af indicates Affect; NT, no training; Pe, Perspective; and Pr, Presence.