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. 2019 Aug:80:193-203.
doi: 10.1016/j.bbi.2019.03.007. Epub 2019 Mar 11.

The goddess who spins the thread of life: Klotho, psychiatric stress, and accelerated aging

Erika J Wolf  1 , Filomene G Morrison  2 , Danielle R Sullivan  2 , Mark W Logue  3 , Rachel E Guetta  4 , Annjanette Stone  5 , Steven A Schichman  5 , Regina E McGlinchey  6 , William P Milberg  6 , Mark W Miller  2
Affiliations

The goddess who spins the thread of life: Klotho, psychiatric stress, and accelerated aging

Erika J Wolf et al. Brain Behav Immun. 2019 Aug.

Abstract

Background: Longevity gene klotho (KL) is associated with age-related phenotypes but has not been evaluated against a direct human biomarker of cellular aging. We examined KL and psychiatric stress, including posttraumatic stress disorder (PTSD), which is thought to potentiate accelerated aging, in association with biomarkers of cellular aging.

Methods: The sample comprised 309 white, non-Hispanic genotyped veterans with measures of epigenetic age (DNA methylation age), telomere length (n = 252), inflammation (C-reactive protein), psychiatric symptoms, metabolic function, and white matter neural integrity (diffusion tensor imaging; n = 185). Genotyping and DNA methylation were obtained on epi/genome-wide beadchips.

Results: In gene by environment analyses, two KL variants (rs9315202 and rs9563121) interacted with PTSD severity (peak corrected p = 0.044) and sleep disturbance (peak corrected p = 0.034) to predict advanced epigenetic age. KL variant, rs398655, interacted with self-reported pain in association with slowed epigenetic age (corrected p = 0.048). A well-studied protective variant, rs9527025, was associated with slowed epigenetic age (p = 0.046). The peak PTSD interaction term (with rs9315202) also predicted C-reactive protein (p = 0.049), and white matter microstructural integrity in two tracts (corrected ps = 0.005 - 0.035). This SNP evidenced a main effect with an index of metabolic syndrome severity (p = 0.015). Effects were generally accentuated in older subjects.

Conclusions: Rs9315202 predicted multiple biomarkers of cellular aging such that psychiatric stress was more strongly associated with cellular aging in those with the minor allele. KL genotype may contribute to a synchronized pathological aging response to stress and could be a therapeutic target to alter the pace of cellular aging.

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Figures

Figure 1
Figure 1
shows the consistent pattern of association between PTSD symptom severity (Panel A, top left), pain severity in the past month (Panel B, top right), and sleep disturbance (Panel C, bottom) with DNAm age residuals as a function of rs9315202 genotype. Those with two copies of the minor allele (AA) at this locus evidenced a stronger association between each measure of psychiatric stress and DNAm age residuals.
Figure 2
Figure 2
shows the association between PTSD severity and inflammation (CRP values) as a function of rs9315202 genotype.
Figure 3
Figure 3
shows the white matter tracts that were associated with the rs9315202 by PTSD severity interaction term. The right cingulum bundle/cingulate gyrus is shown in yellow and the right fornix/stria terminalis is identified in green. From left to right, images represent, coronal, sagittal (next two), and axial (last two) slices.
Figure 4
Figure 4
shows the association between PTSD severity and diffusion (FA values) in the right cingulum bundle/cingulate gyrus tract (Panel A, left) and in the right fornix/stria terminalis (Panel B, right) as a function of rs9315202 genotype in the clinical cohort. PTSD was more strongly associated with degraded neural integrity in those with two copies of the minor allele at this locus.
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