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Brain Behav Immun. 2019 Mar 11. pii: S0889-1591(18)31187-5. doi: 10.1016/j.bbi.2019.03.007. [Epub ahead of print]

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

Author information

1
National Center for PTSD at VA Boston Healthcare System, Boston, MA, USA; Boston University School of Medicine, Department of Psychiatry, Boston, MA, USA. Electronic address: Erika.Wolf@va.gov.
2
National Center for PTSD at VA Boston Healthcare System, Boston, MA, USA; Boston University School of Medicine, Department of Psychiatry, Boston, MA, USA.
3
National Center for PTSD at VA Boston Healthcare System, Boston, MA, USA; Boston University School of Medicine, Department of Psychiatry, Boston, MA, USA; Boston University School of Medicine, Department of Medicine, Biomedical Genetics, Boston, MA, USA; Boston University School of Public Health, Department of Biostatistics, Boston, MA, USA.
4
National Center for PTSD at VA Boston Healthcare System, Boston, MA, USA.
5
Pharmacogenomics Analysis Laboratory, Research Service, Central Arkansas Veterans Healthcare System, Little Rock, AR, USA.
6
Geriatric Research Educational and Clinical Center and Translational Research Center for TBI and Stress Disorders, VA Boston Healthcare System, Boston, MA, USA; Department of Psychiatry, Harvard Medical School, Boston, MA, USA.

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.

PMID:
30872092
DOI:
10.1016/j.bbi.2019.03.007

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