Klotho, PTSD, and advanced epigenetic age in cortical tissue

Abstract

This study examined the klotho (KL) longevity gene polymorphism rs9315202 and psychopathology, including posttraumatic stress disorder (PTSD), depression, and alcohol-use disorders, in association with advanced epigenetic age in three postmortem cortical tissue regions: dorsolateral and ventromedial prefrontal cortices and motor cortex. Using data from the VA National PTSD Brain Bank (n = 117), we found that rs9315202 interacted with PTSD to predict advanced epigenetic age in motor cortex among the subset of relatively older (>=45 years), white non-Hispanic decedents (corrected p = 0.014, n = 42). An evaluation of 211 additional common KL variants revealed that only variants in linkage disequilibrium with rs9315202 showed similarly high levels of significance. Alcohol abuse was nominally associated with advanced epigenetic age in motor cortex (p = 0.039, n = 114). The rs9315202 SNP interacted with PTSD to predict decreased KL expression via DNAm age residuals in motor cortex among older white non-Hispanics decedents (indirect β = −0.198, p = 0.027). Finally, in dual-luciferase enhancer reporter system experiments, we found that inserting the minor allele of rs9315202 in a human kidney cell line HK-2 genomic DNA resulted in a change in KL transcriptional activities, likely operating via long noncoding RNA in this region. This was the first study to examine multiple forms of psychopathology in association with advanced DNA methylation age across several brain regions, to extend work concerning the association between rs9315202 and advanced epigenetic to brain tissue, and to identify the effects of rs9315202 on KL gene expression. KL augmentation holds promise as a therapeutic intervention to slow the pace of cellular aging, disease onset, and neuropathology, particularly in older, stressed populations.

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Fig. 1: PTSD is associated with advanced epigenetic age in motor cortex as a function of rs9315202.
Fig. 2: Analysis of the effects of mutation on rs9315202 by a dual-luciferase reporter system in HK-2 cells.

Notes

  1. 1.

    Because this was a smaller subgroup analysis of older, white non-Hispanic decedents, we dropped the seven cell type variables from the path model so as not to overfit the model. None of the cell type variables were significantly associated with KL expression in motor cortex in the multiple regression models (Table 3).

  2. 2.

    The path model fit the data well per standard fit indices: Χ2 (1, n = 43) = 0.17, p = 0.68, root mean square error of approximation < 0.001, standardized root mean square residual = 0.012, confirmatory fit index = 1.00, Tucker-Lewis index = 2.057. The model was estimated with maximum likelihood estimation.

  3. 3.

    The brain bank RNA sequence data did not have coverage of this transcript thus we were unable to examine this ncRNA in the brain bank data directly.

References

  1. 1.

    Arking DE, Krebsova A, Macek M, Macek M, Arking A, Mian IS, et al. Association of human aging with a functional variant of klotho. Proc Natl Acad Sci. 2002;99:856–61.

    CAS  Google Scholar 

  2. 2.

    Kuro-o M, Matsumura Y, Aizawa H, Kawaguchi H, Suga T, Utsugi T, et al. Mutation of the mouse klotho gene leads to a syndrome resembling ageing. Nature. 1997;390:45–51.

    CAS  Google Scholar 

  3. 3.

    Kurosu H, Yamamoto M, Clark JD, Pastor JV, Nandi A, Gurnani P, et al. Suppression of aging in mice by the hormone klotho. Science. 2005;309:1829–33.

    CAS  Google Scholar 

  4. 4.

    Semba RD, Moghekar AR, Hu J, Sun K, Turner R, Ferrucci L, et al. Klotho in the cerebrospinal fluid of adults with and without Alzheimer’s disease. Neurosci Lett. 2014;558:37–40.

    CAS  Google Scholar 

  5. 5.

    Erickson CM, Schultz SA, Oh JM, Darst BF, Ma Y, Norton D, et al. KLOTHO heterozygosity attenuates APOE4-related amyloid burden in preclinical AD. Neurology. 2019;92:e1878.

    CAS  Google Scholar 

  6. 6.

    Kuang X, Chen Y-S, Wang L-F, Li Y-J, Liu K, Zhang M-X, et al. Klotho upregulation contributes to the neuroprotection of ligustilide in an Alzheimer’s disease mouse model. Neurobiol Aging. 2014;35:169–78.

    CAS  Google Scholar 

  7. 7.

    Zeng C-Y, Yang T-T, Zhou H-J, Zhao Y, Kuang X, Duan W, et al. Lentiviral vector–mediated overexpression of Klotho in the brain improves Alzheimer’s disease–like pathology and cognitive deficits in mice. Neurobiol Aging. 2019;78:18–28.

    CAS  Google Scholar 

  8. 8.

    Dubal DB, Yokoyama JS, Zhu L, Broestl L, Worden K, Wang D, et al. Life extension factor klotho enhances cognition. Cell Rep. 2014;7:1065–76.

    CAS  Google Scholar 

  9. 9.

    Dubal DB, Zhu L, Sanchez PE, Worden K, Broestl L, Johnson E, et al. Life extension factor klotho prevents mortality and enhances cognition in hAPP transgenic mice. J Neurosci. 2015;35:2358–71.

    CAS  Google Scholar 

  10. 10.

    Massó A, Sánchez A, Bosch A, Giménez-Llort L, Chillón M. Secreted αKlotho isoform protects against age-dependent memory deficits. Mol Psychiatry. 2018;23:1937–47.

    Google Scholar 

  11. 11.

    Leon J, Moreno AJ, Garay BI, Chalkley RJ, Burlingame AL, Wang D, et al. Peripheral elevation of a klotho fragment enhances brain function and resilience in young, aging, and α-synuclein transgenic mice. Cell Rep. 2017;20:1360–71.

    CAS  Google Scholar 

  12. 12.

    Shardell M, Semba RD, Rosano C, Kalyani RR, Bandinelli S, Chia CW, et al. Plasma klotho and cognitive decline in older adults: findings from the InCHIANTI study. J Gerontol Ser A. 2016;71:677–82.

    CAS  Google Scholar 

  13. 13.

    Yokoyama JS, Sturm VE, Bonham LW, Klein E, Arfanakis K, Yu L, et al. Variation in longevity gene KLOTHO is associated with greater cortical volumes. Ann Clin Transl Neurol. 2015;2:215–30.

    CAS  Google Scholar 

  14. 14.

    Yokoyama JS, Marx G, Brown JA, Bonham LW, Wang D, Coppola G, et al. Systemic klotho is associated with KLOTHO variation and predicts intrinsic cortical connectivity in healthy human aging. Brain Imaging Behav. 2017;11:391–400.

    Google Scholar 

  15. 15.

    Laszczyk AM, Fox-Quick S, Vo HT, Nettles D, Pugh PC, Overstreet-Wadiche L, et al. Klotho regulates postnatal neurogenesis and protects against age-related spatial memory loss. Neurobiol Aging. 2017;59:41–54.

    CAS  Google Scholar 

  16. 16.

    Chen C-D, Sloane JA, Li H, Aytan N, Giannaris EL, Zeldich E, et al. The antiaging protein klotho enhances oligodendrocyte maturation and myelination of the CNS. J Neurosci. 2013;33:1927–39.

    CAS  Google Scholar 

  17. 17.

    Zeldich E, Chen C-D, Avila R, Medicetty S, Abraham CR. The anti-aging protein klotho enhances remyelination following cuprizone-induced demyelination. J Mol Neurosci. 2015;57:185–96.

    CAS  Google Scholar 

  18. 18.

    Mengel-From J, Soerensen M, Nygaard M, McGue M, Christensen K, Christiansen L. Genetic variants in KLOTHO associate with cognitive function in the oldest old group. J Gerontol Ser A. 2016;71:1151–9.

    CAS  Google Scholar 

  19. 19.

    Porter T, Burnham SC, Milicic L, Savage G, Maruff P, Lim YY, et al. Klotho allele status is not associated with Aβ and APOE ε4–related cognitive decline in preclinical Alzheimer’s disease. Neurobiol Aging. 2019;76:162–5.

    CAS  Google Scholar 

  20. 20.

    Jovanovic T, Vance LA, Cross D, Knight AK, Kilaru V, Michopoulos V, et al. Exposure to violence accelerates epigenetic aging in children. Sci Rep. 2017;7:1–7.

    CAS  Google Scholar 

  21. 21.

    Wolf EJ, Logue MW, Hayes JP, Sadeh N, Schichman SA, Stone A, et al. Accelerated DNA methylation age: associations with PTSD and neural integrity. Psychoneuroendocrinology. 2016;63:155–62.

    CAS  Google Scholar 

  22. 22.

    Wolf EJ, Maniates H, Nugent N, Maihofer AX, Armstrong D, Ratanatharathorn A, et al. Traumatic Stress and Accelerated DNA Methylation Age: A Meta-Analysis. Psychoneuroendocrinology. 2018;92:123–34.

    CAS  Google Scholar 

  23. 23.

    Wolf EJ, Logue MW, Stoop TB, Schichman SA, Stone A, Sadeh N, et al. Accelerated DNA methylation age: associations with posttraumatic stress disorder and mortality. Psychosom Med. 2018;80:42–48.

    CAS  Google Scholar 

  24. 24.

    Wolf EJ, Logue MW, Morrison FG, Wilcox ES, Stone A, Schichman SA, et al. Posttraumatic psychopathology and the pace of the epigenetic clock: a longitudinal investigation. Psychol Med. 2019;49:791–800.

    Google Scholar 

  25. 25.

    Verhoeven JE, Yang R, Wolkowitz OM, Bersani FS, Lindqvist D, Mellon SH, et al. Epigenetic age in male combat-exposed war veterans: associations with posttraumatic stress disorder status. Mol Neuropsychiatry. 2018;4:90–9.

    CAS  Google Scholar 

  26. 26.

    Zannas AS, Arloth J, Carrillo-Roa T, Iurato S, Röh S, Ressler KJ, et al. Lifetime stress accelerates epigenetic aging in an urban, African American cohort: relevance of glucocorticoid signaling. Genome Biol. 2015;16:266.

    Google Scholar 

  27. 27.

    Wolf EJ, Morrison FG, Sullivan DR, Logue MW, Guetta RE, Stone A, et al. The goddess who spins the thread of life: Klotho, psychiatric stress, and accelerated aging. Brain Behav Immun. 2019;80:193–203.

    CAS  Google Scholar 

  28. 28.

    Han LKM, Aghajani M, Clark SL, Chan RF, Hattab MW, Shabalin AA, et al. Epigenetic aging in major depressive disorder. Am J Psychiatry. 2018;175:774–82.

    Google Scholar 

  29. 29.

    Li Z, He Y, Ma X, Chen X. Epigenetic age analysis of brain in major depressive disorder. Psychiatry Res. 2018. 2018;269:621–4.

    Google Scholar 

  30. 30.

    Fries GR, Bauer IE, Scaini G, Valvassori SS, Walss‐Bass C, Soares JC, et al. Accelerated hippocampal biological aging in bipolar disorder. Bipolar Disord. 2019;00:1–10.

    Google Scholar 

  31. 31.

    Voisey J, Lawford BR, Morris CP, Wockner LF, Noble EP, Young RM, et al. Epigenetic analysis confirms no accelerated brain aging in schizophrenia. Npj Schizophr. 2017;3:1–3.

    CAS  Google Scholar 

  32. 32.

    McKinney BC, Lin H, Ding Y, Lewis DA, Sweet RA. DNA methylation evidence against the accelerated aging hypothesis of schizophrenia. Npj Schizophr. 2017;3:1–3.

    CAS  Google Scholar 

  33. 33.

    Rosen AD, Robertson KD, Hlady RA, Muench C, Lee J, Philibert R, et al. DNA methylation age is accelerated in alcohol dependence. Transl Psychiatry. 2018;8:1–8.

    Google Scholar 

  34. 34.

    Kozlenkov A, Jaffe AE, Timashpolsky A, Apontes P, Rudchenko S, Barbu M, et al. DNA methylation profiling of human prefrontal cortex neurons in heroin users shows significant difference between genomic contexts of hyper- and hypomethylation and a younger epigenetic age. Genes. 2017;8:152.

    Google Scholar 

  35. 35.

    Fonzo GA, Goodkind MS, Oathes DJ, Zaiko YV, Harvey M, Peng KK, et al. PTSD psychotherapy outcome predicted by brain activation during emotional reactivity and regulation. Am J Psychiatry. 2017;174:1163–74.

    Google Scholar 

  36. 36.

    Hayes JP, Hayes SM, Mikedis AM. Quantitative meta-analysis of neural activity in posttraumatic stress disorder. Biol Mood Anxiety Disord. 2012;2:9.

    Google Scholar 

  37. 37.

    Salat DH, Buckner RL, Snyder AZ, Greve DN, Desikan RSR, Busa E, et al. Thinning of the cerebral cortex in aging. Cereb Cortex. 2004;14:721–30.

    Google Scholar 

  38. 38.

    Salat DH, Tuch DS, Greve DN, van der Kouwe AJW, Hevelone ND, Zaleta AK, et al. Age-related alterations in white matter microstructure measured by diffusion tensor imaging. Neurobiol Aging. 2005;26:1215–27.

    CAS  Google Scholar 

  39. 39.

    Anamizu Y, Kawaguchi H, Seichi A, Yamaguchi S, Kawakami E, Kanda N, et al. Klotho insufficiency causes decrease of ribosomal RNA gene transcription activity, cytoplasmic RNA and rough ER in the spinal anterior horn cells. Acta Neuropathol (Berl). 2005;109:457–66.

    CAS  Google Scholar 

  40. 40.

    Shiozaki M, Yoshimura K, Shibata M, Koike M, Matsuura N, Uchiyama Y, et al. Morphological and biochemical signs of age-related neurodegenerative changes in klotho mutant mice. Neuroscience. 2008;152:924–41.

    CAS  Google Scholar 

  41. 41.

    Miller MW, Greif JL, Smith AA. Multidimensional personality questionnaire profiles of veterans with traumatic combat exposure: Externalizing and internalizing subtypes. Psychol Assess. 2003;15:205–15.

    Google Scholar 

  42. 42.

    Friedman MJ, Huber BR, Brady CB, Ursano RJ, Benedek DM, Kowall NW, et al. VA’s national PTSD brain bank: a national resource for research. Curr Psychiatry Rep. 2017;19:73.

    Google Scholar 

  43. 43.

    Mighdoll MI, Deep‐Soboslay A, Bharadwaj RA, Cotoia JA, Benedek DM, Hyde TM, et al. Implementation and clinical characteristics of a posttraumatic stress disorder brain collection. J Neurosci Res. 2018;96:16–20.

    CAS  Google Scholar 

  44. 44.

    Morrison FG, Miller MW, Wolf EJ, Logue MW, Maniates H, Kwasnik D, et al. Reduced interleukin 1A gene expression in the dorsolateral prefrontal cortex of individuals with PTSD and depression. Neurosci Lett. 2019;692:204–9.

    CAS  Google Scholar 

  45. 45.

    Horvath S. DNA methylation age of human tissues and cell types. Genome Biol. 2013;14:3156.

    Google Scholar 

  46. 46.

    Logue MW, Smith AK, Wolf EJ, Maniates H, Stone A, Schichman SA, et al. The correlation of methylation levels measured using Illumina 450K and EPIC BeadChips in blood samples. Epigenomics. 2017;9:1363–71.

    CAS  Google Scholar 

  47. 47.

    Guintivano J, Aryee MJ, Kaminsky ZA. A cell epigenotype specific model for the correction of brain cellular heterogeneity bias and its application to age, brain region and major depression. Epigenetics. 2013;8:290–302.

    CAS  Google Scholar 

  48. 48.

    Bolger AM, Lohse M, Usadel B. Trimmomatic: a flexible trimmer for Illumina sequence data. Bioinformatics. 2014;30:2114–20.

    CAS  Google Scholar 

  49. 49.

    Dobin A, Davis CA, Schlesinger F, Drenkow J, Zaleski C, Jha S, et al. STAR: ultrafast universal RNA-seq aligner. Bioinformatics. 2013;29:15–21.

    CAS  Google Scholar 

  50. 50.

    Bray NL, Pimentel H, Melsted P, Pachter L. Near-optimal probabilistic RNA-seq quantification. Nat Biotechnol. 2016;34:525–7.

    CAS  Google Scholar 

  51. 51.

    Bray NL, Pimentel H, Melsted P, Pachter L. Erratum: near-optimal probabilistic RNA-seq quantification. Nat Biotechnol. 2016;34:888.

    CAS  Google Scholar 

  52. 52.

    Love MI, Huber W, Anders S. Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol. 2014;15:550.

    Google Scholar 

  53. 53.

    Quach A, Levine ME, Tanaka T, Lu AT, Chen BH, Ferrucci L, et al. Epigenetic clock analysis of diet, exercise, education, and lifestyle factors. Aging. 2017;9:419–37.

    CAS  Google Scholar 

  54. 54.

    Gao X, Zhang Y, Breitling LP, Brenner H. Relationship of tobacco smoking and smoking-related DNA methylation with epigenetic age acceleration. Oncotarget. 2016;7:46878–89.

    Google Scholar 

  55. 55.

    Chen C-D, Zeldich E, Li Y, Yuste A, Abraham CR. Activation of the anti-aging and cognition-enhancing gene klotho by CRISPR-dCas9 transcriptional effector complex. J Mol Neurosci. 2018;64:175–84.

    CAS  Google Scholar 

  56. 56.

    Mercer TR, Mattick JS. Structure and function of long noncoding RNAs in epigenetic regulation. Nat Struct Mol Biol. 2013;20:300–7.

    CAS  Google Scholar 

  57. 57.

    Thurman RE, Rynes E, Humbert R, Vierstra J, Maurano MT, Haugen E, et al. The accessible chromatin landscape of the human genome. Nature. 2012;489:75–82.

    CAS  Google Scholar 

  58. 58.

    Fiorito G, McCrory C, Robinson O, Carmeli C, Rosales CO, Zhang Y, et al. Socioeconomic position, lifestyle habits and biomarkers of epigenetic aging: a multi-cohort analysis. Aging. 2019;11:2045–70.

    CAS  Google Scholar 

  59. 59.

    Luo A, Jung J, Longley M, Rosoff DB, Charlet K, Muench C, et al. Epigenetic aging is accelerated in alcohol use disorder and regulated by genetic variation in APOL2. Neuropsychopharmacology. 2020;45:327–36.

    CAS  Google Scholar 

  60. 60.

    Miller MW, Wolf EJ, Sadeh N, Logue M, Spielberg JM, Hayes JP, et al. A novel locus in the oxidative stress-related gene ALOX12 moderates the association between PTSD and thickness of the prefrontal cortex. Psychoneuroendocrinology. 2015;62:359–65.

    CAS  Google Scholar 

  61. 61.

    Ziegler DA, Piguet O, Salat DH, Prince K, Connally E, Corkin S. Cognition in healthy aging is related to regional white matter integrity, but not cortical thickness. Neurobiol Aging. 2010;31:1912–26.

    Google Scholar 

  62. 62.

    Baluchnejadmojarad T, Eftekhari S-M, Jamali-Raeufy N, Haghani S, Zeinali H, Roghani M. The anti-aging protein klotho alleviates injury of nigrostriatal dopaminergic pathway in 6-hydroxydopamine rat model of Parkinson’s disease: involvement of PKA/CaMKII/CREB signaling. Exp Gerontol. 2017;100:70–6.

    CAS  Google Scholar 

  63. 63.

    Zeldich E, Chen C-D, Boden E, Howat B, Nasse JS, Zeldich D, et al. Klotho is neuroprotective in the superoxide dismutase (SOD1G93A) mouse model of ALS. J Mol Neurosci. 2019;69:264–85.

    CAS  Google Scholar 

  64. 64.

    Abraham CR, Chen C, Cuny GD, Glicksman MA, Zeldich E. Small-molecule Klotho enhancers as novel treatment of neurodegeneration. Future Med Chem. 2012;4:1671–79.

    CAS  Google Scholar 

  65. 65.

    Abraham CR, Mullen PC, Tucker-Zhou T, Chen CD, Zeldich E. Chapter Nine—Klotho is a neuroprotective and cognition-enhancing protein. In: Litwack G (ed) Vitamins & Hormones. Academic Press; 2016. pp. 215–238.

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Acknowledgements

The Traumatic Stress Brain Research Group are Matthew Friedman, M.D., Ph.D.—PTSD BB, Director, Neil Kowall, M.D., PI, VABBB Director, Christopher Brady, Ph.D., Co-I, VABBB Director of Scientific Operations, Ann McKee, M.D., Chief Neuropathologist, Thor Stein, M.D., Ph.D., Neuropathologist, BRH, M.D., Ph.D., Neuropathologist, Victor Alvarez, M.D., Neuropathologist, David Benedek, M.D., Director VA PTSD BB Assessment Core, Robert J. Ursano, MD, Director Center for the Study of Traumatic Stress, Department of Psychiatry, Uniformed Services University, Douglas Williamson, PhD, Site Director, Dianne Cruz, M.S., Co-investigator, Keith Young, PhD, Senior Advisor, Ronald Duman, PhD, Director VA PTSD BB Intramural Research Program, John Krystal, MD, Chair Department of Psychiatry, Deborah Mash, MD, Director, Brain Bank, Melanie Hardegree, RN, Co-Investigator, William Scott, Ph.D. Executive Director of the UM Brain Endowment Bank, David Davis Ph.D UM Brain Endowment Bank, Matthew Girgenti Ph.D., Co-Investigator., Brian Marx, PhD, Deputy Director, National Center for PTSD, Behavioral Science Division and Professor of Psychiatry, Boston University School of Medicine and Paul Holtzheimer, MD, Deputy Director for Research, National Center for PTSD and Associate Professor of Psychiatry and Surgery, Geisel School of Medicine at Dartmouth.

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EJF, CDC, MWL, FGM, CRA, and MWM provided substantial contributions to the conception and design of the work; and the acquisition, analysis, and interpretation of data for the work. XZ, ZZ, NPD, AS, SS, JGG, DFS provided substantial contributions to the analysis and interpretation of data for the work. BRH and the Traumatic Stress Brain Research Group provided substantial contributions to the conception of the work and the acquisition and interpretation of data for the work. EJF, CDC, MWL, CRA, ZZ, and MWM drafted the work and revised it critically for important intellectual content. FGM, XZ, NPD, AS, SS, JGG, DFS, BRH, and the Traumatic Stress Brain Research group critically revised the work for important intellectual content. All authors provided final approval of the version submitted for publication and all authors agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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Correspondence to Erika J. Wolf.

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Wolf, E.J., Chen, CD., Zhao, X. et al. Klotho, PTSD, and advanced epigenetic age in cortical tissue. Neuropsychopharmacol. (2020). https://doi.org/10.1038/s41386-020-00884-5

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