- 2016 - Pilot Grant
Background and Significance
Knowledge gaps exist regarding the biological mechanisms that are involved in trajectories of health and aging. DNA methylation – the addition of a methyl group to the CpG dinucleotide – is an epigenetic mechanism involved in switching genes on and off (gene expression), and it may provide critical insights regarding mechanisms in stress and aging. Epigenetic (meaning “above genetic”) regulation by DNA methylation (covalent addition of a methyl group to the C-5 position of a cytosine base in the 5’-CG’3’ or CpG sequence context) induces mitotically heritable alterations in gene expression without modification of the DNA sequence. Changes in DNA methylation within CpG dinucleotides may represent biological mechanisms that mediate the effects of age on chronic disease and may also provide an explanatory biologic link between psychosocial stress and health outcomes in aging. We hypothesize that psychosocial stress may accelerate cellular aging and may be associated with changes in DNA methylation, which we hypothesize will be correlated with two other molecular markers of aging – telomere length and mitochondrial DNA copy number.
- To obtain DNA methylation markers in a well-characterized, in-clinic sample of participants and to evaluate correlations of DNA methylation with other molecular markers (telomere length [TL] and mitochondrial DNA copy number [mtCN]).
- To evaluate relations of psychological and social stress to DNA methylation at CpG dinucleotides.
In Aim 1, we hypothesize that the epigenetic (DNA methylation) and genetic markers of aging (TL and mtCN) will be positively correlated. In Aim 2, we hypothesize that higher burden of psychosocial stress factors (determined by higher index of depressive symptoms, anxiety, low social support and caregiving strain) will be related to epigenetic acceleration of aging. Using candidate epigenetic biomarkers of aging based on DNA methylation (DNAm) levels – a DNAm age concept developed and applied previously by Horvath – we will conduct a novel examination of the associations of DNAm with both TL and mtCN.
- Farzaneh-Far R, Lin J, Epel ES, Harris WS, Blackburn EH, Whooley MA. Association of marine omega- 3 fatty acid levels with telomeric aging in patients with coronary heart disease. JAMA. 2010;303(3):250-7.
- Kiecolt-Glaser JK, Epel ES, Belury MA, Andridge R, Lin J, Glaser R, et al. Omega-3 fatty acids, oxidative stress, and leukocyte telomere length: A randomized controlled trial. Brain Behav Immun. 2013;28:16-24.
- Liu JJ, Prescott J, Giovannucci E, Hankinson SE, Rosner B, Han J, et Plasma vitamin D biomarkers and leukocyte telomere length. Am J Epidemiol. 2013;177(12):1411-7.
- Jones MJ, Goodman SJ, Kobor MS. DNA methylation and healthy human aging. Aging 2015;14(6):924-32.
- Saretzki G, Von Zglinicki Replicative aging, telomeres, and oxidative stress. Ann N Y Acad Sci. 2002;959:24-9.
- Blackburn EH. Structure and function of telomeres. Nature. 1991;350(6319):569-73.
- Blackburn Telomeres and telomerase: their mechanisms of action and the effects of altering their functions. FEBS Lett. 2005;579(4):859-62.
- Blasco MA. Telomeres and human disease: ageing, cancer and beyond. Nat Rev Genet. 2005;6(8):611-22.
- Chen XJ, Butow The organization and inheritance of the mitochondrial genome. Nat Rev Genet. 2005;6(11):815-25.
- Horvath S. DNA methylation age of human tissues and cell types. Genome Biol. 2013;14(10):R115. Erratum in: Genome Biol. 2015;16:96.
- Marioni RE, Shah S, McRae AF, Chen BH, Colicino E, Harris SE, et al. DNA methylation age of blood predicts all-cause mortality in later life. Genome Biol. 2015;16:25.
- von Zglinicki T, Martin-Ruiz CM. Telomeres as biomarkers for ageing and age-related diseases. Curr Mol Med. 2005;5(2):197-203.
- Kim JH, Kim HK, Ko JH, Bang H, Lee DC. The relationship between leukocyte mitochondrial DNA copy number and telomere length in community-dwelling elderly women. PLoS One. 2013;8(6):e67227.
- Epel ES, Blackburn EH, Lin J, Dhabhar FS, Adler NE, Morrow JD, et al. Accelerated telomere shortening in response to life stress. Proc Natl Acad Sci U S A. 2004;101(49):17312-5.
- Wolkowitz OM, Mellon SH, Epel ES, Lin J, Dhabhar FS, Su Y, et al. Leukocyte telomere length in major depression: correlations with chronicity, inflammation and oxidative stress – preliminary findings. PLoS One. 2011;6(3):e17837.
- Simon NM, Smoller JW, McNamara KL, Maser RS, Zalta AK, Pollack MH, et al. Telomere shortening and mood disorders: preliminary support for a chronic stress model of accelerated aging. Biol Psychiatry. 2006;60(5):432-5.
- Humphreys J, Epel ES, Cooper BA, Lin J, Blackburn EH, Lee KA. Telomere shortening in formerly abused and never abused women. Biol Res Nurs. 2012 14(2):115-23.
- Cherkas LF, Aviv A, Valdes AM, Hunkin JL, Gardner JP, Surdulescu GL, et al. The effects of social status on biological aging as measured by white-blood-cell telomere length. Aging Cell. 2006;5(5):361-5.
- Okereke OI, Prescott J, Wong JYY, Han J, Rexrode KM, De Vivo High phobic anxiety is related to lower leukocyte telomere length in women. PLoS One. 2012;7(7):e40516. Epub 2012 Jul 11.
- Tyrka AR, Parade SH, Price LH, Kao HT, Porton B, Philip NS, et al. Alterations of Mitochondrial DNA Copy Number and Telomere Length With Early Adversity and Psychopathology. Biol Psychiatry. 2016;79(2):78-86.
- Kim D, Kubzansky LD, Baccarelli A, Sparrow D, Spiro A 3rd, Tarantini L, et al. Psychological factors and DNA methylation of genes related to immune/inflammatory system markers: the VA Normative Aging Study. BMJ Open. 2016;6(1):e009790.
- Fitzpatrick AL, Kronmal RA, Kimura M, Gardner JP, Psaty BM, Jenny NS, et al. Leukocyte telomere length and mortality in the Cardiovascular Health Study. J Gerontol A Biol Sci Med Sci. 2011;66(4):421-9.
- Strandberg TE, Saijonmaa O, Tilvis RS, Pitkälä KH, Strandberg AY, Miettinen TA, et Association of telomere length in older men with mortality and midlife body mass index and smoking. J Gerontol A Biol Sci Med Sci. 2011 66(7):815-20.
- Du M, Prescott J, Kraft P, Han J, Giovannucci E, Hankinson SE, et al. Physical activity, sedentary behavior, and leukocyte telomere length in women. Am J Epidemiol. 2012;175(5):414-22.
- Valdes AM, Andrew T, Gardner JP, Kimura M, Oelsner E, Cherkas LF, et al. Obesity, cigarette smoking, and telomere length in women. Lancet. 2005;366(9486):662-4.
- Boks MP, van Mierlo HC, Rutten BP, Radstake TR, De Witte L, Geuze E, et Longitudinal changes of telomere length and epigenetic age related to traumatic stress and post-traumatic stress disorder. Psychoneuroendocrinology. 2015;51:506-12.
- Marioni RE, Harris SE, Shah S, McRae AF, von Zglinicki T, Martin-Ruiz C, et al. The epigenetic clock and telomere length are independently associated with chronological age and mortality. Int J Epidemiol. 2016:Apr 13. pii: dyw041. [Epub ahead of print].
- Grayson DR, Guidotti A. The dynamics of DNA methylation in schizophrenia and related psychiatric disorders. Neuropsychopharmacology. 2013;38(1):138-66.
- Manson JE, Bassuk SS, Lee IM, Cook NR, Albert MA, Gordon D, et al. The VITamin D and OmegA-3 TriaL (VITAL): rationale and design of a large randomized controlled trial of vitamin D and marine omega-3 fatty acid supplements for the primary prevention of cancer and cardiovascular disease. Contemp Clin Trials. 2012;33(1):159-71.
- Spitzer RL, Kroenke K, Williams JB. Validation and utility of a self-report version of PRIME-MD: the PHQ primary care Primary Care Evaluation of Mental Disorders. Patient Health Questionnaire. JAMA. 1999;282(18):1737-44.
- Kroenke K, Spitzer RL. The PHQ-9: a new depression and diagnostic severity measure. Psychiatric Ann. 2002;32:509–21.
- Löwe B, Kroenke K, Herzog W, Gräfe K. Measuring depression outcome with a brief self-report instrument: sensitivity to change of the Patient Health Questionnaire (PHQ-9) Journal of Affective Disorders. 2004;81(1):61-6
- Löwe B, Unützer J, Callahan CM, Perkins AJ, Kroenke K. Monitoring depression treatment outcomes with the patient health questionnaire-9. Med Care. 2004;42(12):1194-201.
- American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition. Fourth ed. Washington, DC: APA;
- Spitzer RL, Kroenke K, Williams JBW, Löwe B. A brief measure for assessing generalized anxiety disorder: the GAD-7. Arch Intern Med. 2006;166:1092-7.
- Koenig HG, Westlund RE, George LK, Hughes DC, Blazer DG, Hybels C. Abbreviating the Duke Social Support Index for use in chronically ill elderly individuals. Psychosomatics. 1993;34(1):61-9.
- Landerman R, George LK, Campbell RT, Blazer DG. Alternative models of the stress buffering hypothesis. Am J Community Psychol. 1989;17(5):625-42.
- Higginson IJ, Gao W, Jackson D, Murray J, Harding Short-form Zarit Caregiver Burden Interviews were valid in advanced conditions. J Clin Epidemiol. 2010;63(5):535-42.
- Sheehan DV, Lecrubier Y, Sheehan KH, Amorim P, Janavs J, Weiller E, et al. The Mini-International Neuropsychiatric Interview (M.I.N.I.): the development and validation of a structured diagnostic psychiatric interview for DSM-IV and ICD-10. J Clin Psychiatry. 1998;59 Suppl 20:22-33;quiz 4-57.
- Aryee MJ, Jaffe AE, Corrada-Bravo H, Ladd-Acosta C, Feinberg AP, Hansen KD, et al. Minfi: a flexible and comprehensive Bioconductor package for the analysis of Infinium DNA methylation microarrays. Bioinformatics. 2014;30(10):1363-9.
- Cawthon RM. Telomere measurement by quantitative PCR. Nucleic Acids Res. 2002;30(10):e47.
The Osher Pilot Grant directly resulted in new funding from the NIH:
Title: Neuropsychiatric symptoms, cognitive aging and DNA methylation age in the VITAL-DEP cohort
Grant Number: 3 R01 MH091448-09S1
Funding agency: NIH/NIMH
Total Award: $341,815