Oct 17, 2023

Abstract GrimAge acceleration has previously predicted age-related morbidities and mortality. In the current study, we sought to examine how GrimAge is associated with genetic predisposition for systemic inflammation and whether psychosocial factors moderate this association. Military veterans from the National Health and Resilience in Veterans study, which surveyed a nationally representative sample of European American male veterans, provided saliva samples for genotyping (N = 1135). We derived polygenic risk scores (PRS) from the UK Biobank as markers of genetic predisposition to inflammation. Results revealed that PRS for three inflammatory PRS markers—HDL (lower), apolipoprotein B (lower), and gamma-glutamyl transferase (higher)—were associated with accelerated GrimAge. Additionally, these PRS interacted with a range of potentially modifiable psychosocial variables, such as exercise and gratitude, previously identified as associated with accelerated GrimAge. Using gene enrichment, we identified anti-inflammatory and antihistamine drugs that perturbate pathways of genes highly represented in the inflammatory PRS, laying the groundwork for future work to evaluate the potential of these drugs in mitigating epigenetic aging. Access options $259.00 per year Prices vary by article type from$1.95 Additional access options: References Kennedy BK, Berger SL, Brunet A, Campisi J, Cuervo AM, Epel ES, et al. Aging: a common driver of chronic diseases and a target for novel interventions. Cell. 2014;159:709. Dugué P-A, Hodge AM, Ulvik A, Ueland PM, Midttun Ø, Rinaldi S, et al. Association of markers of inflammation, the kynurenine pathway and B vitamins with age and mortality, and a signature of inflammaging. J Gerontol A Biol Sci Med Sci. 2022;77:826–36. Verschoor CP, Vlasschaert C, Rauh MJ, Paré G. A DNA methylation based measure outperforms circulating CRP as a marker of chronic inflammation and partly reflects the monocytic response to long‐term inflammatory exposure: A Canadian longitudinal study of aging analysis. Aging Cell. 2023;22:e13863. Mason NL, Szabo A, Kuypers KP, Mallaroni PA, de la Torre R, Reckweg JT, et al. Psilocybin induces acute and persisting alterations in immune status in healthy volunteers: An experimental, placebo-controlled study. Brain Behav Immun. 2023;114:299–310. Mellner C, Dahlen M, Simonsson O. Association between lifetime classic psychedelic use and sick leave in a population-based sample. Int J Environ Res Public Health. 2022;19:11353. Don BR, Kaysen G. Poor nutritional status and inflammation: serum albumin: relationship to inflammation and nutrition. In Seminars in dialysis. Oxford, UK: Blackwell Science Inc.; 2004. Vol. 17, pp. 432–37. Burger D, Dayer J-M. High-density lipoprotein-associated apolipoprotein AI: the missing link between infection and chronic inflammation? Autoimmun Rev. 2002;1:111–7. Subramanian A, Narayan R, Corsello S, Peck D, Natoli T, Lu X, et al. A next generation connectivity map: L1000 Platform and the first 1,000,000 profiles. Cell. 2017;171:1437–1452.e17. Tamman AJ, Nagamatsu S, Krystal JH, Gelernter J, Montalvo-Ortiz JL, Pietrzak RH. Psychosocial factors associated with accelerated GrimAge in male US military veterans. Am J Geriatric Psychiatry. 2022;31:97–109. Supek F, Bošnjak M, Škunca N, Šmuc T. REVIGO summarizes and visualizes long lists of gene ontology terms. PLoS One. 2011;6:e21800. Richardson TG, Wang Q, Sanderson E, Mahajan A, McCarthy MI, Frayling TM, et al. Effects of apolipoprotein B on lifespan and risks of major diseases including type 2 diabetes: a mendelian randomisation analysis using outcomes in first-degree relatives. Lancet Healthy Longev. 2021;2:e317–e26. Tamman AJ, Wendt FR, Pathak GA, Krystal JH, Montalvo-Ortiz JL, Southwick SM, et al. Attachment style moderates polygenic risk for posttraumatic stress in United States military veterans: results from the national health and resilience in veterans study. Biol Psychiatry. 2021;89:878–87. Funding RP would like to acknowledge the following funding sources: Horizon 2020 Marie Sklodowska-Curie Individual Fellowship (101028810), the National Institutes of Drug Abuse (R33 DA047527), the National Institute of Mental Health (RF1 MH132337). Author information Amanda J. F. Tamman & Chadi Abdallah Division of Human Genetics, Department of Psychiatry, Yale School of Medicine, New Haven, CT, USA Dora Koller, Sheila Nagamastu, Brenda Cabrera-Mendoza, Joel Gelernter, Janitza L. Montalvo-Ortiz & Renato Polimanti Department of Psychiatry, Yale School of Medicine, New Haven, CT, USA Dora Koller, Sheila Nagamastu, Brenda Cabrera-Mendoza, Chadi Abdallah, John H. Krystal, Joel Gelernter, Janitza L. Montalvo-Ortiz, Renato Polimanti & Robert H. Pietrzak U.S. Department of Veterans Affairs National Center for Posttraumatic Stress Disorder, Clinical Neurosciences Division, VA Connecticut Healthcare System, West Haven, CT, USA John H. Krystal, Joel Gelernter, Janitza L. Montalvo-Ortiz & Robert H. Pietrzak Department of Social and Behavioral Sciences, Yale School of Public Health, New Haven, CT, USA Robert H. Pietrzak Dora Koller Sheila Nagamastu Brenda Cabrera-Mendoza Chadi Abdallah John H. Krystal Joel Gelernter Janitza L. Montalvo-Ortiz Renato Polimanti Robert H. Pietrzak Contributions Formal analysis: AJFT, DK, RP, and SN; Investigation: RHP; Resources: RHP; Writing – original draft: AJFT, DK, and RHP; Visualization: AJFT, DK, and RHP; Writing – review and editing: RHP, JK, JG, JLMO, SN, CA, RP, and BCM; Supervision: RHP; Funding acquisition: RHP; Conceptualization: JK, AJFT, and RHP; Methodology: RP and JG. Corresponding author Competing interests This manuscript contains original research, has not been published elsewhere and has not been submitted simultaneously for publication elsewhere. We have the following disclosures to report: JG is named as an inventor on PCT patent application #15/878,640 entitled: “Genotype-guided dosing of opioid agonists,” filed January 24, 2018. JG and RP are paid for their editorial work on the journal Complex Psychiatry. RP received a research grant from Alkermes. JHK has served as a scientific consultant to the following companies (the Individual Consultant Agreements listed are less than $5000 per year): AMGEN; AstraZeneca Pharmaceuticals; Bigen, Idec, MA; Biomedisyn Corporation; Forum Pharmaceuticals; Janssen Research & Development; Otsuka America Pharmaceutical, Inc.; Sunovion Pharmaceuticals, Inc.; Takeda Industries; Taisho Pharmaceutical Co., Ltd. He is on the Scientific Advisory Board for the following companies: Biohaven Pharmaceuticals; Blackthorn Therapeutics,Inc. ; Lohocla Research Corporation; Luc Therapeutics, Inc.; Pfizer Pharmaceuticals; TRImaran Pharma. He holds stock in Biohaven Pharmaceuticals Medical Sciences and stock options in Blackthorn Therapeutics, Inc. and Luc Therapeutics, Inc. He is the editor of Biological Psychiatry (Income greater than $10,000). CGA has served as a consultant and/or on advisory boards for Aptinyx, Genentech, Janssen, Psilocybin Labs, Lundbeck, Guidepoint, and FSV7, and as editor of Chronic Stress for Sage Publications, Inc. He also filed a patent for using mTORC1 inhibitors to augment the effects of antidepressants (Aug 20, 2018). AJFT, BCM, DK, RHP, SN, and JLMO reported no biomedical financial interest. Additional information Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Supplementary information