Epigenetic Age Acceleration Markers Are Associated With Physiologic Frailty and All-Cause Mortality in People With Human Immunodeficiency Virus

Krisann K Oursler, Vincent C Marconi, Zeyuan Wang, Ke Xu, Monty Montano, Kaku So-Armah, Amy C Justice, Yan V Sun, Krisann K Oursler, Vincent C Marconi, Zeyuan Wang, Ke Xu, Monty Montano, Kaku So-Armah, Amy C Justice, Yan V Sun

Abstract

Background: Biomarkers that provide insight into drivers of aging are needed for people with human immunodeficiency virus (PWH). The study objective was to determine if epigenetic age acceleration (EAA) markers are associated with physiologic frailty measured by the Veterans Aging Cohort Study (VACS) Index and predict all-cause mortality for PWH.

Methods: Epigenome-wide DNA methylation was profiled in VACS total white blood cell samples collected during 2005-2007 from 531 PWH to generate 6 established markers of EAA. The association of each EAA marker was tested with VACS Index 2.0. All-cause mortality was assessed over 10 years. For each EAA marker, the hazard ratio per increased year was determined using Cox regression. To evaluate mortality discrimination, C-statistics were derived.

Results: Participants were mostly men (98.5%) and non-Hispanic Black (84.4%), with a mean age of 52.4 years (standard deviation [SD], 7.8 years). Mean VACS Index score was 59.3 (SD, 16.4) and 136 deaths occurred over a median follow-up of 8.7 years. Grim age acceleration (AA), PhenoAA, HannumAA, and extrinsic epigenetic AA were associated with the VACS Index and mortality. HorvathAA and intrinsic epigenetic AA were not associated with either outcome. GrimAA had the greatest mortality discrimination among EAA markers and predicted mortality independently of the VACS Index. One-year increase in GrimAA was associated with a 1-point increase in VACS Index and a 10% increased hazard for mortality.

Conclusions: The observed associations between EAA markers with physiologic frailty and mortality support future research to provide mechanistic insight into the accelerated aging process and inform interventions tailored to PWH for promoting increased healthspan.

Keywords: DNA methylation; aging; epigenetics; frailty; mortality.

Conflict of interest statement

Potential conflicts of interest. V. C. M. has received investigator-initiated research grants (paid to institution) and consulting fees (both unrelated to the current work) from Eli Lilly, Bayer, Gilead Sciences, and ViiV; grants or contracts from Gilead (for ACTT2, ACTT3, and ACTT4), ViiV (for DISCO and ASPIRE), and the Centers for Disease Control and Prevention, NIH, and Department of Veterans Affairs (other studies); honorarium in 2019 and support for attending meeting and/or travel from Eli Lilly (Ground Transportation 2019); participation on a data and safety monitoring board (DSMB) for IL-1b inhibitor study sponsored by the NIH and Novartis; and was the Study Section Chair for NIH. K. K. O. is the DSMB chair (1R01AG066562 from NIH, payment in-kind). K. S. reports grants or contracts from NIH. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.

Published by Oxford University Press on behalf of Infectious Diseases Society of America 2022.

Figures

Figure 1.
Figure 1.
Association of epigenetic age acceleration (EAA) markers with the Veterans Aging Cohort Study (VACS) Index. Mean and 95% confidence interval of the VACS Index score by age acceleration present (>0, squares) or absent (≤0, circles) for each EAA marker. The difference was tested by Student t test. *P < .001. Abbreviations: EAA, epigenetic age acceleration; EEAA, extrinsic epigenetic age acceleration; GrimAA, Grim age acceleration; HannumAA, Hannum DNA methylation age acceleration; HorvathAA, Horvath DNA methylation age acceleration; IEAA, intrinsic epigenetic age acceleration; PhenoAA, Pheno age acceleration; VACS, Veterans Aging Cohort Study.
Figure 2.
Figure 2.
Kaplan-Meier estimates of 10-year all-cause mortality for the predictors Veterans Aging Cohort Study (VACS) Index and Grim age acceleration (GrimAA). The number of participants at risk are below each graph. A, For the VACS Index, the median value of the score was used as the cutoff point to define comparison groups. B, For the GrimAA marker, the value of zero was used as the cutoff point to define accelerated aging (>0) or expected aging (≤0). Abbreviation: CI, confidence interval.

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