Investigating Biological Aging Measures, Neurocognitive Performance, and Depressive Symptoms: Moderating Effects of HIV and Childhood Maltreatment

Introduction: Neurocognitive impairment and depression remain common among people with HIV (PWH), and childhood maltreatment (CM) may further increase vulnerability. In this cohort, we previously reported that PWH exhibited shorter absolute telomere length, lower MRI-based brain-predicted age difference, and greater epigenetic age acceleration (AA) compared to controls, with limited associations with CM severity. Building on this, the present study examines whether these markers are linked to neurocognitive performance and depressive symptoms, and whether HIV status or CM severity moderates such associations. Methods: In this study of 238 women (122 PWH), biological aging was assessed using absolute telomere length, mitochondrial DNA copy number, MRI-based brain-predicted age difference, and DNA methylation AA measures, including Horvath, Hannum, PhenoAge, Horvath intrinsic epigenetic, and Hannum intrinsic epigenetic and extrinsic epigenetic AA. Neurocognitive performance was measured using a standardised assessment battery and global deficit scores (GDS) were derived. Depressive symptoms were assessed with the Centre for Epidemiologic Studies - Depression Scale. Linear regression models examined associations with GDS and depressive symptoms, with interaction models evaluating moderation by HIV status and CM severity. Results: Biological aging markers were not associated with either neurocognitive performance or depressive symptoms. Though HIV infection in combination with higher mitochondrial DNA copy number and extrinsic epigenetic AA was nominally associated with higher GDS (p = 0.012 and p = 0.047, respectively), these associations did not survive correction for multiple testing. Neither HIV nor CM moderated the association between biological aging markers and depression scores. Conclusions: Despite accelerated biological aging being evident in PWH, we found limited evidence of association with neurocognitive performance or depressive symptoms, underscoring their multifactorial nature. Larger longitudinal studies are needed to determine whether these markers predict neurocognitive and psychiatric trajectories.