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Background: Older people with HIV experience more comorbidities and geriatric syndromes than their HIV-negative peers, perhaps due to residual inflammation despite suppressive antiretroviral therapy. Cell-free mitochondrial DNA (cfmtDNA) released during necrosis-mediated cell death potentially acts as both mediator and marker of inflammatory dysregulation. Thus, we evaluated plasma cfmtDNA as a potential biomarker of geriatric syndromes., Methods: Participants underwent the Montreal Cognitive Assessment (MoCA), frailty testing, and measurement of plasma cfmtDNA by qPCR and inflammatory markers including C-reactive protein, interleukin-6 (IL-6), interferon gamma, and tumor necrosis factor alpha in this cross-sectional study., Results: Across 155 participants, the median age was 60 years (Q1, Q3: 56, 64), one-third were female, and 92% had HIV-1 viral load <200 copies/mL. The median MoCA score was 24 (21, 27). The plasma cfmtDNA level was higher in those with cognitive impairment (MoCA <23) ( P = 0.02 by the t test) and remained significantly associated with cognitive impairment in a multivariable logistic regression model controlling for age, sex, race, CD4 T-cell nadir, HIV-1 viremia, and depression. Two-thirds of participants met the criteria for a prefrail or frail state; higher plasma cfmtDNA was associated with slow walk and exhaustion but not overall frailty state. Cognitive dysfunction was not associated with C-reactive protein, IL-6, interferon gamma, or tumor necrosis factor alpha, and frailty state was only associated with IL-6., Conclusions: Plasma cfmtDNA may have a role as a novel biomarker of cognitive dysfunction and key components of frailty. Longitudinal investigation of cfmtDNA is warranted to assess its utility as a biomarker of geriatric syndromes in older people with HIV., Competing Interests: E.L.S., M.C.R., and Y.-S.Z. have no conflicts of interest. C.D.J is a consultant for TheraTechnologies. K.C.H. receives consulting fees from Faeth Therapeutics, Inc.; is on the review board for PESI, Inc.; and receives personal fees for reviewing professional nutrition education programing for PESI, Inc. The spouse of H.M.D.-V. holds employment at Elanco. The spouse of M.E.C. is a cofounder and shareholder and serves on the Scientific Advisory Board of Proterris, Inc. M.J.G. reports research support to the institution (Weill Cornell) from Gilead Sciences and Regeneron; is a consultant for Enzychem, Regeneron, ReAlta Life Sciences, and Sobi and receives royalties from Springer and UpToDate., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Older adults with HIV (OAH) experience more comorbidities and geriatric syndromes than their HIV-negative peers, perhaps because of chronic inflammation. Cell-free mitochondrial DNA (cfmtDNA) released from cells undergoing necrosis-mediated cell death potentially acts as both a mediator and marker of inflammatory dysregulation. We hypothesized that urinary cfmtDNA would be associated with frailty, body composition, and fall history in OAH., Methods: OAH completed frailty testing, a psychosocial survey, body composition assessment, and measurement of urine cfmtDNA and urine albumin:creatinine in this cross-sectional study. Urine cfmtDNA was measured by quantative polymerase chain reaction and normalized to urinary creatinine., Results: Across 150 participants, the mean age was 61 years (SD 6 years), half identified as Black, one-third were women, and 93% had HIV-1 viral load <200 copies/mL. Two-thirds met criteria for a prefrail or frail state. Those with unintentional weight loss had higher urine cfmtDNA concentrations (P = 0.03). Higher urine cfmtDNA was inversely associated with the skeletal muscle index (β = -0.19, P < 0.01) and fat mass index (β = -0.08, P = 0.02) in separate multiple linear regression models adjusted for age, sex, and presence of moderate-severe albuminuria., Conclusions: In this cross-sectional study of OAH, higher levels of urine cfmtDNA were more common in subjects with less robust physical condition, including unintentional weight loss and less height-scaled body mass of fat and muscle. These findings suggest urine cfmtDNA may reflect pathophysiologic aging processes in OAH, predisposing them to geriatric syndromes. Longitudinal investigation of urine cfmtDNA as a biomarker of geriatric syndromes is warranted., Competing Interests: K.C.H. reports personal fees from Faeth Therapeutics, Inc., other from PESI, Inc, outside the submitted work; M.E.C. is supported by the NIH. The spouse of M.E.C. is a cofounder and shareholder and serves on the Scientific Advisory Board of Proterris, and S.K.G. is supported by unrestricted research grants from the NIH, Indiana University, and GlaxoSmithKline/ViiV. He has also received advisory fees from GlaxoSmithKline/ViiV and Gilead Sciences. E.L.S reports a grant from Gilead Sciences during the conduct of the study, and M.J.G. reports grants from Gilead Sciences, during the conduct of the study, grants and personal fees from Regeneron, personal fees from Sobi, personal fees from UpToDate, and personal fees from Springer, outside the submitted work. The remaining authors report no conflicts of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)