Do People Living With HIV Experience Greater Age Advancement Than Their HIV-Negative Counterparts?

Davide De Francesco; Ferdinand W. Wit; Alexander Bürkle; Sebastian Oehlke; Neeltje A. Kootstra; Alan Winston; Claudio Franceschi; Paolo Garagnani; Chiara Pirazzini; Claude Libert; Tilman Grune; Daniela Weber; Eugène H.J.M. Jansen; Caroline A. Sabin; Peter Reiss; on behalf of the the Co-morBidity in Relation to AIDS (COBRA) Collaboration


AIDS. 2019;33(2):259-268. 

In This Article

Abstract and Introduction


Objectives: Despite successful antiretroviral therapy, people living with HIV (PLWH) may show signs of premature/accentuated aging. We compared established biomarkers of aging in PLWH, appropriately chosen HIV-negative individuals, and blood donors, and explored factors associated with biological age advancement.

Design: Cross-sectional analysis of 134 PLWH on suppressive antiretroviral therapy, 79 lifestyle-comparable HIV-negative controls aged 45 years or older from the Co-morBidity in Relation to AIDS (COBRA) cohort, and 35 age-matched blood donors.

Methods: Biological age was estimated using a validated algorithm based on 10 biomarkers. Associations between 'age advancement' (biological minus chronological age) and HIV status/parameters, lifestyle, cytomegalovirus (CMV), hepatitis B (HBV) and hepatitis C virus (HCV) infections were investigated using linear regression.

Results: The average (95% CI) age advancement was greater in both HIV-positive [13.2 (11.6–14.9) years] and HIV-negative [5.5 (3.8–7.2) years] COBRA participants compared with blood donors [−7.0 (−4.1 to −9.9) years, both P's < 0.001)], but also in HIV-positive compared with HIV-negative participants (P < 0.001). Chronic HBV, higher anti-CMV IgG titer and CD8+ T-cell count were each associated with increased age advancement, independently of HIV-status/group. Among HIV-positive participants, age advancement was increased by 3.5 (0.1–6.8) years among those with nadir CD4+ T-cell count less than 200 cells/μl and by 0.1 (0.06–0.2) years for each additional month of exposure to saquinavir.

Conclusion: Both treated PLWH and lifestyle-comparable HIV-negative individuals show signs of age advancement compared with blood donors, to which persistent CMV, HBV co-infection and CD8+ T-cell activation may have contributed. Age advancement remained greatest in PLWH and was related to prior immunodeficiency and cumulative saquinavir exposure.


Despite the success of combination antiretroviral therapy, people living with HIV (PLWH) have an increased burden of noncommunicable age-associated comorbidities compared with HIV-negative individuals.[1,2] The causes of this increased burden of comorbidities remain unclear but may involve an accelerated or accentuated aging process,[3,4] resulting from a complex mix of HIV infection, antiretroviral treatment, chronic viral co-infections and lifestyle/behavioral factors.

Aging can be defined as the time-dependent decline of functional capacity and stress resistance associated with increased risk of disability, morbidity and mortality.[5] There is clear evidence that the rate of aging differs significantly between individuals, because of genetic heterogeneity and environmental factors.[6] Therefore, chronological age may not represent the best way of measuring aging and may not accurately reflect an individual's position in his/her total lifespan.[7] This has led to a search for reliable biomarkers of aging, defined as biological parameters that capture the age-related changes in body function or composition. These biomarkers could serve to measure 'biological' age, a hypothetical value denoting the extent of age-related changes in function and composition of a human body, and predict the onset of age-related diseases and/or expectant residual lifetime more accurately than chronological age.[8]

Many candidate biomarkers of aging have been proposed in the scientific literature and have been used to investigate the association between HIV and aging.[9] Among these, there are markers of chronic systemic immune activation (soluble CD14+ and CD163+ [10,11]), inflammation (C-reactive protein and interleukin-6[12]), coagulation (D-dimer[13]), leukocyte telomere length,[14] somatic mitochondrial DNA mutations,[15] expression levels of the cell cycle regulator CDKN2A,[14] DNA methylation levels,[16] ophthalmological parameters[17] and age-related brain atrophy.[18]

Combinations of biomarkers may more reliably measure these age-related changes (or what is called also 'biological age'), giving more accurate estimates of residual lifetime than that obtained from any single biomarker in isolation. The MARK-AGE project has proposed a method to combine powerful biomarkers of human aging (most of which have been shown to be good markers of age when taken in isolation[19,20]) to predict biological age of individuals, and therefore, assess the aging process.[21,22]

The current study aimed to compare established biomarkers of aging and their combination (as proposed by the MARK-AGE study) in order to evaluate the biological age of PLWH, demographically and lifestyle-matched HIV-negative individuals, and blood donors with similar chronological age. Furthermore, we investigated the associations between any observed age advancement and lifestyle risk factors, chronic viral co-infections including hepatitis B virus (HBV), hepatitis C virus (HCV) and cytomegalovirus (CMV), HIV-related parameters and (cumulative) past or current exposure to antiretroviral drugs.