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Do people living with HIV experience greater age advancement than their HIV-negative counterparts?
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than their HIV-negative counterparts?
"Importantly, the study found that HIV-infected individuals had an age advancement of 13 years, which was significantly greater than both control groups. Lifestyle-matched uninfected controls reported age advancements of 5.5 years whereas healthy blood donors reported a younger biological age of 7 years, highlighting the contribution of lifestyle factors on the rate of aging."
Editorial - Integrative biomarkers of biologic aging in HIV
Rajasuriar, Reenaa,b; Palmer, Clovisc; Abdel-Mohsen, Mohamedd; Kamaruzzaman, Shahrul Bahyahe
AIDS: February 1, 2019
Aging is a highly complex process impacted by several genetic and environmental factors. Thus, an individual may experience comorbidities and age-associated dysfunction well before they reach the traditional age cut-offs of 'old.' Epidemiological evidence has suggested that certain diseases and/or its treatment may increase the susceptibility of individuals to age-associated dysfunction later in life, as observed with patients surviving cancer and people living with HIV (PLHIV) [1]. This suggests that fundamental cellular and molecular pathways common to the aging process may be altered as a function of the disease or its treatment and understanding this interaction may help alter the trajectory of aging in these individuals.
There has been significant interest in defining biomarkers of aging, which can offer a means of identifying individuals vulnerable to age-associated functional decline [2,3]. As aging is multicausal, a multidisciplinary approach is needed to comprehensively examine the interaction between diseases and aging, and to identify a set of reliable biomarkers. In studies among PLHIV, exploration of biomarkers has largely focused on candidate pathways including markers of immune activation [4], inflammation [5], cell cycle/proliferation [6] or DNA methylation [7], while studies considering the interaction of multiple pathways are lacking. To this end, the study by De Francesco et al. [8] leverages on a panel of 10 biomarkers developed by the MARK AGE collaboration to explore if HIV infection and lifestyle factors contribute to 'age advancement.' The biological age of participants was derived from the combination of these biomarkers using a weighted algorithm previously validated in over 3000 individuals (35-74 years) from eight European countries [3]. Participants from the Co-morbidity in related to AIDS (COBRA) cohort were studied and included HIV-infected individuals on suppressive ART, lifestyle-matched HIV-negative controls, and healthy blood donors who were stringently screened for sexual risk behaviours and chronic infections. Individuals with neurological or psychiatric conditions were, however, excluded; a bias, which significantly impacts the generalizability of the study findings, given the importance of psychosocial factors in driving age-associated dysfunction [9]. Nevertheless, this is an important study, which assessed not only the influence of HIV-related parameters, but also the influence of lifestyle factors and chronic co-infections on biological age. Importantly, the study found that HIV-infected individuals had an age advancement of 13 years, which was significantly greater than both control groups. Lifestyle-matched uninfected controls reported age advancements of 5.5 years whereas healthy blood donors reported a younger biological age of 7 years, highlighting the contribution of lifestyle factors on the rate of aging.
When all HIV-related factors including exposure to antiretroviral therapy (ART) were assessed in a multivariate analysis, age advancement was independently associated with chronic HBV co-infection (average increase = 7.4 years), total cytomegalovirus (CMV) IgG levels (1.9 years for every 1 log AU increase), nadir CD4+ less than 200 cells/μl (3 years), and cumulative saquinavir exposure (1.2 years for every year of exposure). Prior studies both in the general and HIV-infected population have also suggested that increased biologic aging may be associated with chronic viral infections particularly CMV and the extent of immune deficiency previously experienced by PLHIV [10-12]. In the low and middle-income country (LMIC) setting, HIV treatment is generally started late and endemic infections are highly prevalent. These realities raise the question if age advancements differ in ART-suppressed HIV-infected individuals residing in high vs. low-middle income settings. The role of exposure to specific ART regimens and the increased risk of age-associated dysfunction is controversial with some studies reporting increased risks with protease inhibitors [13], Efavirenz [14] and D-drug exposure [15] whereas others not [16]. However, many of these studies have not been sufficiently powered to address this issue comprehensively, a limitation, which also applies to the study by De Francesco et al. [8].
Despite the 'older' biological age of lifestyle-matched controls, it was surprising that none of the lifestyle factors of smoking, alcohol consumption, recreational drug use or sexual risk behaviour were independently associated with age advancement in adjusted analysis, a finding, which the authors ascribed to the low frequency of smokers and potential collinearity in their analysis. It is still unknown whether the multiple processes, which converge to drive aging in PLHIV are mechanistically different from those involved in the normal aging process in uninfected individuals. The adaptation of the MARK AGE algorithm, which was developed for the general population in PLHIV assumes it does, though this needs further validation. Ultimately any set of aging biomarkers established to be used in PLHIV will need to be validated against other established markers of morbidity and mortality in HIV including markers of immune activation, inflammation and hypercoagulation; as well as the presentation of not just chronic comorbidities but also geriatric syndromes, which more accurately capture the phenotype of aging.
The work by De Francesco et al. [8] illustrates the need to uncover novel biomarkers that take into account the fundamental cellular and molecular mechanisms of the aging process in HIV. Work from our group and others have suggested the involvement of other systems including the oral and gut microbiome [17,18], metabolic pathways of glucose and lipids [19,20], as well as glycomics [21,22] as potential regulators of aging in HIV that warrant further assessment. Plasma lipid classes including phosphatidylethanolamine, triacylglycerol ganglioside and monohexosylceramide are strongly associated with inflammation and frailty in ART-treated individuals [19], suggesting the role of altered lipid metabolism in the development of aging phenotypes. Additionally, glycomic studies in the general population have revealed that IgG glycosylation is closely linked to both chronological and biological age whereas certain glycomic traits predict chronological and biological age better than other markers such as telomere length [21,22]. We have recently shown that HIV infection is associated with certain glycomic alterations that are persistent despite several years of viral suppression [23]. Understanding the link between the host glycome and aging with HIV may provide new insights into the mechanistic underpinnings of age-associated and inflammation-associated diseases in PLHIV.
More studies assessing novel, integrative biomarkers, which reflect the multisystem nature of aging and its biology are needed to meaningfully predict an individuals' biologic age.
Do people living with HIV experience greater age advancement than their HIV-negative counterparts?
De Francesco, Davidea; Wit, Ferdinand W.b,c; Bürkle, Alexanderd; Oehlke, Sebastiand; Kootstra, Neeltje A.e; Winston, Alanf; Franceschi, Claudiog; Garagnani, Paolog; Pirazzini, Chiarag; Libert, Claudeh,i; Grune, Tilmanj; Weber, Danielaj; Jansen, Eugène H.J.M.k; Sabin, Caroline A.a; Reiss, Peterb,c on behalf of the the Co-morBidity in Relation to AIDS (COBRA) Collaboration
AIDS: February 1, 2019
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.
Cohort characteristics
The 79 HIV-negative COBRA participants were comparable with the 134 HIV-positive participants in terms of age, sex, years of education, smoking and recreational drug use. HIV-positive participants were more likely to be of black-African origin (P = 0.03) and were less likely to report current alcohol consumption (P = 0.04) than the HIV-negative participants. Compared with both groups of COBRA participants, the blood donor group included a greater proportion of women (P < 0.001). CMV, chronic HBV and HCV co-infections were all more frequent in HIV-positive COBRA participants compared with both the HIV-negative participants and blood donors, with CMV also being more frequent in HIV-negative participants than in blood donors. All HIV-positive COBRA participants had plasma HIV RNA less than 50 copies/ml and were on antiretroviral therapy at study visit, they had a median (IQR) CD4+ T-cell count of 618 (472-806) cells/μl, and 31% had a prior clinical AIDS diagnosis (Table 1). The number and proportion of people who had ever been exposed to each antiretroviral drug and the median (IQR) duration of exposure are reported in Supplementary Table 2, http://links.lww.com/QAD/B389.
Age advancement in HIV-positive and HIV-negative COBRA participants and blood donors
Biological age was significantly greater than chronological age by a mean of 13.2 (95% CI 11.6-14.9) years in HIV-positive COBRA participants and by 5.5 (3.8-7.2) years in HIV-negative participants (P < 0.001 for each). In contrast, biological age was a mean of 7.0 (4.1-9.9) years lower than chronological age in blood donors (P < 0.001, Fig. 1a). Whilst age advancement was greater in both COBRA groups compared with blood donors (P < 0.001 for each), the HIV-positive COBRA participants also demonstrated greater age advancement than the HIV-negative participants (P < 0.001). Age advancement was also negatively correlated with chronological age (Pearson's r = -0.17, P = 0.08) with no significant interaction with HIV-status/group (P = 0.66, Fig. 1b).
Both successfully treated PLWH and people without HIV with similar lifestyles show signs of age advancement compared with healthy blood donors who, conversely, appear younger than their chronological age. This may be explained by the strict requirements around blood donation in the Netherlands. This hypothesis is supported, for example, by the observation that the prevalence of CMV infection was higher in HIV-negative participants (79.8%), and lower in blood donors (22.9%), than in the general Dutch population (50% prevalence at 50 years of age) [27].
Whilst both groups of COBRA participants exhibited age advancement, this was significantly greater in HIV-positive than in HIV-negative participants. Whilst this difference in age advancement did not appear to be explained by differences in participant characteristics, chronic viral co-infections such as CMV and HBV, prior immunosuppression and exposure to some antiretroviral drugs may have contributed to this age advancement. CMV and HBV co-infections may cause premature aging of the immune system in PLWH by their chronic antigenic stimulation, inducing systemic immune activation [28]. In particular, CMV reactivation and concurrent immune responses to control infection are associated with aging and increased morbidity and mortality in both the general population and PLWH [29,30]. In the same group of people reported here, we previously found that increased anti-CMV IgG levels are associated with a higher proportion of terminally differentiated CD4+ and CD8+ T cells as well as CD4+ T-cell activation [31], which may, in turn, have contributed to the observed greater age advancement.
Interestingly, current or past smoking did not appear to affect age advancement. Whilst more direct and accurate measures of smoking (including duration and frequency of smoking) would be more appropriate to evaluate the effect on the agingprocess, we cannot exclude that our findings reflect a lack of association with markers used in this study, especially in cohorts with relatively low smoking frequency (COBRA participants who self-reported current smoking, reported a mean of 12 cigarettes smoked per day). Other factors that have been shown to be associated with different aspects of the aging process of PLWH in previous studies (i.e. HCV co-infection [32] and CD4+ : CD8+ T-cell count ratio [33]) were not linked to greater age advancement. Whilst this is likely to be because of a combination of low statistical power (only five participants were infected with chronic HCV) and collinearity with other lifestyle factors (e.g. recreational drugs for HCV and CD8+ T-cell count for CD4+ : CD8+ ratio), further studies are needed to elucidate potential contributors to the age advancement seen in PLWH.
Among antiretroviral drugs, we found a significant association between age advancement and duration of past exposure to saquinavir, which was independent of concomitant exposure to other drugs generally considered to have the greatest mitochondrial toxicities and potential effects on aging such as didanosine, stavudine, zalcitabine and zidovudine (data not shown). Whereas saquinavir has been shown to directly induce vascular endothelial toxicity in vitro [34], other HIV protease inhibitors were shown to be able to induce vascular smooth muscle cell senescence by downregulating ZMPSTE24, leading to prelamin A accumulation and potential premature vascular aging, changes, which were also observed in peripheral blood mononuclear cells from HIV-infected patients who were treated with the same protease inhibitors [35]. The reason why we only observed an association between age advancement and exposure to saquinavir, but not other HIV protease inhibitors, remains unclear, and suggests this observation should be interpreted with caution. Importantly, having experienced more pronounced immunodeficiency in HIV-positive participants was also linked to an increased age advancement suggesting that a greater effect on aging is likely to occur as the infection remains untreated for longer.
Our findings are consistent with previous reports of brain aging in the COBRA study [18] and with other studies of cellular and molecular markers of biological aging. Indeed, studies of telomere length and CDKN2A [14,36], CD8+ T-cell senescence [37], and DNA methylation profiles ('epigenetic clock') [16,38] showed similar indications of age advancement in PLWH. Other studies reported evidence of accentuated aging only in PLWH with low nadir CD4+ T-cell counts compared with HIV-negative individuals [39,40]. Of note, however, these previous studies often included untreated PLWH (some with detectable HIV RNA) and HIV-negative controls that differed with regards to some lifestyle behaviors, such as smoking and alcohol consumption. In our study, effectively treated PLWH with high CD4+ T-cell counts and highly comparable HIV-negative controls were purposely recruited in order to reduce the influence of sociodemographic and lifestyle confounding factors. The importance of an appropriately chosen control group of HIV-negative individuals is also highlighted by the finding that HIV-negative COBRA participants showed greater age advancement compared with blood donors. Furthermore, these studies only focus on one single tissue or body system, and are therefore unable to reflect the intrinsic multicausal and multisystem nature of the aging process [41]. Chronic HIV may differently affect the rate of aging at the levels of cells, tissues or body systems within the same organism and this complexity is more likely reflected by a method used in our study, which integrates multiple sources of molecular, cellular and physiologic data.
Age advancement reflects the difference in body function and composition of an individual relative to that of a similarly-aged 'healthy' individual. As such, it is not surprising that we found a weak negative correlation with chronological age that, if anything, may reflect survivorship bias. Moreover, as we found no interaction between the correlation of age advancement with chronological age and HIV-status/group, our results are more suggestive of accentuated rather than accelerated aging in the context of treated HIV disease. However, longitudinal follow-up is required to more appropriately address this issue. Accentuated aging occurs when there is an increased burden of aging-related damage but the year-on-year damage remains static over time whereas accelerated aging occurs when the decline arises earlier than expected and implies a progressive increase in the rate of decline [42].
Unmeasured confounders (e.g. living settings (urban vs. rural), diet, physical activity, sleep habits and direct, rather than self-reported, information on smoking and substance/alcohol use) may also have contributed to the increased age advancement we observed in both PLWH and lifestyle-matched HIV-negative individuals and also to the apparent increase due to HIV. Our study has further limitations. Given the cross-sectional design, it can only assess associations and longitudinal studies would be necessary to evaluate the potential causal role of HIV and the interplay with antiretroviral drugs and viral co-infections. The sample size was believed to be sufficient to allow meaningful analysis; however, the study may not be powered enough to evaluate associations with cumulative exposure to antiretroviral drugs as they were evaluated only on participants with prior exposure to a drug. Also our cohort predominantly constitutes white, northern European MSM over the age of 45 years. Results may, therefore, not be generalizable to younger populations or populations within a different HIV epidemic setting. Also, individuals with major depression were excluded from the study; as psychological stress has been linked with molecular changes that can affect the aging process [43], this could have resulted in an underestimation of age advancement in both COBRA groups. Finally, the age advancement observed in PLWH, COBRA HIV-negative individuals and blood donors is relative to the population used by the MARK-AGE project to develop the algorithm to estimate biological age. Individuals with self-reported HIV, HBV (except seropositivity by vaccination), HCV or cancer were excluded but the representativeness of the sample to European countries involved in the MARK-AGE study still needs to be assessed. Whilst the algorithm has not been yet validated in external population (including cohort of PLWH), it showed promising results in individuals affected by Down's syndrome who, as expected, showed greater age advancement compared with the general population (manuscript in preparation). Moreover, sensitivity analysis in our cohort suggest a positive correlation between age advancement and the number of age-associated comorbidities (Pearson's r = 0.18, P = 0.007) and time needed to walk 15 feet (Pearson's r = 0.13, P = 0.04) as well as a negative correlation with hand grip (Pearson's r = -0.12, P = 0.05), a validated measure of frailty.
In conclusion, our results suggest that PLWH with undetectable plasma HIV RNA may experience accentuated aging compared with HIV-negative individuals with similar lifestyles, as estimated using a set of validated biomarkers of aging. This age advancement appears to be related to viral co-infections such as CMV and chronic HBV, but also to historic severe immunosuppression and possibly exposure to particular antiretroviral drugs. Future longitudinal studies are required to further help clarifying the effect of HIV and its treatment on the natural aging process and the functional and clinical consequences in the millions of PLWH worldwide.

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