Now that effective antiretroviral therapy (ART) has been available for 25 years, research has shown that people living with HIV (PLWH) in the United States who have access to health care have a life expectancy close to that of people without HIV. While the longevity among PLWH who are virally suppressed can be looked at as a major success, there’s no denying the fact that increasing age comes with an increased risk of disease.
Moreover, the age-related comorbidities observed among PLWH suggest that they suffer from accelerated aging relative to the general population. A number of conditions typically observed among older adults are now showing up in relatively young PLWH, including neurocognitive disorders, cardiovascular disease, metabolic syndrome, bone abnormalities, and non-HIV-associated cancers. Most of these age-related conditions are caused, at least in part, by the chronic inflammation and immune activation commonly seen among the elderly, and potentially exacerbated by HIV itself or by antiretroviral drugs.
The Difference Between Biological and Chronological Aging
Those who study the physiology of aging speak of two types of it: chronological age and biological age. Chronological age, of course, means how many years you’ve been alive—think, the number of candles on your birthday cake.
Biological age, by contrast, refers to the aging process on a cellular and metabolic level, factors that impact one’s overall health and lifestyle habits regardless of chronological age. Biological aging is also called epigenetic aging, that is, those aspects of aging that are not regulated by genetics, but rather by environmental factors. These range from demographics to habits such as the foods you tend to eat and how often you exercise, to contingencies such as medical conditions and treatments. While chronological age is a major risk factor for functional impairments, there is a great deal of heterogeneity in the health outcomes of older people, with some becoming more frail at a relatively young age and others remaining quite “youthful” into advanced old age. For those who study HIV and care for PLWH, key questions include how the disease, HIV, and its treatment, ART, impact biological aging.
As the world population ages, gerontologists are seeking a deeper understanding of the biological aging process, including the determinants of more and less healthy aging. Toward this aim, scientists continue to search for biological markers, aka biomarkers, of aging—measures that capture individual differences in health, disease, and death on a cellular and metabolic level. One such biomarker that has garnered interest in recent years is DNA methylation (DNAm). Methylation is the cellular process by which methyl groups are added to the DNA molecule, thereby modifying the function of the genes. Since age strongly affects DNA methylation levels, DNA methylation provides a highly accurate biological (aka epigenetic) clock.
Do People Living With HIV Show Accelerated Biological Aging?
To address the gap in data on the effect of HIV and ART on epigenetic biomarkers of aging, a team of European researchers conducted a substudy of a clinical trial comparing ritonavir-boosted darunavir with either raltegravir or tenofovir disoproxil fumarate and emtricitabine in ART-naive PLWH. They analyzed frozen whole blood samples from 168 study participants both before they started treatment, and after two years on ART (with 84 participants on ritonavir-boosted darunavir with raltegravir and 84 participants on ritonavir-boosted darunavir with tenofovir disoproxil fumarate and emtricitabine). The study compared the treated participants to 44 age- and sex-matched control participants without HIV. They analyzed DNA methylation for participants using four commercially available epigenetic age estimators—Horvath’s clock, Hannum’s clock, GrimAge, and PhenoAge.
The study found that, compared to those without HIV, ART-naive PLWH showed higher mean epigenetic age acceleration (EAA) according to all four estimators, with statistical significance for all but Hannum-EAA:
- 2.5 years, 95% confidence interval (CI) 1.89–3.22 for Horvath-EAA;
- 1.4 years, 95% CI 0.74–1.99 for Hannum-EAA;
- 2.8 years, 95% CI 1.97–3.68 for GrimAge-EAA; and
- 7.3 years, 95% CI 6.40–8.13 for PhenoAge-EAA.
The study found more pronounced epigenetic aging among those with CD4 counts less than 200 cells/μL (significant for PhenoAge and Hannum’s clock, P = .0015 and P = .034, respectively) or viral loads over 100,000 copies/mL at baseline (significant for PhenoAge, P = .017). After two years of ART, epigenetic age acceleration was reduced, although estimates remained significantly higher among PLWH compared to those without HIV according to PhenoAge (mean difference 3.69 years, 95% CI 1.77–5.61; P = .0002) and GrimAge (mean difference 2.2 years, 0.47–3.99; P = .013).
The study observed no significant differences in the impact of ART on epigenetic aging between treatment regimens. Among participants with HIV at baseline, the study observed dysregulation of DNA methylation-based estimated leucocyte, or white blood cell, subsets toward more differentiated T-cell phenotypes and proinflammatory leucocytes. This dysregulation was corrected to some degree by ART.
Thus, the study’s authors concluded that initiating ART partially reversed epigenetic aging associated with untreated HIV infection. The authors stated that further studies are needed to explain the long-term dynamics and clinical relevance of epigenetic aging biomarkers among PLWH. “More evidence is needed to elucidate whether biomarkers of epigenetic aging could help to identify people with chronic HIV who are more likely to suffer premature age-related comorbidities,” the authors wrote.
Questioning the Clinical Relevance
In an accompanying editorial, Jacqueline Capeau, M.D., Ph.D., a professor of cell biology and metabolism at the Pierre and Marie Curie Faculty of Medicine in Paris, noted that the advance in epigenetic age was smaller than that observed in previous studies and was not associated with clinical outcomes; thus, the clinical utility of evaluating epigenetic age among PLWH remains questionable. “Perhaps not evaluation of epigenetic age at the individual level, but in clinical studies, especially in aging people living with HIV, such evaluation could be useful,” Capeau stated. Moreover, she noted, the epigenetic impact of viral co-infections, including cytomegalovirus, hepatitis C, and hepatitis B, as well as some ART agents and regimens, warrants further investigation. Nevertheless, Capeau added, “Enhanced epigenetic age in those who initiate ART late, even if their HIV is well controlled thereafter, indicates a need for careful follow-up in terms of age-related comorbidities.”