HIV infection is no longer a death sentence: modern antiretroviral therapy keeps the virus in check for decades, and life expectancy for people with HIV is approaching that of the general population. But as they age, they develop cancer, cardiovascular disease, osteoporosis, and kidney failure more often than their HIV-negative peers. This suggests that HIV accelerates biological aging. Epigenetic clocks based on DNA methylation have become a popular tool for quantifying biological age. Western studies have shown that in people with HIV, epigenetic age often runs ahead of chronological age, but once therapy begins, that acceleration can slow down. Data from the Japanese population are almost nonexistent, and genetic background and lifestyle can strongly influence methylation.
This is a single-center, cross-sectional observational study of adult Japanese men with HIV who have been on antiretroviral therapy for at least 12 months. Participants are being recruited at Tokyo Metropolitan Komagome Hospital. Each person provides a whole-blood sample, from which DNA is extracted and treated with bisulfite to reveal methylation at roughly 930,000 CpG sites using the Illumina Infinium MethylationEPIC v2.0 array. Epigenetic age is calculated with several clocks: PC-Horvath, PC-Hannum, and PC-PhenoAge (trained on Japanese people), plus Horvath, Hannum, PhenoAge, GrimAge, GrimAge v2, and DunedinPACE. Epigenetic age acceleration is defined as the residual from regressing epigenetic age on chronological age. The primary analysis examines the link between treatment duration and acceleration; secondary analyses look at drug classes, frailty, lifestyle (smoking, alcohol, physical activity, sleep, diet), and immune, metabolic, and inflammatory markers. To uncover biological mechanisms, the team will also search for differentially methylated positions and regions, followed by gene ontology analysis.
The study is not yet complete: recruitment is scheduled from January 2026 to March 2027, so there are no concrete results so far. The expectation is that epigenetic age acceleration will correlate negatively with treatment duration, meaning that those who have been treated longer may have a biological age closer to their chronological age. The researchers also expect to find differences between classes of antiretroviral drugs and a link between acceleration and markers of inflammation and lifestyle. Statistical power was calculated for 100 participants, enough to detect a correlation of −0.30 at a 5% significance level with 90% power.
The work fills a gap in data from a non-Western population: most studies of epigenetic aging in HIV have been conducted in Europe and the United States. Using clocks trained on a Japanese sample improves the accuracy of the estimate and makes it possible to test how universal the findings of Western studies really are. If the link between drug classes and epigenetic aging holds up, it could sway treatment choices toward regimens that accelerate biological aging less. In addition, a detailed assessment of diet and lifestyle will, for the first time, allow researchers to gauge their contribution to epigenetic aging in people with HIV.
Looking ahead, this study could lay the groundwork for longitudinal observations that track changes in epigenetic age in the same people over time. If epigenetic age acceleration turns out to be reversible with a change of therapy or lifestyle, that would open the door to interventional trials. Expansion to other populations is also possible, including women and people of different ethnic backgrounds, to find out how universal the results are.
The findings could shape the clinical management of people with HIV, in particular the choice of antiretroviral drugs with an eye to their effect on biological aging. They also matter for gerontology and the epidemiology of aging, because they demonstrate how applicable epigenetic clocks are in a specific population with a chronic infection.
The immediate steps include completing recruitment, running the methylation analysis, and calculating epigenetic clocks, followed by a statistical analysis of associations. Further down the line, the team plans to publish the results and possibly to launch a longitudinal follow-up of the cohort.
In HIV medicine, one question remains unresolved: why do people with suppressed viral load still face a higher risk of age-related diseases? This study directly ties epigenetic aging to clinical and behavioral factors, which could shed light on the mechanisms of accelerated aging and point to modifiable targets for intervention.
The Horvath epigenetic clock, created in 2013, can predict chronological age with an error of only about 3.6 years from a sample of almost any tissue, including blood, brain, and skin.
Not published on arXiv. Here are its page, the PDF and the formalization: you can check it yourself, not only read our account.