A 16-week exercise training program showed broad benefits, including cellular damage repair and slowdown in epigenetic aging, in people with HIV (PWH), based on new data presented at the Conference on Retroviruses and Opportunistic Infections (CROI) 2026 Annual Meeting.

Exercise improves overall health and slows the progression of aging-related comorbidities in PWH, but understanding of the feasibility and effects of exercise in this population is limited, lead author Jing Sun, MD, MPH, PhD, associate research professor of epidemiology at the Johns Hopkins Bloomberg School of Public Health in Baltimore, told Medscape Medical News. Evaluation of exercise-related changes at the cellular level may inform targeted strategies to enhance the benefits of exercise, Sun said.

Sun and colleagues designed a study to evaluate the impact of a 16-week exercise intervention on muscle DNA methylation in older PWH using data from the HEALTH trial. “A better understanding of methylation changes will help clarify the mechanisms by which exercise affects physical function and recovery over time,” Sun explained.

The HEALTH study was a randomized controlled trial comparing changes in physical function and fatigue between high-intensity interval training and continuous moderate-intensity training in PWH aged 50 years or older over a 16-week period.

The researchers analyzed DNA methylation data from skeletal muscle lysate and used the Muscle Epigenetic Age Test (MEAT) to evaluate changes in muscle epigenetic age, with tissue specimens from baseline and after 16 weeks. The study population included 38 PWH with a media age of 58 years; 92% were male and 69% were White.

Longitudinal epigenome-wide associations (EWAS) were compared before and after the exercise training in an analysis that controlled for age, sex, race/ethnicity, risk behavior such as smoking and alcohol use, and current CD4 cell counts. The researchers assessed methylation based on CpG site changes, the regions of DNA needed for gene regulation.

After the 16-week training program, longitudinal EWAS identified 44,007 out of 839,410 nominally significant CpG site changes (P < .05) after exercise training; however, none remained significant after correction for False Discovery Rate.

Two types of pathway analyses, namely, gene ontology pathway analyses and the Kyoto Encyclopedia of Genes and Genomes, were used for the nominally significant CpG sites. Between them, they identified significant molecular pathways, including axonogenesis cellular assembly chemical, negative cycle DNA damage, epithelial neural tube formation, endocrine gland mesoderm morphogenesis, embryonic pattern specification, pharyngeal stem cell development, and central nervous neuron differentiation.

In addition, epigenetic age based on the MEAT revealed a nonsignificant 0.9-year (95% CI, -3 to 1.2) age deceleration after 16 weeks of intervention.

The researchers expected the exercise intervention to improve the muscle methylation profile, Sun told Medscape Medical News. “What is new in this study is the identification of several CpG sites linked to multiple genomic pathways that regulate functions beyond muscle tissue, such as the central neural system, suggesting a positive systemic change in methylation that may result from the exercise intervention,” she said.

The sample size of this study was relatively small, although it is among the largest conducted in this area among PWH, Sun noted. “In future studies, we plan to further investigate how hallmarks of aging interact with changes following the exercise intervention,” she said.

The Basis for Exercise Benefits

The current study provides a scientific evaluation on the benefits of exercise for PWH and how the benefits occur on a molecular level, said Shirin Mazumder, MD, an infectious diseases specialist and an associate professor at the University of Tennessee Health Science Center in Memphis, Tennessee.

“Using healthy lifestyle modifications such as exercise as a nonpharmaceutical approach in contributing to health gains in people living with HIV is important,” said Mazumder, who was not involved in the study. Although the evidence regarding the benefits of exercise and its promotion of longevity is overwhelming, the new findings help support the physiologic gains and advantages of physical exercise in PWH in particular, she said.

Despite the known benefits, barriers to implementing an exercise training regimen include individual factors such as lack of time and motivation, as well as fear of injury and lack of support, Mazumder told Medscape Medical News. “People with HIV may have issues with fatigue and mental health challenges, such as depression, that may make it difficult to implement lifestyle modifications,” she added.

“Additional research is needed regarding how other coexisting chronic medical conditions and how external factors such as tobacco use, diet, and alcohol use affect gene regulation in people with HIV,” she said.

The study was funded by the National Institute on Aging and the National Institute of Allergy and Infectious Diseases. The researchers had no financial conflicts to disclose. Mazumder had no financial conflicts to disclose.