Abstract
Introduction Despite the success of antiretroviral therapy (ART) in making HIV a chronic condition, People living with HIV (PLWH) experience an increased prevalence of age-related diseases earlier than HIV-negative individuals. These conditions span cardiovascular, metabolic, and neurologic illnesses, suggesting an advanced aging process influenced by chronic inflammation, known as “Inflammaging.” HIV-associated-mitochondrial dysfunction (HIVAMD) is proposed as a significant factor driving this accelerated aging, linked to chronic low-grade inflammation, immune activation, and the side effects of ART. Methods The review delves into the mechanics of mitochondrial dysfunction, highlighting how HIV infection and ART disrupt mitochondrial bioenergetics, leading to oxidative stress and cellular damage. Additionally, the document explores the roles of HIV proteins and ART in exacerbating mitochondrial dysfunction, alongside the effects of CD38 overactivation and IDO-1 pathways, which further deplete NAD+ levels and impair cellular metabolism. Results The analysis underscores the pivotal role of mitochondrial dysfunction in driving accelerated aging in PLWH, highlighting its association with chronic inflammation, immune dysregulation, and ART-related effects. By elucidating the mechanisms underlying HIVAMD, the review emphasizes the importance of targeting mitochondrial dysfunction and associated metabolic pathways as therapeutic strategies to mitigate accelerated aging in PLWH. Conclusion The review advocates for future research endeavors aimed at exploring interventions that could reverse or ameliorate HIVAMD, employing a geroscience-guided approach to enhance the healthspan and quality of life for PLWH. It underscores the need for comprehensive strategies combining pharmacological and non-pharmacological interventions to address the complex interplay between HIV, its treatment, and aging processes.