Exercise to Prevent Accelerated Vascular Aging in People Living With HIV

Abstract

Given advances in antiretroviral therapy, the mortality rate for HIV infection has dropped considerably over recent decades. However, people living with HIV (PLWH) experience longer life spans coupled with persistent immune activation despite viral suppression and potential toxicity from long-term antiretroviral therapy use. Consequently, PLWH face a cardiovascular disease (CVD) risk more than twice that of the general population, making it the leading cause of death among this group. Here, we briefly review the epidemiology of CVD in PLWH highlighting disparities at the intersections of sex and gender, age, race/ethnicity, and the contributions of social determinants of health and psychosocial stress to increased CVD risk among individuals with marginalized identities. We then overview the pathophysiology of HIV and discuss the primary factors implicated as contributors to CVD risk among PLWH on antiretroviral therapy. Subsequently, we highlight the functional evidence of premature vascular dysfunction as an early pathophysiological determinant of CVD risk among PLWH, discuss several mechanisms underlying premature vascular dysfunction in PLWH, and synthesize current research on the pathophysiological mechanisms underlying accelerated vascular aging in PLWH, focusing on immune activation, chronic inflammation, and oxidative stress. We consider understudied aspects such as HIV-related changes to the gut microbiome and psychosocial stress, which may serve as mechanisms through which exercise can abrogate accelerated vascular aging. Emphasizing the significance of exercise, we review various modalities and their impacts on vascular health, proposing a holistic approach to managing CVD risks in PLWH. The discussion extends to critical future study areas related to vascular aging, CVD, and the efficacy of exercise interventions, with a call for more inclusive research that considers the diversity of the PLWH population.

Keywords: aging; antiretroviral therapy; arteries; cardiovascular diseases; exercise therapy; inflammation; oxidative stress.

Figure 1.

Overview of the potential underlying mechanisms contributing to premature vascular aging and cardiovascular risk among individuals with PLWH included in this review. Created with Biorender.com.

Figure 2.

The hypothesized association of age with CVD risk by HIV serostatus and marginalized identity. The data included are hypothetical but based on review of current evidence. Additional work is necessary to better understand CVD epidemiology among PLWH at the intersections of race, ethnicity, sex, gender identity, and sexual orientation, with further contextualization by consideration of social determinants of health. Created with Biorender.com.

Figure 3.

Detailed overview indicating the potential mechanisms contributing to accelerated vascular aging, as well as the pathways by which exercise may prove beneficial for reducing vascular aging among PLWH. Note that many of these pathways have been established in pre-clinical or clinical aging studies using models or people without HIV infection. Therefore, while a strong theoretical basis exists for these pathways in PLWH, studies are desperately needed to test these hypothesized benefits. eNOS, endothelial nitric oxide synthase; SASP, senescence-associated secretory phenotype; NFkB, Nuclear factor kappa-light-chain-enhancer of activated B cells; MAPK, mitogen-activated protein kinase; JNK, c-Jun N-terminal kinases; oxLDL, oxidized low density lipoproteins. Created with Biorender.com.

Figure 4.

The effects of exercise modalities, including steady state aerobic exercise, resistance exercise, and high intensity interval training (HIIT) on endothelial function, arterial stiffness, and immune cell function. Arrows indicate the directionality of the association between the exercise modality and the physiological response of interest. The darker arrows indicate investigator-determined strength of evidence, and the question marks indicate we could not find adequate evidence to establish directionality. Created with Biorender.com.