BACKGROUND: HIV-1 is associated with accelerated aging. The senescence-associated secretory phenotype (SASP) includes biological and cytokine profiles that induce cellular senescence and inflammaging. In this study, we leveraged the Multicenter AIDS Cohort Study (MACS) to evaluate the role of SASP in aging, HIV-1 reservoir, and inflammation in people with HIV-1 (PWH) on long-term suppressive antiretroviral therapy (ART). METHODS: In this retrospective study we included plasma and serum samples from 27 virally- suppressed PWH and 10 people without HIV-1 (PWoH) collected in 2019 and 2023. SASP markers were quantified in the 2019 and 2023 samples. Plasma residual viremia, intact and defective proviral DNA were quantified in the 2019 samples. Correlations between SASP markers and HIV-1 reservoir were performed using the Spearman test, and the sparse partial least squares discrimination analysis was used to identify variables that distinguish HIV-1 serostatus. RESULTS: All study participants were male with a median age of 59 years. SASP markers did not show significant changes longitudinally in either group. We identified a set of markers that had moderate performance in distinguishing PWH and PWoH, including CMV serum antibody titer, matrix metalloproteinase 9 (MMP-9), Growth/differentiation factor-15, Stanniocalcin-1 and SerpinE1. Among all the SASP markers, MMP-9 was significantly associated with intact HIV-1 proviral levels (rho=0.60, P=0.002). CONCLUSION: In this cohort study, we revealed the relationship between SASP markers and HIV-1 persistence. Future interventions targeting the senescence pathways may impact HIV-1 persistence.