Background <p>The role and relevance of macrophages both as causes and therapeutics of cellular senescence is rapidly emerging. However, current knowledge regarding the extent and depth of senescence in macrophages in vivo is limited and controversial. Further, acute models of stress-induced senescence in transformed/cancerous macrophage cell lines are being used although their efficacy and relevance are not characterized.</p> Methods and results <p>The present study sought to address these aspects by first comparing prevalent senescence in naturally aged murine peritoneal macrophages, and then assessing the effects of two different stressors (LPS and H₂O₂) in inducing premature senescence in young peritoneal macrophages. Next, RAW264.7 cell line was exposed to respective stressors and their efficiency in recapitulating the effects of natural senescence markers was characterized. We observed strong upregulation of primary markers of senescence such as SA-β-gal activity, p53, p21, p16^Inka4a, Rb, ATM, and Lamin B1in naturally aged mice along with increased SASP proteins (IL-6/TNF-α/MCP-1) and redox stress (ROS and NO). Aged macrophages also demonstrated severely reduced phagocytosis. Exposure to both LPS and H₂O₂ in young macrophages invoked the expression of all primary markers of senescence although SASP protein expression was exaggerated in LPS stimulation. Similarly, ROS and NO expression increased while phagocytosis decreased. Stimulation of RAW264.7 cells generally revealed a similar trend although the depth of all measured parameters was ostensibly stronger in young peritoneal macrophages. Among the two stressors, LPS stimulation appeared to be relatively more potent.</p> Conclusion <p>Overall, this study emphasizes that LPS exposure to young peritoneal macrophages more strongly recapitulates in vivo cellular senescence in macrophages.</p>