The COVID-19 pandemic has drawn significant attention to factors affecting disease severity, especially in older adults. This study explores the relationship between Klotho, an anti-aging protein, and COVID-19 severity. Conducted at Tehran's Firouzgar Hospital, this case-control study involved 279 participants, assessing serum levels of Klotho, inflammatory markers (C-reactive protein (CRP), Interleukin 6 (IL-6)), and Vitamin D. The findings indicate significantly lower Klotho levels in COVID-19 patients, especially those in the ICU, which correlate with elevated inflammatory markers and reduced Vitamin D levels. This inverse relationship between Klotho levels and disease severity underscores the protein's potential modulatory role in the inflammatory response to COVID-19. The study not only highlights the importance of Klotho as a biomarker for aging and disease severity but also suggests its potential therapeutic value in managing COVID-19, offering a novel perspective on targeting aging-related pathways to mitigate the impact of the disease. These insights open new avenues for research and intervention strategies to leverage anti-aging mechanisms to combat COVID-19 and potentially other age-related diseases.