Host immunosenescence compromises <i>Mycobacterium tuberculosis</i> clearance

Abstract Immunosenescence increases susceptibility to infectious diseases like tuberculosis (TB) in older subjects (≥60 years) and may impact containment of Mycobacterium tuberculosis (Mtb) during therapeutic intervention. A deeper understanding of cellular and molecular changes with age could inform new strategies to improve therapeutic outcomes. Here, we monitored the immunopathology, frequency and functionality of immune cells across extreme age groups of C57BL/6 mice following low aerosol dose infection (100-120 cfu) with Mtb H37Rv and treatment with rifampicin and isoniazid (RIF-INH). Up to 6 weeks of infection, tissue (lung, spleen and liver) mycobacterial load in old (17-19 months; M) and aged (31M) C57BL/6 mice was similar compared to young (2-4M) mice. However, at two weeks post-treatment, older mice showed a slower rate of Mtb clearance in the lungs. Old Mtb-infected mice had higher splenic T-follicular cytotoxic (T FC )-like cells and proteomic analysis of flow-sorted CD4 + CD44 + T cells revealed deregulated mitochondrial proteins (4-hydroxy-2-oxoglutarate aldolase, aspartate aminotransferase and prostaglandin E synthase), pointing to impaired mitochondrial function. Collectively, these findings suggest that age-associated immune alterations may impair immunometabolic processes contributing to delayed Mtb clearance. These results highlight the potential importance of targeting immunometabolic dysfunction to improve TB treatment outcomes in older populations and reduce morbidity. Summary The elderly population is particularly susceptible to tuberculosis (TB), making it crucial to understand the cellular and molecular mechanisms contributing to the decline in immune responses with age. Evaluating the immunopathology, frequency and functionality of immune cells and Mtb-specific antibody responses across different age groups is essential for developing adjunct therapies for geriatric TB patients.