Far too little research into infectious disease and the development of vaccines and other approaches to therapy employs old animals. It is accepted that infectious disease becomes worse with age and treatments become less effective, and then left to the smaller aging research community to see if anything can be done about it. Here, for example, is an example of research in which scientists attempt to build an incrementally better picture as to what exactly is going wrong in the aging immune system, in the specific context of a single infectious disease, tuberculosis. Matters move slowly.
Aging profoundly impairs immune competence, a phenomenon termed immunosenescence, rendering older adults (≥60 years) highly vulnerable to infectious diseases such as tuberculosis (TB). Clinically, older adults exhibit reduced vaccine effectiveness alongside heightened susceptibility to TB, with epidemiological data indicating 2-3 times higher TB incidence and up to four times higher mortality than younger patients. Despite this growing burden, current TB research predominantly employs young adult mouse models (6-8 weeks old, equivalent to ~18-year-old humans), which do not adequately capture the immune landscape of older hosts. Evidence from studies suggests that old mice exhibit higher bacterial burden, delayed CD4+ T cell responses, and altered immune activation compared to younger counterparts. However, the impact of immunosenescence on bacterial clearance dynamics, immune cell phenotypes, and host responses during TB treatment remain largely unexplored.
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 TB and treatment with rifampicin and isoniazid (RIF-INH). Up to 6 weeks post infection, mycobacterial load in tissues (lung, spleen, and liver) of old (17-19 months old) and aged (31 months old) C57BL/6 mice was similar to that of young (2-4 month old) mice. However, at two weeks post-treatment, older mice showed a slower rate of TB clearance in the lungs. TB-infected old mice had higher splenic T-follicular cytotoxic (TFC)-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), suggesting impaired mitochondrial function.
Collectively, these findings suggest that age-associated immune alterations may disrupt immunometabolic pathways, thereby contributing to the delayed TB clearance. Targeting immunometabolic dysfunction therefore represents a promising strategy to enhance TB treatment efficacy and reduce disease burden in older populations.
Link: https://doi.org/10.18632/aging.206374
View the full article at FightAging
