Introduction
Tuberculosis (TB), caused by the bacterium Mycobacterium tuberculosis (M.tb), remains a formidable global health challenge. While approximately one-fourth of the world’s population is infected, the majority maintain a state of asymptomatic, latent infection. However, the risk of progressing to active, life-threatening disease is not uniform across all populations. The elderly represent a particularly vulnerable group, exhibiting a significantly higher susceptibility to both primary infection and the reactivation of latent TB [1]. This increased vulnerability is not merely a consequence of a weakened immune system but is deeply rooted in a series of age-related changes within the lung itself. A phenomenon known as “inflamm-aging”—a chronic, low-grade pro-inflammatory state that develops with age—transforms the lung’s mucosal environment from a robust defensive barrier into a more permissive ground for M.tb to thrive. This article will explore the stark contrast between the lung’s defense mechanisms in a healthy adult versus an aged individual, as illustrated in the diagram below, to explain why the elderly lung is more susceptible to M.tb infection.
The Healthy Lung: A State of Defensive Homeostasis
In a healthy, young individual, the lung mucosa represents a highly effective first line of defense against inhaled pathogens like M.tb. This defense is a dynamic interplay between structural components and a vigilant immune system, maintaining a state of homeostasis.
•The Alveolar Structure: The alveoli, the tiny air sacs where gas exchange occurs, are lined by two main types of epithelial cells, or pneumocytes. Type I pneumocytes are thin, squamous cells that form the vast majority of the alveolar surface, providing a physical barrier while facilitating gas exchange. Type II pneumocytes are cuboidal cells that secrete pulmonary surfactant, a complex mixture of lipids and proteins that reduces surface tension and has crucial antimicrobial properties. This entire surface is bathed in Alveolar Lining Fluid (ALF), a thin liquid layer containing surfactant and a host of antimicrobial molecules that can trap and neutralize pathogens [2].
•The Immune Response: When M.tb bacilli breach the upper airways and reach the alveoli, they are met by a swift and effective innate immune response. Resident alveolar macrophages are the primary responders, recognizing and engulfing the bacteria in a process called phagocytosis. They are quickly supported by neutrophils and other immune cells like B cells, which are recruited to the site of infection. In this state of homeostasis, these immune cells are highly functional. They efficiently contain and often eliminate the bacteria, leading to a decreased susceptibility to infection and preventing the establishment of a clinical disease [3].
The Aged Lung: A Pro-Inflammatory Environment of Increased Susceptibility
With advancing age, the lung undergoes a profound transformation. The well-regulated state of homeostasis gives way to inflamm-aging, a condition characterized by chronic, low-grade inflammation that fundamentally alters the lung’s structure and immune function. This creates an environment that, paradoxically, is less effective at fighting off new infections despite being in a constant state of inflammation.
As individuals age they experience an increase in basal inflammation, now recognized as an event called inflammaging. Inflammatory cytokines, including TNF and IL-6, are associated with increased risk for many diseases including sarcopenia, osteoarthritis, and many infectious diseases [1].
This age-related shift dramatically increases susceptibility to M.tb infection through several key mechanisms:
•Cellular Senescence and a Compromised Barrier: The pneumocytes that form the alveolar barrier become senescent. These aged cells lose their regenerative capacity and normal function. Senescent pneumocytes are less effective at maintaining the barrier, and their presence contributes to the overall pro-inflammatory state of the lung. This weakened barrier can be more easily breached by M.tb, allowing the bacteria to infect the pneumocytes themselves, as seen with the Infected Pneumocyte in the diagram.
•Oxidized Alveolar Lining Fluid: The protective ALF becomes a liability. The chronic inflammation and oxidative stress characteristic of the aging lung lead to an Oxidized ALF. Research has shown that this altered fluid not only loses its antimicrobial potency but can actually be utilized by M.tb to its advantage. Studies have demonstrated that ALF from elderly individuals can alter the M.tb cell envelope and gene expression, leading to increased bacterial virulence and pathogenicity [4].
•Dysfunctional Immune Cells: The immune cells that were once efficient defenders become impaired. Alveolar macrophages in the aged lung exhibit decreased phagocytic ability, making them less capable of engulfing and destroying M.tb. Neutrophils show dysregulated chemotaxis and reduced phagocytosis. The entire immune response is delayed and less coordinated. As depicted in the diagram, these Dysfunctional Immune Cells fail to contain the infection. The chronic inflammatory environment impairs the function of both innate and adaptive immune cells, a state known as immunosenescence [4].
Collectively, these changes—a weakened epithelial barrier, a compromised biochemical defense in the ALF, and dysfunctional immune responders—result in a significantly increased susceptibility to infection. The aged lung provides a fertile ground for M.tb to establish itself, replicate, and cause active disease.
Conclusion: The Clinical Challenge of TB in the Elderly
The contrast between the healthy and the aged lung environment highlights why tuberculosis poses such a significant threat to the elderly. The age-associated shift towards inflamm-aging dismantles the lung’s primary defense systems, creating a uniquely vulnerable state. Understanding these specific mechanisms is critical for developing new strategies to protect this growing population. Future interventions may focus not just on targeting the bacterium itself, but on mitigating the effects of inflamm-aging, restoring the integrity of the lung mucosa, and rejuvenating the function of the aged immune system. By addressing the root causes of this age-related susceptibility, we can hope to better protect the elderly from the devastating impact of tuberculosis.
References
1.Piergallini, T. J., & Turner, J. (2017). Tuberculosis in the elderly: Why inflammation matters. Experimental Gerontology, 105, 32–39. https://doi.org/10.1016/j.exger.2017.12.021
2.Khan, Y. S., & Lynch, D. T. (2023). Histology, Lung. In StatPearls. StatPearls Publishing. https://www.ncbi.nlm.nih.gov/books/NBK534789/
3.Gupta, N., Kumar, R., & Agrawal, B. (2018). New Players in Immunity to Tuberculosis: The Host Microbiome, Lung Epithelium, and Innate Immune Cells. Frontiers in Immunology, 9, 709. https://doi.org/10.3389/fimmu.2018.00709
4.Olmo-Fontánez, A. M., & Turner, J. (2022). Tuberculosis in an Aging World. Pathogens, 11(10), 1101. https://doi.org/10.3390/pathogens11101101