Review Evaluates Factors of Pulmonary Disease Subtype Development

Three authors from institutions in the Denver, Colorado area conducted a review evaluating the roles of sex, ancestry, senescence, and aging (SAnSA) in the development of nontuberculous mycobacterial (NTM) pulmonary disease (PD).

The review, which was published in Journal of Clinical Tuberculosis and Other Mycobacterial Diseases, also highlighted molecular tools and biomarkers to contextualize SAnSA in NTM PD.

More than 86,000 Americans live with NTM PD, which typically adults age 65 and older.

“Aging is a risk factor for the development of a number of medical conditions including PD and increased susceptibility to respiratory infections,” the authors explained. “Consequently, aging can cause the progressive accumulation of cellular metabolic products and increased DNA damage, resulting in the development of a low-grade inflammatory phenotype commonly referred as ‘inflammaging’.”

Many past studies have found NTM PD disproportionately affects older White women. One study included in the review found that women were 1.1 to 1.6 times more likely to develop NTM PD compared with men, and a Japanese study showed that women were more likely to experience more severe NTM PD than men. According to the review authors, this has been shown to be caused by more cavitation in the lung, lower body mass index, and extensive treatment history in women.

Ancestry also plays a role in the disease, as genealogical ancestry can provide a biogeographic history of genetic variations that can be generalized to a population. While not widely studied in regard to respiratory diseases, ancestry has helped in other research on pulmonary function, coronary artery risk, and asthma in African populations, as well as on COPD risk among Native Americans and pulmonary fibrosis in Europeans.

Where someone lives geographically—regardless of their ethnicity—may also contribute to NTM exposure, as some areas have high levels of air pollution and other hazards that can affect gene expression in people with respiratory disease.

Senescence refers to the irreversible loss of somatic cell proliferation and is a widely recognized marker of age. However, senescent cells remain metabolically active and secrete an array biologically active molecules called the senescence-associated secretory phenotype (SASP). Because most studies on mycobacterial PD have been reported in the context of mycobacterium tuberculosis, the authors noted that more research to differentiate the effect of senescence versus inflammaging on NTM PD is needed.

“However, from other generalized studies on senescence, an enhanced SASP response can be triggered by tumor suppressor p21 activation of p38 mitogen-activated protein kinase and Janus-activated kinases resulting in the activation of the proinflammatory transcription factor nuclear factor κB (NFκB),” the authors said. “Upon NFκB activation, multiple inflammatory proteins such as cytokines, chemokines, proteases, and growth factors increase particularly during chronic PD.”

The final category in SAnSA is aging, which can alter the respiratory system’s physiological and molecular function. Adjusted odds ratio (OR) for NTM PD by age group showed the lowest OR (7.4; 95% CI, 2.9-19.3) for people aged younger than 18 and the highest OR (106.4; 95% CI, 42.0-270.0) for people aged 65 and older. Additionally, the disease is rare in women younger than 50.

FEV1 and FVC are indicators of lung volume that peak at age 25 and decline slowly with age alongside lung capacity, and depressed beating of lung cilia can begin as early as age 40.

“Decreased respiratory muscle strength, as much as 20%, is commonly observed in individuals over 70 years of age,” the authors said. “Physiological changes in the lung also occurs across the lifespan caused by exposure to common cellular stressors such as cigarette smoke or oxidative stress due to an imbalance of natural antioxidants and reactive oxygen species.”

While molecular biomarkers of NTM PD and age-related changes in the lung microbiome are not as heavily studied, the authors noted 3 established molecular markers of senescence and 1 marker of aging that could be applied in further research: sirtuins, α-Klotho, senescence marker protein-30 (SMP30), and age marker mTOR.

As current therapeutics are inefficient at controlling NTM PD progression, the review suggested senolytic therapies and potentially a caloric restriction (CR) diet, with exercise to slow down age-related PD.

“An alternative to CR is intermittent fasting regimes and changes in diet regimes that give sufficient CR to activate anti-aging pathways,” the authors noted. “Such options are currently being explored in animal models, but the effectiveness of CR, diet changes, and increased exercise in age-related PD and NTM is yet to be realized.”

Reference

Fifor A, Krukowski K, Honda JR. Sex, ancestry, senescence, and aging (SAnSA) are stark drivers of nontuberculous mycobacterial pulmonary disease. J Clin Tuberc Other Mycobact Dis. 2022;26:100297. doi:10.1016/j.jctube.2022.100297