STING SNP R293Q Is Associated with a Decreased Risk of Aging-Related Diseases

Abstract

Background: Aging is a multifactorial process driven by several conditions. Among them, inflamm-aging is characterized by chronic low-grade inflammation driving aging-related diseases. The aged immune system is characterized by the senescence-associated secretory phenotype, resulting in the release of proinflammatory cytokines contributing to inflamm-aging. Another possible mechanism resulting in inflamm-aging could be the increased release of danger- associated molecular patterns (DAMPs) by increased cell death in the elderly, leading to a chronic low-grade inflammatory response. Several pattern recognition receptors of the innate immune system are involved in recognition of DAMPs. The DNA-sensing cGAS-STING pathway plays a pivotal role in combating viral and bacterial infections and recognizes DNA released by cell death during the process of aging, which in turn may result in increased inflamm-aging. Objective: The aim of this study was to investigate whether a variation within the STING gene with known impaired function may be associated with protection from aging-related diseases by decreasing the process of inflamm-aging. Methods: STING (Tmem173) R293Q was genotyped in a cohort of 3,397 aged subjects (65–103 years). The distribution of the variant allele in healthy subjects and subjects suffering from aging-associated diseases was compared by logistic regression analysis. Results: We show here that STING 293Q allele carriers were protected from aging-associated diseases (OR = 0.823, p = 0.038). This effect was much stronger in the subgroup of subjects suffering from chronic lung diseases (OR = 0.730, p = 0.009). Conclusion: Our results indicate that decreased sensitivity of the innate immune receptors is associated with healthy aging, most likely due to a decreased process of inflamm-aging.

Aging aggravated liver ischemia and reperfusion injury by promoting STING‐mediated NLRP3 activation in macrophages

“…Cells from older subjects harbored higher levels of extranuclear DNA than cells from younger subjects, which triggered innate immune responses through the DNA‐sensing cGAS‐STING pathway (Lan et al, 2019). Lutz Hamann et al investigated the influence of a STING mutant, which led to known impaired function and found that STING SNP R293Q was associated with a decreased risk of aging‐related diseases (Hamann et al, 2019). Here, we demonstrated that elevated mtDNA release from the aged hepatocytes post‐IR, which was suppressed by STING inhibition in macrophages.…”

Aging, Melatonin, and the Pro- and Anti-Inflammatory Networks

“…cGAS appears as a mediator of cell stress reactions and has been assumed to be involved in aging-related diseases [131]. This interpretation has received support by recent findings on a human Sting gene polymorphism that is associated with low-risk of aging-related diseases, presumably by reducing inflammaging [136].…”

Self-DNA Sensing in Lung Inflammatory Diseases

“…The concentrations of free circulating mtDNA have been reported to increase in elderly people relative to young adults and may contribute to low-grade, chronic inflamm-aging [14]. Protection against aging-associated chronic lung diseases was recently reported in seniors carrying a defective STING allele TMEM173 R293Q, suggesting that decreased STING sensitivity might be associated with healthy aging, likely through reduced inflamm-aging, although this warrants further assessment [103]. With a large and raising global aging population, it is critical to better understand how cells and tissues evolve with age and how this can affect the respiratory system, including the specific role of self-DNA sensing through STING pathway.…”