Fight Aging!

It has taken some time for researchers involved in the study of the comparative biology of aging between species to start moving genes from long-lived species into short-lived species. This is now underway to some degree, however. One research group reported on the results of moving a naked mole-rat cancer resistance gene into mice not so long ago. In today's open access paper, a different set of researchers report on the results of moving the STING gene from a long-lived bat species into very much shorter-lived mice. STING is involved in innate immune sensing of pathogens and damage. Pathways involving STING are maladaptively triggered in later life, contributing to a rising level of chronic inflammation. That chronic inflammation is disruptive to tissue structure and function, contributing to age-related disease.

Bats are notoriously resilient to the consequences of viral infection, making them able to act as reservoirs of viral pathogens that can be spread to other species while apparently causing little to no harm to the bats themselves. It is thought that the mechanisms granting this form of resilience may also confer resistance to the inflammation that occurs in other mammals due to maladaptive innate immune reactions to forms of molecular damage characteristic of aging. The pathways for pathogen-driven and aging-drive inflammatory signaling are known to overlap, and STING is particularly implicated.

Myotis bat STING attenuates aging-related inflammation in female mice

Bats are also recognized as natural reservoir hosts for diverse highly pathogenic viruses, some of which have precipitated large-scale infectious diseases in humans, such as SARS-related coronaviruses and Ebola virus. Bats are also noted for their unparalleled longevity among mammals relative to their size, with those within the genus Myotis exhibiting the greatest longevity, living up to 40 years. However, the mechanisms underlying these unique characteristics, particularly their roles as viral reservoir hosts and long-lived animals, remain inadequately understood.

In recent years, research efforts have predominantly centered on unraveling the coexistence of bats and viruses. Our work, along with that of other researchers, has revealed that bats maintain a constitutively expressed interferon system, with a simultaneous dampening of stimulator of interferon gene (STING) expression and inflammatory response. These characteristics may enable early inhibition of viral replication or moderate the immune response upon viral infection. Notably, a low-level, overactive inflammatory response is also a hallmark of human aging, attributed to the senescence-associated secretory phenotype (SASP), which largely depends on the DNA-cGAS-STING pathway.

We previously identified a universal replacement of the serine 358 residue (a critical activation residue) in STING in bats, leading to attenuated downstream interferon responses and antiviral activity. In recent years, extensive research has explored the role of STING in the human aging process. Studies have shown that the cGAS-STING pathway acts as a driver of the senescence-associated secretory phenotype (SASP) in humans, and inhibiting cGAS-STING signaling may be a potential strategy for impeding neurodegenerative processes in old age. Consequently, we hypothesized that the uniquely dampened character of STING in bats may contribute to their relatively extended healthspan. In this study, we established a Myotis davidii bat STING (MdSTING)-knock-in mouse model and conducted a comprehensive comparative analysis of aging-related genotypes with wild-type (WT) mice over a 3-year period.

Blood transcriptomic analysis indicated a reduction in aging-related inflammation in female MdSTING mice, as evidenced by significantly lower levels of pro-inflammatory cytokines and chemokines, immunopathology, and neutrophil recruitment in aged female MdSTING mice compared to aged wild-type mice in vivo. These results indicated that MdSTING knock-in attenuates the aging-related inflammatory response and may also improve the healthspan in mice in a sex-dependent manner. Although the underlying mechanism awaits further study, this research has critical implications for bat longevity research, potentially contributing to our comprehension of healthy aging in humans.