Although research into the natural mechanisms of disease resistance in bats is still at its infancy, significant breakthroughs have been made in the last decade. Recent studies into bat biology demonstrate a unique balance between enhanced host defense and immune tolerance (Irving et al., 2021). Some examples of enhanced host defense responses include constitutive expression of some IFNs and/or IFN-stimulated genes, higher basal expression of heat-shock proteins (HSPs), an efficient efflux of genotoxic compounds mediated by the ABCB1 transporter, and age-related increase of autophagy. On the other hand, loss (reduction)-of-function mutation in stimulator of IFN genes (STING) molecule and dampened inflammasome activation are the key examples of immune tolerance in bats. It is noteworthy that pathogenesis of many bat-borne viruses, including Ebola virus, SARS-CoV, and SARS-CoV-2, strongly correlates with an aberrant activation of innate immune response that is excessive and/or prolonged (Mandl et al., 2015). In contrast, bats can effectively control the infection without developing signs of diseases during the acute phase response. This observation led to more in-depth investigation into how bats limit excessive or inappropriate innate activation, especially host inflammatory responses. Strikingly, recent studies have demonstrated multi-level mechanisms of dampened inflammasome activation in bats, including the genomic loss of PYHIN gene family including AIM2 (Ahn et al., 2016), dampened transcriptional up-regulation and protein function of NLRP3 (Ahn et al., 2019), and reduced activity of caspase-1 and/or cleavage of IL-1β (Goh et al., 2020). These mechanisms can lead to overall reduction in both virus-induced and age-related inflammation, contributing at least partially to their resistance of viral disease.

Although bats appear to be an excellent model for anti-aging or anticancer research, there have been limited mechanistic studies and few in vivo studies. Recent studies, however, have provided some insights into the potential roles of mitochondrial function, autophagy, telomeres, HSPs, ABCB1 transporter, STING, growth hormone/insulin-like growth factor 1 axis, microRNA, and certain genes in DNA damage checkpoint pathways with altered expression or under strong selection pressure, in cancer resistance and longevity (Foley et al., 2018; Irving et al., 2021; Seluanov et al., 2018). These studies still largely lack functional validation. In addition, there are quite a few important and relevant areas yet to be explored or further studied, such as ROS, immunosenescence, cell cycle or proliferation, and innate lymphoid cells. The high metabolic demand of flight might have triggered significant metabolic stress and release of metabolic byproducts like ROS, ATP, and damaged DNA in ancient bats, leading to immune activation and collateral damage. Therefore, the adaptation to flight could have been the primary driving force for the different molecular mechanisms of unique traits in bats. Such mechanisms can be universal mechanisms shared by all bats or specific strategies harnessed by certain lineage of bats. Some might have pleiotropic effects responsible for more than one phenotype.