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• W3041837368 abstract "For centuries, people believed that bats possessed sinister powers. Bats are thought to be ancestral hosts to many deadly viruses affecting humans including Ebola, rabies, and most recently SARS-CoV-2 coronavirus. However, bats themselves tolerate these viruses without ill effects. The second power that bats have is their longevity. Bats live much longer than similar-sized land mammals. Here we review how bats’ ability to control inflammation may be contributing to their longevity. The underlying mechanisms may hold clues to developing new treatments for age-related diseases. Now may be the time to use science to exploit the secret powers of bats for human benefit. For centuries, people believed that bats possessed sinister powers. Bats are thought to be ancestral hosts to many deadly viruses affecting humans including Ebola, rabies, and most recently SARS-CoV-2 coronavirus. However, bats themselves tolerate these viruses without ill effects. The second power that bats have is their longevity. Bats live much longer than similar-sized land mammals. Here we review how bats’ ability to control inflammation may be contributing to their longevity. The underlying mechanisms may hold clues to developing new treatments for age-related diseases. Now may be the time to use science to exploit the secret powers of bats for human benefit. There are more than 1,400 species of bats (Figure 1A) that inhabit all continents except Antarctica. A majority of bats are active at night and inhabit “spooky” places such as caves, wells, attics, and hollow trees, which has caused people to (falsely) attribute devilish properties to bats. Many bats live in large colonies, which promotes transmission of viruses and other pathogens. Bats are diverse in their feeding habits. Many bats feed on flying insects, others feed on fruits and nectar, but there are also carnivorous bats that catch fish and small crustaceans such as scorpions and, of course, vampire bats that feed on blood. Bats are the only species of mammal capable of powered flight, and some species can reach speeds of up to 100 miles per hour, making them the fastest mammals on earth (McCracken et al., 2016McCracken G.F. Safi K. Kunz T.H. Dechmann D.K. Swartz S.M. Wikelski M. Airplane tracking documents the fastest flight speeds recorded for bats.R. Soc. Open Sci. 2016; 3: 160398Crossref PubMed Scopus (28) Google Scholar). Bats play important role in many ecosystems. Insectivorous bats provide pest control by consuming large quantities of insects. Bats suppress crop pests and decrease pesticide use in farming (Maine and Boyles, 2015Maine J.J. Boyles J.G. Bats initiate vital agroecological interactions in corn.Proc. Natl. Acad. Sci. USA. 2015; 112: 12438-12443Crossref PubMed Scopus (77) Google Scholar). Bats also consume mosquitoes that spread human diseases. Furthermore, many plants depend on fruit bats for pollination and seed dispersal. One of the most amazing properties of bats is their longevity. Many bat species such as little brown bat, Brandt’s bat, mouse-eared bat, and Indian flying fox have maximum lifespans of 30–40 years (Tacutu et al., 2018Tacutu R. Thornton D. Johnson E. Budovsky A. Barardo D. Craig T. Diana E. Lehmann G. Toren D. Wang J. et al.Human ageing genomic resources: new and updated databases.Nucleic Acids Res. 2018; 46: D1083-D1090Crossref PubMed Scopus (68) Google Scholar). Other bat species have maximum lifespans around 20 years, which is still very long for species of this size (Tacutu et al., 2018Tacutu R. Thornton D. Johnson E. Budovsky A. Barardo D. Craig T. Diana E. Lehmann G. Toren D. Wang J. et al.Human ageing genomic resources: new and updated databases.Nucleic Acids Res. 2018; 46: D1083-D1090Crossref PubMed Scopus (68) Google Scholar). In general, species maximum lifespan correlates positively with body mass (Austad and Fischer, 1991Austad S.N. Fischer K.E. Mammalian aging, metabolism, and ecology: evidence from the bats and marsupials.J. Gerontol. 1991; 46: B47-B53Crossref PubMed Google Scholar). Larger species tend to be longer lived. However, all bats fall above the regression line for mammals as they live longer than other mammals of similar size (Austad and Fischer, 1991Austad S.N. Fischer K.E. Mammalian aging, metabolism, and ecology: evidence from the bats and marsupials.J. Gerontol. 1991; 46: B47-B53Crossref PubMed Google Scholar; Healy et al., 2014Healy K. Guillerme T. Finlay S. Kane A. Kelly S.B. McClean D. Kelly D.J. Donohue I. Jackson A.L. Cooper N. Ecology and mode-of-life explain lifespan variation in birds and mammals.Proc. Biol. Sci. 2014; 281: 20140298Crossref PubMed Scopus (94) Google Scholar) (Figure 1B). As mentioned earlier, bats live in large dense colonies and they stay around for many years, which creates an ideal ground for transmitting pathogens. Indeed, bats are believed to be ancestral hosts for many deadly viruses including rabies, Ebola, Marburg, Nipah, and Hendra viruses (reviewed in Banerjee et al., 2020aBanerjee A. Baker M.L. Kulcsar K. Misra V. Plowright R. Mossman K. Novel insights into immune systems of bats.Front. Immunol. 2020; 11: 26Crossref PubMed Scopus (6) Google Scholar). The recent zoonotic transmissions of SARS-CoV (Li et al., 2005Li W. Shi Z. Yu M. Ren W. Smith C. Epstein J.H. Wang H. Crameri G. Hu Z. Zhang H. et al.Bats are natural reservoirs of SARS-like coronaviruses.Science. 2005; 310: 676-679Crossref PubMed Scopus (1041) Google Scholar), MERS-CoV (Anthony et al., 2017Anthony S.J. Gilardi K. Menachery V.D. Goldstein T. Ssebide B. Mbabazi R. Navarrete-Macias I. Liang E. Wells H. Hicks A. et al.Further evidence for bats as the evolutionary source of Middle East respiratory syndrome coronavirus.MBio. 2017; 8: e00373-17Crossref PubMed Scopus (82) Google Scholar), and SARS-CoV-2 (Lu et al., 2020Lu R. Zhao X. Li J. Niu P. Yang B. Wu H. Wang W. Song H. Huang B. Zhu N. et al.Genomic characterisation and epidemiology of 2019 novel coronavirus: implications for virus origins and receptor binding.Lancet. 2020; 395: 565-574Abstract Full Text Full Text PDF PubMed Scopus (991) Google Scholar; Zhou et al., 2020Zhou P. Yang X.L. Wang X.G. Hu B. Zhang L. Zhang W. Si H.R. Zhu Y. Li B. Huang C.L. et al.A pneumonia outbreak associated with a new coronavirus of probable bat origin.Nature. 2020; 579: 270-273Crossref PubMed Scopus (1340) Google Scholar) coronaviruses are believed to have originated in bats, or were transmitted by bats to other species and then passed on to humans. Remarkably, these viruses are tolerated by bats and do not cause clinical symptoms. Even experimental inoculation of bats with some of the deadliest viruses only produced subclinical infections (Halpin et al., 2011Halpin K. Hyatt A.D. Fogarty R. Middleton D. Bingham J. Epstein J.H. Rahman S.A. Hughes T. Smith C. Field H.E. Daszak P. Henipavirus Ecology Research GroupPteropid bats are confirmed as the reservoir hosts of henipaviruses: a comprehensive experimental study of virus transmission.Am. J. Trop. Med. Hyg. 2011; 85: 946-951Crossref PubMed Scopus (196) Google Scholar; Middleton et al., 2007Middleton D.J. Morrissy C.J. van der Heide B.M. Russell G.M. Braun M.A. Westbury H.A. Halpin K. Daniels P.W. Experimental Nipah virus infection in pteropid bats (Pteropus poliocephalus).J. Comp. Pathol. 2007; 136: 266-272Crossref PubMed Scopus (0) Google Scholar; Munster et al., 2016Munster V.J. Adney D.R. van Doremalen N. Brown V.R. Miazgowicz K.L. Milne-Price S. Bushmaker T. Rosenke R. Scott D. Hawkinson A. et al.Replication and shedding of MERS-CoV in Jamaican fruit bats (Artibeus jamaicensis).Sci. Rep. 2016; 6: 21878Crossref PubMed Scopus (58) Google Scholar; Paweska et al., 2016Paweska J.T. Storm N. Grobbelaar A.A. Markotter W. Kemp A. Jansen van Vuren P. Experimental inoculation of Egyptian fruit bats (Rousettus aegyptiacus) with Ebola virus.Viruses. 2016; 8: 29Crossref PubMed Scopus (0) Google Scholar; Schuh et al., 2017Schuh A.J. Amman B.R. Sealy T.K. Spengler J.R. Nichol S.T. Towner J.S. Egyptian rousette bats maintain long-term protective immunity against Marburg virus infection despite diminished antibody levels.Sci. Rep. 2017; 7: 8763Crossref PubMed Scopus (18) Google Scholar). What biological mechanisms make bats so special that they can tolerate such scourges and innocently transmit them to humans (Figure 2)? It is important to point out that bats are a very diverse group, so a mechanism found in one species does not necessarily apply to all bats. Here, we will discuss these adaptations as they apply to individual species and the common trends that emerge. The innate immune response is the first line of defense against viruses. Cells express pattern recognition receptors, such as Toll-like receptors, that recognize pathogen-associated molecular patterns originating from viruses, bacteria, or parasites. These receptors then initiate signaling cascades that lead to expression of antiviral and proinflammatory cytokines. Antiviral cytokines include interferons (IFN), which activate expression of downstream genes that inhibit viral replication or induce death of infected cells. Bats have a robust interferon response to RNA viruses. In the Australian black flying fox Pteropus alecto, IFN regulatory factor 7 (IRF7) is expressed in a wider range of tissues compared to other mammals (Zhou et al., 2014Zhou P. Cowled C. Mansell A. Monaghan P. Green D. Wu L. Shi Z. Wang L.F. Baker M.L. IRF7 in the Australian black flying fox, Pteropus alecto: evidence for a unique expression pattern and functional conservation.PLoS One. 2014; 9: e103875Crossref PubMed Scopus (23) Google Scholar). In multiple bat species, IFN regulatory factor 3 (IRF3) has evolved a potential novel phosphorylation site, S185, that enhances activation of the downstream IFN response (Banerjee et al., 2020bBanerjee A. Zhang X. Yip A. Schulz K.S. Irving A.T. Bowdish D. Golding B. Wang L.F. Mossman K. Positive selection of a serine residue in bat IRF3 confers enhanced antiviral protection.iScience. 2020; 23: 100958Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar). Bats also constitutively express IFN-α (Zhou et al., 2016Zhou P. Tachedjian M. Wynne J.W. Boyd V. Cui J. Smith I. Cowled C. Ng J.H. Mok L. Michalski W.P. et al.Contraction of the type I IFN locus and unusual constitutive expression of IFN-α in bats.Proc. Natl. Acad. Sci. USA. 2016; 113: 2696-2701Crossref PubMed Scopus (86) Google Scholar), which in other mammals would lead to widespread inflammation. However, bats have evolved unique adaptations that counteract inflammation. For instance, they show significantly dampened activation of the NLRP3 inflammasome in primary immune cells compared to their human or mouse counterparts (Ahn et al., 2019Ahn M. Anderson D.E. Zhang Q. Tan C.W. Lim B.L. Luko K. Wen M. Chia W.N. Mani S. Wang L.C. et al.Dampened NLRP3-mediated inflammation in bats and implications for a special viral reservoir host.Nat. Microbiol. 2019; 4: 789-799Crossref PubMed Scopus (28) Google Scholar). NLRP3 is an important sensor that recognizes both endogenous cellular damage and infections of either bacterial or viral origin. NLRP3 over-activation has been linked to the inflammatory state and to age-related diseases (Guo et al., 2015Guo H. Callaway J.B. Ting J.P. Inflammasomes: mechanism of action, role in disease, and therapeutics.Nat. Med. 2015; 21: 677-687Crossref PubMed Scopus (1031) Google Scholar; Youm et al., 2013Youm Y.H. Grant R.W. McCabe L.R. Albarado D.C. Nguyen K.Y. Ravussin A. Pistell P. Newman S. Carter R. Laque A. et al.Canonical Nlrp3 inflammasome links systemic low-grade inflammation to functional decline in aging.Cell Metab. 2013; 18: 519-532Abstract Full Text Full Text PDF PubMed Scopus (220) Google Scholar). Remarkably, dampened NLRP3 activity was observed in distant bat species, such as the fruit bat P. alecto and an insectivorous bat Myotis davidii (Ahn et al., 2019Ahn M. Anderson D.E. Zhang Q. Tan C.W. Lim B.L. Luko K. Wen M. Chia W.N. Mani S. Wang L.C. et al.Dampened NLRP3-mediated inflammation in bats and implications for a special viral reservoir host.Nat. Microbiol. 2019; 4: 789-799Crossref PubMed Scopus (28) Google Scholar), suggesting that this is a common mechanism across species. Treating kidney cells from the big brown bat Eptesicus fuscus and human with poly(I:C), a viral double-stranded RNA surrogate, showed that although cells from both species induced expression of IFN-β, only human cells expressed tumor necrosis factor α (TNF-α) (Banerjee et al., 2017Banerjee A. Rapin N. Bollinger T. Misra V. Lack of inflammatory gene expression in bats: a unique role for a transcription repressor.Sci. Rep. 2017; 7: 2232Crossref PubMed Scopus (21) Google Scholar), a cell signaling protein involved in systemic inflammation. Analysis of the TNF promoter in the big brown bat revealed a potential repressor c-REL binding motif (Banerjee et al., 2017Banerjee A. Rapin N. Bollinger T. Misra V. Lack of inflammatory gene expression in bats: a unique role for a transcription repressor.Sci. Rep. 2017; 7: 2232Crossref PubMed Scopus (21) Google Scholar). Thus, downregulated TNF-α expression may be yet another strategy bats use to suppress inflammation. Whole-genome sequencing revealed that several genes involved in innate immunity, including c-REL and NLRP3, are under positive selection in P. alecto and Myotis davidii (Zhang et al., 2013Zhang G. Cowled C. Shi Z. Huang Z. Bishop-Lilly K.A. Fang X. Wynne J.W. Xiong Z. Baker M.L. Zhao W. et al.Comparative analysis of bat genomes provides insight into the evolution of flight and immunity.Science. 2013; 339: 456-460Crossref PubMed Scopus (262) Google Scholar). Bats may also express unique sets of interferon stimulated genes (ISGs). Some of these genes, such as Myxovirus resistance 1 (Mx1), evolved under positive selection in bats and are reported to reduce viral replication when expressed in human cells (Fuchs et al., 2017Fuchs J. Hölzer M. Schilling M. Patzina C. Schoen A. Hoenen T. Zimmer G. Marz M. Weber F. Müller M.A. Kochs G. Evolution and antiviral specificities of interferon-induced Mx proteins of bats against Ebola, influenza, and other RNA viruses.J. Virol. 2017; 91: e00361-17Crossref PubMed Scopus (17) Google Scholar). Although bats mount a strong response to RNA viruses, they exhibit remarkably dampened DNA sensing. The entire PYHIN gene family was found to be missing in 10 bat species, including both fruit- and insect-eating bats (Ahn et al., 2016Ahn M. Cui J. Irving A.T. Wang L.F. Unique loss of the PYHIN gene family in bats amongst mammals: implications for inflammasome sensing.Sci. Rep. 2016; 6: 21722Crossref PubMed Google Scholar; Zhang et al., 2013Zhang G. Cowled C. Shi Z. Huang Z. Bishop-Lilly K.A. Fang X. Wynne J.W. Xiong Z. Baker M.L. Zhao W. et al.Comparative analysis of bat genomes provides insight into the evolution of flight and immunity.Science. 2013; 339: 456-460Crossref PubMed Scopus (262) Google Scholar). This gene family includes cytoplasmic DNA sensors AIM2 and IFI16 that activate the inflammasome and interferon pathways (reviewed in Schattgen and Fitzgerald, 2011Schattgen S.A. Fitzgerald K.A. The PYHIN protein family as mediators of host defenses.Immunol. Rev. 2011; 243: 109-118Crossref PubMed Scopus (132) Google Scholar). AIM2 recognizes bacterial and host DNA in the cytoplasm (Muruve et al., 2008Muruve D.A. Pétrilli V. Zaiss A.K. White L.R. Clark S.A. Ross P.J. Parks R.J. Tschopp J. The inflammasome recognizes cytosolic microbial and host DNA and triggers an innate immune response.Nature. 2008; 452: 103-107Crossref PubMed Scopus (670) Google Scholar), forming the AIM2 inflammasome that mediates maturation of proinflammatory cytokines (IL-1β and IL-18) (reviewed in Broz and Dixit, 2016Broz P. Dixit V.M. Inflammasomes: mechanism of assembly, regulation and signalling.Nat. Rev. Immunol. 2016; 16: 407-420Crossref PubMed Scopus (598) Google Scholar). Although loss of the PYHIN locus appears to be universal, genomic analysis of the remaining sequences suggests different evolutionary processes leading to gene loss, rather than a single ancestral event (Ahn et al., 2016Ahn M. Cui J. Irving A.T. Wang L.F. Unique loss of the PYHIN gene family in bats amongst mammals: implications for inflammasome sensing.Sci. Rep. 2016; 6: 21722Crossref PubMed Google Scholar). Additionally, bats have dampened STING-dependent IFN activation (Xie et al., 2018Xie J. Li Y. Shen X. Goh G. Zhu Y. Cui J. Wang L.F. Shi Z.L. Zhou P. Dampened STING-dependent interferon activation in bats.Cell Host Microbe. 2018; 23: 297-301.e4Abstract Full Text Full Text PDF PubMed Scopus (41) Google Scholar). Upon binding to cytosolic DNA, cGAS binds and activates STING, leading to its phosphorylation on S358. Phosphorylated STING ultimately triggers the type I IFN response. Remarkably, an analysis of 30 bat species revealed that while the S358 residue is absolutely conserved among all known non-bat mammalian STING proteins, none of the bat STING proteins retain S358, leading to a weakened IFN response. The TLR9 receptor, which preferentially recognizes DNA, appears to have evolved under purifying selection in bats and contains multiple mutations in the ligand-binding domain (Escalera-Zamudio et al., 2015Escalera-Zamudio M. Zepeda-Mendoza M.L. Loza-Rubio E. Rojas-Anaya E. Méndez-Ojeda M.L. Arias C.F. Greenwood A.D. The evolution of bat nucleic acid-sensing Toll-like receptors.Mol. Ecol. 2015; 24: 5899-5909Crossref PubMed Scopus (18) Google Scholar). TLR9 in bats shows reduced activation by CpG-containing oligonucleotides compared to human TLR9 (Banerjee et al., 2017Banerjee A. Rapin N. Bollinger T. Misra V. Lack of inflammatory gene expression in bats: a unique role for a transcription repressor.Sci. Rep. 2017; 7: 2232Crossref PubMed Scopus (21) Google Scholar). Interestingly, the DNA repair protein DNA-PK, which also serves as cytoplasmic DNA sensor, is positively selected in bats (Zhang et al., 2013Zhang G. Cowled C. Shi Z. Huang Z. Bishop-Lilly K.A. Fang X. Wynne J.W. Xiong Z. Baker M.L. Zhao W. et al.Comparative analysis of bat genomes provides insight into the evolution of flight and immunity.Science. 2013; 339: 456-460Crossref PubMed Scopus (262) Google Scholar), possibly compensating for the lack of other DNA sensors. Macrophages from the greater mouse-eared bat, Myotis myotis, challenged with various inflammatory stimuli upregulated interferon β (INF-β), TNF, and interleukin-1β (Il-1β). However, in bat macrophages, but not mice, this antiviral, proinflammatory response was associated with high-level transcription of the anti-inflammatory cytokine Il-10, which may help neutralize proinflammatory responses (Kacprzyk et al., 2017Kacprzyk J. Hughes G.M. Palsson-McDermott E.M. Quinn S.R. Puechmaille S.J. O’Neill L.A.J. Teeling E.C. A potent anti-inflammatory response in bat macrophages may be linked to extended longevity and viral tolerance.Acta Chiropt. 2017; 19: 219-228Crossref Scopus (10) Google Scholar). The picture that emerges from the large number of studies of bat immunity is somewhat counterintuitive. A majority of immune system adaptations found in bats dampen the immune response rather than activating it. We can learn from bats that to co-exist with viruses, controlling inflammation is more important than ramping up the immune system to combat the virus, which could lead to an inflammatory cytokine storm, exacerbating disease phenotypes and contributing to mortality. Perhaps in certain contexts, controlling inflammation is more important than ramping up the immune system to combat the virus, which could lead to an inflammatory cytokine storm, exacerbating disease phenotypes and contributing to mortality. Outside of the immune system, autophagy is a process that may help bats fight viruses. Autophagy, or “self-eating,” is a cellular process that destroys and recycles cellular proteins and organelles (Saha et al., 2018Saha S. Panigrahi D.P. Patil S. Bhutia S.K. Autophagy in health and disease: a comprehensive review.Biomed. Pharmacother. 2018; 104: 485-495Crossref PubMed Scopus (67) Google Scholar). Autophagy can remove damaged proteins and can also help rid the cell of viruses. Cells from the black flying fox P. alecto are less susceptible than human cells to death induced by Australian bat lyssavirus, a virus related to rabies. P. alecto cells showed elevated basal autophagic levels, which are further induced in response to high doses of virus (Laing et al., 2019Laing E.D. Sterling S.L. Weir D.L. Beauregard C.R. Smith I.L. Larsen S.E. Wang L.F. Snow A.L. Schaefer B.C. Broder C.C. Enhanced autophagy contributes to reduced viral infection in black flying fox cells.Viruses. 2019; 11: 260Crossref PubMed Scopus (9) Google Scholar). Why did bats evolve such tolerance to viruses? It has been proposed that unique evolution of immunity in bats is driven by flight (Banerjee et al., 2020aBanerjee A. Baker M.L. Kulcsar K. Misra V. Plowright R. Mossman K. Novel insights into immune systems of bats.Front. Immunol. 2020; 11: 26Crossref PubMed Scopus (6) Google Scholar; Kacprzyk et al., 2017Kacprzyk J. Hughes G.M. Palsson-McDermott E.M. Quinn S.R. Puechmaille S.J. O’Neill L.A.J. Teeling E.C. A potent anti-inflammatory response in bat macrophages may be linked to extended longevity and viral tolerance.Acta Chiropt. 2017; 19: 219-228Crossref Scopus (10) Google Scholar; O’Shea et al., 2014O’Shea T.J. Cryan P.M. Cunningham A.A. Fooks A.R. Hayman D.T. Luis A.D. Peel A.J. Plowright R.K. Wood J.L. Bat flight and zoonotic viruses.Emerg. Infect. Dis. 2014; 20: 741-745Crossref PubMed Scopus (121) Google Scholar; Zhang et al., 2013Zhang G. Cowled C. Shi Z. Huang Z. Bishop-Lilly K.A. Fang X. Wynne J.W. Xiong Z. Baker M.L. Zhao W. et al.Comparative analysis of bat genomes provides insight into the evolution of flight and immunity.Science. 2013; 339: 456-460Crossref PubMed Scopus (262) Google Scholar). Bats are the only flying mammals and flight requires metabolic adaptation to sudden surges in activity, rapid increases in body temperature (O’Shea et al., 2014O’Shea T.J. Cryan P.M. Cunningham A.A. Fooks A.R. Hayman D.T. Luis A.D. Peel A.J. Plowright R.K. Wood J.L. Bat flight and zoonotic viruses.Emerg. Infect. Dis. 2014; 20: 741-745Crossref PubMed Scopus (121) Google Scholar), and perhaps, dealing with the molecular damage, such as misfolded proteins and damaged DNA, that arise (Banerjee et al., 2020aBanerjee A. Baker M.L. Kulcsar K. Misra V. Plowright R. Mossman K. Novel insights into immune systems of bats.Front. Immunol. 2020; 11: 26Crossref PubMed Scopus (6) Google Scholar). Thus, bats may have downregulated their inflammatory pathways in order not to suffer from bouts of inflammation every time they fly. Flight is indeed a unique feature of bats, and it is plausible that some of the adaptations are related to flight. However, the fastest evolving genes, in general, are genes related to the host-pathogen arms race (Lazzaro and Clark, 2012Lazzaro B.P. Clark A. Rapid evolution of innate immune response genes.in: Singh R.S. Xu J. Kulathinal R.J. Rapidly Evolving Genes and Genetic Systems. Oxford Scholarship Online, 2012Crossref Google Scholar). This evolution is driven by the presence of pathogens and happens much faster than evolution of such complex functions as flight, which require major changes to body structures. We speculate that the driving force in the evolution of bat immunity has been their lifestyle, which promotes rapid transmission of viruses. Many bat species live in gigantic colonies, where individuals spend resting periods hanging very close together on a cave ceiling or in a tree. Bat colony size may range from a few individuals to hundreds of thousands. This is the highest density among mammals, with the exception perhaps of humans in large metropolises, and considering their high mobility and foraging behavior, bats are exposed to an exceptionally high variety of viruses. The long lifespan of bats is quite striking. A recent study by Wilkinson and Adams was able to reconstruct longevity across a wide range of bat species, proposing that the ancestral bat species likely lived 2.6 times longer than a similar-sized placental mammal (Wilkinson and Adams, 2019Wilkinson G.S. Adams D.M. Recurrent evolution of extreme longevity in bats.Biol. Lett. 2019; 15: 20180860Crossref PubMed Scopus (10) Google Scholar). Moreover, extreme longevity has arisen at least four separate times during bat speciation, with the longest-lived bat on record, the Brandt’s bat, surviving 41 years (Podlutsky et al., 2005Podlutsky A.J. Khritankov A.M. Ovodov N.D. Austad S.N. A new field record for bat longevity.J. Gerontol. A Biol. Sci. Med. Sci. 2005; 60: 1366-1368Crossref PubMed Google Scholar). These findings suggest that long lifespan is no accident; it either arose because long lifespan has fitness benefits for bats or because some other phenotype is selected that also precipitates longevity, one of which being a dampened immune response. The reasons behind the long lifespan of bats remain debated, with scientists developing hypotheses based either on evolutionary life history or molecular studies testing known longevity pathways. Bats have several features that would favor selection for low mortality rates, including small litters (Barclay and Harder, 2003Barclay R.M.R. Harder L.D. Life histories of bats: life in the slow lane.in: Kunz T.H. Fenton M.B. Ecology of Bats. Chicago University Press, 2003: 209-253Google Scholar; Racey and Entwhistle, 1999Racey P.A. Entwhistle A.C. Life history and reproductive strategies of bats.in: Krutzsch P.H. Crichton E.G. Reproductive Biology of Bats. Academic Press, 1999Google Scholar; Speakman, 2008Speakman J.R. The physiological costs of reproduction in small mammals.Philos. Trans. R. Soc. Lond. B Biol. Sci. 2008; 363: 375-398Crossref PubMed Scopus (412) Google Scholar), the capacity of flight (which permits escape from predators; Austad and Fischer, 1991Austad S.N. Fischer K.E. Mammalian aging, metabolism, and ecology: evidence from the bats and marsupials.J. Gerontol. 1991; 46: B47-B53Crossref PubMed Google Scholar; Holmes and Austad, 1994Holmes D.J. Austad S.N. Fly now, die later: life-history correlates of gliding and flying in mammals.J. Mammal. 1994; 75: 224-226Crossref Google Scholar), and (in many species) the ability to hibernate, or enter into a low-energy torpor state. Torpor is linked to longevity in bats and other species (Turbill et al., 2011Turbill C. Bieber C. Ruf T. Hibernation is associated with increased survival and the evolution of slow life histories among mammals.Proc. Biol. Sci. 2011; 278: 3355-3363Crossref PubMed Scopus (146) Google Scholar; Turbill and Prior, 2016Turbill C. Prior S. Thermal climate-linked variation in annual survival rate of hibernating rodents: shorter winter dormancy and lower survival in warmer climates.Funct. Ecol. 2016; 30: 1366-1372Crossref Scopus (10) Google Scholar; Wilkinson and South, 2002Wilkinson G.S. South J.M. Life history, ecology and longevity in bats.Aging Cell. 2002; 1: 124-131Crossref PubMed Google Scholar) and may protect the animal from bouts of starvation and/or promote homeostatic maintenance during periods of low metabolic rate. Consistent with a beneficial role for hibernation, other species that can enter hibernation, such as gray mouse lemurs and 13-lined squirrels, have longer lifespan than mice of similar size (Al-Attar and Storey, 2020Al-Attar R. Storey K.B. Suspended in time: molecular responses to hibernation also promote longevity.Exp. Gerontol. 2020; 134: 110889Crossref PubMed Scopus (0) Google Scholar). In the Wilkinson and Adams study, enhanced longevity was associated with body mass, hibernation, and cave use, which presumably provides a safer environment (Wilkinson and Adams, 2019Wilkinson G.S. Adams D.M. Recurrent evolution of extreme longevity in bats.Biol. Lett. 2019; 15: 20180860Crossref PubMed Scopus (10) Google Scholar). Recent reviews have described pathways modulating aging, termed hallmarks or pillars (Figure 3) (Kennedy et al., 2014Kennedy B.K. Berger S.L. Brunet A. Campisi J. Cuervo A.M. Epel E.S. Franceschi C. Lithgow G.J. Morimoto R.I. Pessin J.E. et al.Geroscience: linking aging to chronic disease.Cell. 2014; 159: 709-713Abstract Full Text Full Text PDF PubMed Scopus (569) Google Scholar; López-Otín et al., 2013López-Otín C. Blasco M.A. Partridge L. Serrano M. Kroemer G. The hallmarks of aging.Cell. 2013; 153: 1194-1217Abstract Full Text Full Text PDF PubMed Scopus (4120) Google Scholar). The overlapping pathways these reviews describe are all intimately linked to aging in a variety of eukaryotic models. Yet it remains unclear to what extent each contributes to different aspects of aging and whether they are connected in a hierarchical structure. Almost certainly they are connected in some kind of homeostatic network that functions to maintain health in the face of damage that accrues with age. One piece of evidence for this is that genetic, dietary, or pharmacological interventions that delay aging typically affect many or all aging pillars. While an intervention likely has a direct target, the net effect is network preservation, and this affects many or all pillars. If this concept extends across species, then long-lived bats may expect to have alterations in many longevity pillars. Early evidence suggests that this is the case, and here we describe evidence connecting longevity to specific hallmarks of aging. Genomic studies have pointed to some longevity clues. For instance, the genome of the Brandt’s bat and several other species has a mutation in the growth hormone receptor gene that may interfere with transmembrane domain function (Seim et al., 2013Seim I. Fang X. Xiong Z. Lobanov A.V. Huang Z. Ma S. Feng Y. Turanov A.A. Zhu Y. Lenz T.L. et al.Genome analysis reveals insights into physiology and longevity of the Brandt’s bat Myotis brand" @default.
• W3041837368 created "2020-07-16" @default.
• W3041837368 creator A5013113087 @default.
• W3041837368 creator A5052978985 @default.
• W3041837368 creator A5077419383 @default.
• W3041837368 date "2020-07-01" @default.
• W3041837368 modified "2023-10-18" @default.
• W3041837368 title "The World Goes Bats: Living Longer and Tolerating Viruses" @default.
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