The Longest-Lived Bats Have Unusual Telomere Biology
Researchers here find that the longest lived bats have unusual telomere biochemistry, and in fact unusual enough that the new knowledge may turn out to be of little relevance to the understanding of telomeres, telomerase, and aging in other mammals. It appears that they rely upon alternative lengthening of telomeres (ALT) to maintain telomere length, a process that doesn't operate in any normal adult human cell. Given that loss of telomere length appears to be a marker of aging rather than a cause, and a fairly loosely coupled marker at that, the real relevance of this area of biochemistry probably lies in the relationship between telomerase and important cellular activities, such as ability and willingness of somatic cells to replicate, or stem cells to support tissue function.
Bats exhibit cellular biochemistry that is somewhat different from that of ground-based species in a number of other ways. The metabolic demands of flight have led to, for example, greater resilience to stress and damage arising from the normal operation of cellular metabolism. When charting life span against metabolic rate, where high metabolic rates usually imply short life spans, some small bat species are noteworthy outliers. Brandt's bat, for example, has a life span of four decades despite being the same size as ground-dwelling mammals that live for only a couple of years.
One of the principal caveats at the present stage of research into telomeres and the use of telomerase gene therapies - or other means of enhancing telomerase activity - as a treatment for aspects of aging is that mice and humans have quite different telomere dynamics and patterns of natural telomerase activity. The balance between cancer risk and beneficially increased stem cell activity resulting from telomerase therapies may turn out to be significantly different in different species. That these bats have their own unique evolved dynamics, ones that are much further removed, suggests that this portion of the comparative biology might not be as useful to the practical science of aging as hoped. The fastest path to understanding is probably to extend present work on telomerase therapies to species more like humans in their telomere biology, such as dogs and pigs perhaps. Or, as some advocate, running human trials immediately.
We urgently need to better understand the mechanisms of the aging process, with a view to improving the future quality of life of our aging populations. Most aging studies have been carried out in shorter-lived laboratory model species, given the ease of manipulation, housing, and length of life span. Although they are excellent study species, it is difficult to extrapolate experimental findings in these short-lived laboratory species to long-lived, outbred species such as humans. Therefore, it has been argued that long-lived, outbred species such as bats may be better models to investigate the aging processes of relevance to people.
Only 19 species of mammal are longer-lived than humans in proportion to their body size, and 18 of these species are bats. Bats are the longest-lived mammals relative to their body size, with the oldest bat recaptured (Myotis brandtii) being more than 41 years old, weighing ~7 g, and living ~9.8 times longer than predicted for its size. Although an excellent model species to study extended healthspan, logistically, it is difficult to study aging in bats because they are not easily maintained in captivity. Here, uniquely drawing on more than 60 years of cumulative long-term, mark-recapture studies from four wild populations of long-lived bats, we determine whether telomeres, a driving factor of the aging process, shorten with age in Myotis myotis (n = 239; age, 0 to 6+ years), Rhinolophus ferrumequinum (n = 160; age, 0 to 24 years), Myotis bechsteinii (n = 49; age, 1 to 16 years), and Miniopterus schreibersii (n = 45; age, 0 to 17 years).
We show that telomeres shorten with age in Rhinolophus ferrumequinum and Miniopterus schreibersii, but not in the bat genus with greatest longevity, Myotis. As in humans, telomerase is not expressed in Myotis myotis blood or fibroblasts. Selection tests on telomere maintenance genes show that ATM and SETX, which repair and prevent DNA damage, potentially mediate telomere dynamics in Myotis bats. Twenty-one telomere maintenance genes are differentially expressed in Myotis, of which 14 are enriched for DNA repair, and 5 for alternative telomere-lengthening mechanisms. These results, coupled with differential expression of ATM, SETX, MRE11a, RAD50, and WRN across all tissues in the genus Myotis compared to other mammals, suggest a potential role for alternative lengthening of telomeres (ALT) mechanisms in the maintenance of telomeres in these species. If telomeres are maintained by ALT mechanisms in Myotis species, then these genes may represent excellent therapeutic targets given that cancer incidence in bats is rare.