Fight Aging!

Today's open access research is a good companion piece to a recent paper that investigates biochemical differences between long-lived and short-lived bats. Bats are renowned for, firstly, an exceptional resistance to classes of virus that are fatal to other mammals, allowing bat populations to act as reservoirs for potentially dangerous pathogens, and secondly for an exceptional longevity in comparison to other mammalian species of a similar size. In mammals, species longevity tends to scale up with size, with a few notable and well-studied long-lived exceptions such as naked mole-rats, humans, and some bats.

In terms of asking why longevity occurs in these species, for naked mole-rats (and near relative species) it may be a side-effect of tolerating oxygen-poor underground environments, providing greater resistance to mechanisms of cell damage that also occur with age. For we humans, the grandmother hypothesis suggests that our culture and intelligence allows older individuals to contribute to the fitness of descendants in ways that other primates do not, and thus there is selection pressure for a longer, slower decline after menopause. As for bats (and birds, which are also, as a rule, long-lived for their size) the high metabolic demands of flight are thought to provide the side-effect of greater longevity for similar reasons to the longevity of naked mole rats, a resistance to cellular damage that occurs with both exertion and aging.

Finding out whether or not these proposals are in fact the case requires a deep analysis of cellular biochemistry, comparing long-lived and short-lived mammals. That analysis is very much a work in progress, providing a great many potential mechanisms to consider and compare, while the present consensus on what is important and what is relevant remains subject to being overturned at short notice. Today's open access paper is a good review of what is known of bat longevity, with the added bonus of a discussion of viral resistance in these species, which may well turn out to be relevant to the question of life span, given the interactions between infection, inflammation, and aging.

The World Goes Bats: Living Longer and Tolerating Viruses

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. Other bat species have maximum lifespans around 20 years, which is still very long for species of this size. Extreme longevity has arisen at least four separate times during bat speciation. 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, the capacity of flight (which permits escape from predators), 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 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.

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. Growth hormone receptor loss of function mutations are associated with protection from diabetes and cancer in humans and long lifespan in mice. Indeed, bats have physiologic (e.g., pancreatic structure) and transcriptomic changes that resemble growth hormone receptor knockout mice. There are also intriguing changes in the transmembrane region of the IGF1 receptor, which is associated with longevity in a range of model organisms and in centenarians. Both of these hormonal signaling pathways are intimately linked to nutrient signaling, one of the most robust pillars of aging.

Genome maintenance is an important longevity assurance mechanism and another recognized pillar of aging. In an 8-year longitudinal study of blood samples from free-living greater mouse-eared bats (Myotis myotis), it was reported that DNA repair and DNA damage signaling pathways are maintained throughout lifespan, consistent with the low levels of cancer in bat species. Among DNA repair pathways, DNA double-strand break repair shows the strongest correlation with longevity. Remarkably several DNA double-strand break repair genes were shown to be under positive selection in two species of bats. Interestingly, some of these DNA repair genes, such as DNA-PK and Rad50, also function as DNA sensors in innate immune response. Hence, the genetic changes that evolved in bats may modulate both processes simultaneously and the innate immune response may be an evolutionary driver of positive selection.

Mitochondrial dysfunction is a feature of aging across the evolutionary spectrum and another highly supported pillar of aging. Energetic demands associated with flight in bats require enhanced mitochondrial respiratory metabolism, which is expected to generate excess oxidative damage. To counteract this damage, bats have evolved more efficient mitochondria, producing less H2O2 per unit oxygen consumed. Bat fibroblasts have also been shown to have lower levels of oxidative damage to proteins and to be resistant to acute oxidative stress. To help maintain proteostasis upon oxidative stress, bats express major heat shock proteins at higher levels. This may simultaneously permit bats to endure high temperatures with flight and maintain protein homeostasis with age. Bats also exhibit enhanced autophagy activity with advancing age, suggesting that their cells are better able to clear damaged proteins and organelles. Increased mitochondrial oxidative stress would also be expected to generate mitochondrial DNA alterations, or heteroplasmy. However, oxidative lesions in M. myotis are found only at low rates in an age-independent manner, suggesting better repair or removal of damaged mitochondria.

As they age, bats avoid upregulation of genes involved in chronic inflammation, which is typically not observed in mammals. This likely results from the multitude of mechanisms that evolved to suppress inflammation due to viral infections. Microbiome studies indicate that Myotis myotis may have stable microbiome composition that does not change over time in contrast to mice and humans, where the microbiome undergoes significant changes with age. As aging-related gut dysbiosis triggers inflammation, the ability of bats to maintain stable microbiome may contribute to the lack of age-related inflammation, or by contrast, low levels of inflammation may promote a more stable microbiome.

One major unanswered question is the extent to which cell senescence occurs with age in bats. Since cell senescence may be a major driver of chronic inflammation during mammalian aging, it will be important to determine whether cell senescence, another pillar, is altered with age in bat species. In-depth studies are needed to address this question in vivo and in cell culture. Among other hallmarks of aging, telomere attrition has been addressed to a limited extent, with mixed results. The shorter-lived bat species, Rhinolophus ferrumequinum and Miniopterus schreibersii, do exhibit telomere shortening, but no evidence was found in the longest-lived species, Myotis myotis. This bat apparently does not express telomerase but exhibits differential expression of genes involved in telomere maintenance and the alternative lengthening of telomeres (ALT) pathway.

A majority of the mechanisms that have evolved to protect bats from viruses likely contribute to their longevity. Bats evolved multiple strategies to combat inflammation, such as dampened NLRP3 inflammasome activity. Inflammation has emerged as a driver of multiple age-related pathologies, including cardiovascular diseases, cancer, Alzheimer's disease, and diabetes. This led to the concept of inflammaging, defined as the long-term result of the chronic physiological stimulation of the innate immune system, which becomes damaging during aging. Factors that trigger inflammaging include viruses, microbiome bacteria, senescent cells, and self-products of cellular damage such as debris containing cellular DNA and proteins. Reducing inflammation due to any of these factors can be beneficial for longevity; however, bat evolution seems to have attenuated mechanisms of cytoplasmic DNA sensing specifically.

Remarkably, bats are unique in their ability to tolerate DNA transposable elements. DNA transposons move in the genome via a cut-and-paste mechanism involving DNA intermediates. Such transposons are found in invertebrates but are generally inactivated and fossilized in the genomes of mammals. Only the vespertilionid family of bats is known to harbor significant levels of active DNA transposable elements. This bat family includes genus Myotis, which contains the longest-lived bats, which suggests that these animals are exceptionally healthy. The ability to tolerate active DNA transposons is likely linked to dampened cytoplasmic DNA sensing.

In the continuing arms race against pathogens, evolutionary fitness requires a functional immune system. However, a highly active immune system may increase fitness in young age but limit longevity. Why did bat evolution result in adjusted immune system functions in a way that favors longevity? We speculate that bats' exceptionally high exposure to viral pathogens forced them to develop ways to co-exist with viruses rather than to fight them. Bats are unique among mammals in the size and density of their colonies, and in their ability to fly long distances, a trait that further increases pathogen exposure. Modern humans living in large metropolises and enjoying air travel may be coming close to the bat level of viral exposure. However, humans have only been enjoying this lifestyle for less than 100 years, while bats evolved 60-70 million years ago.