Abstract
It is accepted that smaller mammals with higher metabolic rates have shorter lifespans. The very few species that do not follow these rules can give insights into interesting differences. The recorded maximum lifespans of bats are exceptional - over 40 years, compared with the laboratory mouse of 4 years. We investigated the differences in the biochemical composition of mitochondria between bat and mouse species. We used proteomics and ultra-high-performance liquid chromatography coupled with high resolution mass spectrometry lipidomics, to interrogate mitochondrial fractions prepared from Mus musculus and Pipistrellus pipistrellus brain and skeletal muscle. Fatty acid binding protein 3 was found at different levels in mouse and bat muscle mitochondria and its orthologues were investigated in Caenorhabditis elegans knock-downs for LBP 4, 5 and 6. In the bat, high levels of free fatty acids and N-acylethanolamine lipid species together with a significantly greater abundance of fatty acid binding protein 3 in muscle (1.8-fold, p=0.037) were found. Manipulation of fatty acid binding protein orthologues in C. elegans suggest these proteins and their role in lipid regulation are important for mitochondrial function.
Recent figures indicate that 21% of the world’s population will be aged 60 or over by 2050 [1]. Determining the mechanisms underpinning the ageing process is vital so that we can improve healthspan to match these increased years of life. In humans, the brain and skeletal muscle both deteriorate as part of the ageing process and mitochondrial dysfunction has been implicated to play a critical role in the age-related decline of these tissues [2–4].
Some common observations have been used to generate theories of ageing. The rate of living theory of ageing proposes to explain the variation in mammalian lifespans, it states that lifespan and metabolic rate are inversely correlated [5]. Another theory is the mitochondrial free radical theory of ageing, this states that animals with high basal metabolic rates will generate greater levels of reactive oxygen species (ROS) and due to their detrimental effect, have shorter lifespans [6]. Observed mammalian biology mostly aligns with these theories however there are a few notable exceptions, including the naked mole rat and microbats, that live much longer than their small body size and high metabolic rates would predict [7]. The naked mole rat has given insight into mechanisms that prevent cancer, considered to be a disease of ageing [8] [9]. Microbats are exceptionally long-lived considering their small body size and high metabolic rates [10]. For instance, the maximum lifespan for the bat; Myotis lucifugus (weight ~8g) is 34 years. In comparison the maximum lifespan of a mouse (Mus musculus) (weight ~30g) is 4 years [11]. Bats have been shown to expend double the amount of energy in comparison to non-flying eutherian mammals and yet they live on average three times longer than non-flying eutherian mammals [12]. This raises the question; how do bats maintain such high metabolic rates without succumbing to accumulating damage over their lifespan?.
Oxidative stress has been a key focus for the majority of studies investigating longevity in bats. Mitochondrial dysfunction is evident in ageing and age-related diseases. Mitochondrial DNA (mtDNA) is considered to be more susceptible to mutagenesis due to the close proximity of mtDNA to ROS and also the high number of direct repeat regions (8-10 bp) which are prone to deletions [13]. Bat mtDNA was found to have a lower number of repeat regions compared with other mammals [14]. A study by Brunet Rossini compared the production of free radicals in bats (Myotis lucifugus), shrews (Blarina brevicauda) and white-footed mice (Peromyscus leucopus). Bats were found to produce half to one third of the amount of hydrogen peroxide per oxygen molecular consumed compared to both shrews and mice [15]. Research thus far indicates that bats produce less ROS and may also be more resistant to oxidative stress [15].
Hibernation has also been suggested to contribute to longevity in bats, however, when comparing the life span of non-hibernating bats to non-flying eutherian mammals, bats still live on average 7 years longer [11]. Interestingly, during hibernation the fibre composition of the pectoralis muscle of the M.lucifugusremains unchanged [16]. Deterioration of cognition coupled with the functional loss of skeletal muscle strength are common features of ageing [17–19]. Studying the mechanisms by which dormant animals, such as bats, prevent muscle atrophy may develop our understanding of age associated muscle loss.
An active mitochondrial population is considered to be an intrinsic cellular requirement for healthy ageing. Loss of mitochondrial functionality has been implicated in neurodegenerative diseases as well as in age related sarcopenia [2,20]. Previously, we have interrogated skeletal muscle and brain tissue mitochondria profiles in young and middle-aged mice and shown that there are characteristic, measurable differences in proteins and lipids [21,22]. There are few published studies investigating ageing in bats, and research on captive populations in the UK is limited by their protected status [10,23,24]. In this study we compared the mitochondrial lipidome and proteome of whole brain and skeletal tissues from adult Pipistrelle bats (maximal lifespan 12 years) with parallel sample types prepared from young and middle-aged Mus musculus [21,22].
Source: https://www.aging-us...cle/101861/text
