Evidence for the relevance of mitochondrial damage to the progression of degenerative aging can be found in many places, such as when comparing species with divergent life spans and metabolic needs. Birds and bats have significantly higher metabolic rates than we ground-based mammals, but along with that they also have much longer life spans than you might expect given their size. So the thinking goes, the evolutionary adjustments to mitochondria, the power plants of the cell, that were needed for flight have also produced a greater resistance to the mitochondrial molecular damage that contributes to aging. As this open access paper shows, there are mitochondrial differences that seem significant for longevity even between bird species. This isn't to say that we should be trying to alter our mitochondria via gene therapy to make them more like longer-lived species, however. No, we should instead take this and other similar research as indicators that more funding and attention should go towards rejuvenation therapies that focus on mitochondrial repair, ways to completely remove this contribution to aging rather than just slowing it down.
Mitochondria play an essential dual role in homeotherms by encoding proteins that form the essential components of the mitochondrial energy generation pathway, oxidative phosphorylation (OXPHOS). OXPHOS generates heat that is used to maintain the organism's body temperature and energy that is utilised for synthesis of adenosine triphosphate (ATP) to perform work. This is achieved "at the cost" of reactive oxygen species (ROS) and free radical production due to electron leakage from the respiratory chain. The mitochondrial theory of ageing suggests that ROS contribute to a progressive accumulation of somatic mutations in DNA during an individual's lifetime leading to both a decline in the bioenergetic function of mitochondria and to cell apoptosis associated with ageing and has been associated with a wide range of age-related diseases, but the relationship between ROS levels and ageing is not a simple one.
As an originally free-living prokaryotic organism that was engulfed by a precursor of the modern eukaryotic cell about two billion years ago, cytoplasmic mitochondria have retained their own plasmid-like circular genome (mitochondrial DNA, mtDNA). Mitochondrial genome regulation is vital for normal assembly and functional operation of the complexes involved in oxidative phosphorylation (OXPHOS), and therefore, for ATP production and metabolic homeostasis. Many of these functions are fundamental cellular processes and hence the mitogenome organisation appears highly conserved across vertebrates. In birds, several different arrangements of mitochondrial gene order have been observed and in some species the noncoding control region (CR) sequence with the adjacent genes have been duplicated creating a second non-coding region sometimes referred to as the pseudo control region (YCR). YCRs appear to have originated independently and sporadically in several distantly related taxa across the avian phylogeny.
Birds have several biochemical and life characteristics that should increase the risk of reactive oxygen species (ROS) damage to their mtDNA relative to mammals. Such characteristics include higher metabolic rates, higher body temperatures, higher blood glucose levels, seasonally high blood lipid levels and very high total lifetime energy expenditures. As such one would reasonably predict that relative to mammals, birds should age faster and have higher mutation rates rendering them more prone to cancer and other pathologies. Yet, paradoxically, most birds live longer compared to similar sized mammals in absolute and relative terms and although estimated mutation rates vary greatly across avian phyla, they are on average up to four times lower than those in comparable mammals. To the best of our knowledge, the presence of two sets of CR sequences is mainly an avian specific phenomenon, and the relationship between this feature and mitochondrial function has not been fully investigated. Considering the extraordinarily long life spans of birds and the pivotal role of the mitochondria in energy metabolism, the major aim of the work presented here is to explore the possibility that the additional sequences in the YCR are associated with variation in avian longevity.
Around 60% of the variation in lifespan of higher animals can be explained by body mass: animals that diverge from this basic allometry of life span may harbour unique longevity enhancing features and their study may lead to new insights into the evolutionary forces shaping longevity and aging. To explore a possible link between YCR duplication and longevity, we correlated longevity/body mass with presence/absence of YCR sequence for a total of 92 avian families. We detected a relationship between a duplicated control region and longevity. This, we believe, strongly argues for a positive functional role of these duplicated sequences in those species that carry them. We hypothesize that there are two, not incompatible, possibilities that relate to the mitochondrial ageing hypothesis. Extra control region sequences may result in constant increased mtDNA copy number and/or increased flexibility and speed of cellular response when increased metabolism is required to cope with environmental stresses. This mechanism might effectively lower local ROS damage from increased metabolic throughput during periods of stress response. A second possibility is that extra copies of the control region sequences protect mtDNA from the age related effects of sequence losses and hence offer the opportunity for species to retain higher levels of functional mitochondria into later life, hence slowing the negative effects of accumulated mitochondrial deletions on senescence. Alternatively, our results may simply reflect a molecular marker of long-lived species, rather than being the causative agent for that longevity. Our results suggest that even if truly causative the associated effect is a relative minor one accounting for around a 15% difference in life expectancy for an average sized family with and without the YCR.