The gerontology community is most interested in identifying and quantifying the mechanisms that determine species longevity. Why do different mammalian species have radically different life spans, from the year of a shrew to the centuries of large whales? Some inroads have been made into which portions of cellular metabolism are likely contributing to sizable life span differences, but there is no map of relative contributions or exhaustive list of mechanisms – this is a project that still has a long way to go before completion.
Will knowing more about species life span determination help in producing interventions to increase longevity in our species? This may or may not be the case. There is no particular reason why the important factors in species life span must correlate well with the classes of therapy that will produce rejuvenation. A given species will accumulation forms of molecular damage and dysfunction at a given pace, and effective periodic repair of that damage may well involve completely different mechanisms to those that determine the rate at which damage accumulates.
One area of overlap between mechanisms known to be of interest to species longevity and mechanisms known to be of interest to aging within a species is the structure and function of mitochondria. Mitochondrial dysfunction is prevalent in aging, for reasons that appear to involve an imbalance of fusion and fission of mitochondria, and a consequent failure of the quality control mechanism of mitophagy. Equally, mitochondrial DNA damage can produce mutant mitochondria that overtake cells and cause them to export damaging reactive molecules into surrounding tissue. In the study of aging and life span by species, researchers have shown that mitochondrial composition and metabolic rate correlate well with species life span, giving rise the the membrane pacemaker theory of aging. Some species have mitochondria that are more resilient to oxidative damage, which can slow the onset of dysfunction with aging.
Today’s open access paper is an interesting addition to this body of literature. Researchers show that some components of mitochondrial machinery vary in abundance in ways that correlate with mammalian species life span. This seems likely to affect the generation of oxidative molecules by mitochondria, and thus also alter the balance of oxidative damage and mitochondrial dysfunction. This part of the field is still very much a collection of correlations and hypotheses, however. It is quite possible to argue for other interpretations of what is observed, or to expect that more data might upturn an existing consensus.
Complex I (Cx I) (NADH-ubiquinone oxidoreductase) is an electron entry point in the mitochondrial respiratory electron transport chain (ETC). Cx I catalyses NADH oxidation reducing ubiquinone to ubiquinol, importantly contributing to the proton motive force used to synthesize ATP by the oxidative phosphorylation. Cx I also produce reactive oxygen species (ROS), initially superoxide radicals, which can damage all cellular components. Although at least 11 sites producing ROS have been identified, Cx I and complex III (Cx III) are conventionally recognized as the major sources of ROS at the ETC. Mitochondrial ROS production (mitROSp) has been considered one of the main effectors responsible for aging and longevity.
Low rates of mitROSp have been described in many long-lived mammalian and bird species. These studies generally demonstrated the existence of a negative correlation between mitROSp and longevity. Among the two main ROS generating ETC complexes, the low ROS production of various long-lived species has been localized at Cx I. Interestingly, different pro-longevity nutritional and pharmacological interventions like dietary restriction (DR) and methionine restriction, and rapamycin treatment have been also associated with decreased mitROSp at Cx I.
Mammalian Cx I is the largest component of the ETC built of 45 different subunits in mammals. Among the 14 core subunits, the 7 mitochondrial-encoded ND subunits are present in the hydrophobic membrane domain, and the other 7 nuclear-encoded (NDUF) subunits are present in the hydrophilic matrix domain. The 31 supernumerary NDUF accessory subunits are also nuclear coded. However, it is totally unknown if some particular Cx I subunits, especially some NDUF subunits of the Cx I hydrophilic domain, could be involved in the determination of the longevity-related low complex I ROS production of long-lived animal species.
The present study follows a comparative approach to analyse Cx I in heart tissue from 8 mammalian species with a longevity ranging from 3.5 to 46 years. Gene expression and protein content of selected Cx I subunits were analysed. Our results demonstrate: 1) the existence of species-specific differences in gene expression and protein content of Cx I in relation to longevity; 2) the achievement of a longevity phenotype is associated with low protein abundance of subunits NDUFV2 and NDUFS4 from the matrix hydrophilic domain of Cx I; and 3) long-lived mammals show also lower levels of VDAC (voltage-dependent anion channel) amount. These differences could be associated with the lower mitochondrial ROS production and slower aging rate of long-lived animals and, unexpectedly, with a low content of the mitochondrial permeability transition pore in these species.