Outliers Such as Mole Rats Break and Enhance the Models of Aging and Metabolism

Models and trends established across collections of species are used as a tool to try to understand the complex relationship between metabolism and aging, meaning how exactly the natural variations between individuals and species arise from the behavior of cells and interaction with the surrounding environment. This is something of a sideshow to the main business of rejuvenation research, but since the scientific impulse is to map and understand, there is much more of the sideshow taking place than actual efforts to repair the causes of aging. In this slow and expensive business of deciphering the detailed progression of aging, the greatest insight can arise from the outlying examples that do not fit into the models and hypotheses that manage to explain most observations. Some of the various long-lived mole-rat species provide good examples of the type, as illustrated by this open access paper.

Reproduction is an energetically expensive process that supposedly impairs somatic integrity in the long term, because resources are limited and have to be allocated between reproduction and somatic maintenance, as predicted by the life history trade-off model. The consequence of reduced investment in somatic maintenance is a gradual deterioration of function, i.e. senescence. However, this classical trade-off model gets challenged by an increasing number of contradicting studies that show no negative effect of high metabolic rate on lifespan, or even a positive association. Consequently, more research is needed to gather representative data from animals with different life histories, to gain a comprehensive understanding of how life history trade-offs influence lifespan.

Ansell's mole-rats (Fukomys anselli) are subterranean rodents with an extraordinary long lifespan, 22 years being the maximum recorded age thus far. They live in multigenerational families where typically only the founder pair (breeders) reproduces. Most of the offspring (non-breeders) forego reproduction and remain in the natal family. A clear contradiction to the classic trade-off model has been shown in this species: breeding individuals live up to twice as long as their non-breeding counterparts, a feature which is unique amongst mammals. Previous studies showed that daily activity between breeders and non-breeders does not show differences, and social rank does not influence life expectancy. Hence, extrinsic factors like aggression, fighting and higher workload in non-breeders are not likely to influence the lifespan difference. Here, we test the hypothesis that breeders and non-breeders of Ansell's mole-rats differ in their mass specific resting metabolic rate (msRMR), as a possible approach to understand the bimodal aging pattern.

Low msRMR is a common trait in bathyergid rodents interpreted as an adaptation to the subterranean habitat, and our measurements generally confirm previous studies. However, our finding that long-lived breeders of F. anselli have higher metabolic rates compared to shorter-lived non-breeders is novel. This aspect is most interesting since investment in reproduction was long thought to impair somatic maintenance according to the classical trade-off model, but recent findings refer to the trade-off model as being too simplistic. Especially in terms of female reproduction, a meta-analysis from different homeothermic vertebrates has shown that in intraspecific comparisons between breeders and non-breeders, breeders had lower levels of oxidative damage in certain tissues.

This effect could be attributed to upregulation of antioxidant defense mechanisms, such as glutathione or superoxide dismutase activity, which shows a tissue-dependent upregulation in several species during reproduction. This oxidative shielding hypothesis, even if not consistent across different studies, suggests a reproduction-induced protection of mothers and offspring. Ansell's mole-rats are continuously reproducing once they achieve the reproductive status. Oxidative shielding might protect the animals from detrimental pregnancy effects due to a higher energy turnover in female breeders compared to non-breeders. However, the bimodal lifespan in Ansell's mole-rats is not sex-dependent, indicating a general effect in terms of reproductive status, msRMR, and lifespan rather than just a pregnancy effect restricted to females.

Oxidative stress as a main factor contributing to life history trade-offs is getting challenged by increasing contradictory studies. The uncoupling-to-survive hypothesis complements simplistic theories of senescence by explaining apparent exceptions. It suggests that elevated oxygen consumption, a measure for msRMR in the present study, could be also observed due to uncoupling of proton flux in the mitochondria. This process, also referred to as inducible proton-leak, is facilitated by uncoupling proteins and increases RMR. On the other hand, inducible proton-leak is known to reduce ROS production by reducing mitochondrial membrane potentials. Hence the higher msRMR measured in breeders of Ansell's mole-rats could be due to higher rates of mitochondrial uncoupling compared to non-breeders.

Several studies found higher rates of uncoupling in those laboratory mice that lived longer compared to other individuals with shorter lifespans. However, in the case of mole-rats this model should be considered carefully, since in naked mole-rats, surprisingly high levels of oxidative damage to DNA, lipids and proteins were found, which contrasts with the proposed benefit of mitochondrial uncoupling. In general, our finding stresses the complexity of currently discussed aging mechanisms.

Link: https://doi.org/10.1186/s12983-017-0229-6


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