A sizable amount of effort is devoted to the comparative biology of aging, and in particular mapping the noteworthy differences between naked mole-rats and other similar-sized rodent species. Naked mole-rats live nearly ten times longer than mice and are near immune to cancer. It is possible that a sufficiently comprehensive understanding of why this is the case could result in therapies for humans, though I believe the odds of this coming to pass in the near future of the next couple of decades are much larger for cancer than aging. Research into calorie restriction mimetic drugs has demonstrated that safely inducing even small shifts in the operation of metabolism, even when aiming to mimic states that occur naturally and are very well studied, is very expensive and very slow work. While naked mole-rat resistance to cancer may boil down to just a couple of mechanisms, any one of which might be exploited alone, their longevity most likely has many contributing factors, and will be much harder to map and understand.
The open access papers noted here report on what are fairly standard fishing expeditions into the cellular biochemistry of the naked mole-rat, comparing it with that of the guinea pig. This sort of work takes place throughout the research community, and in many contexts. Researchers pick likely tissues and processes to examine, and then compare as much genetic, epigenetic, and proteomic data as they have the capacity to produce and process. Differences are pulled up from the depths for examination, and theories advanced based on what is presently known. Of the findings in these papers, some reinforce earlier theories on the damage resistance of specific cellular components in naked mole-rats, particularly mitochondria, while the most interesting item is the presence of raised levels of enzymes that are protective against oxidative damage. Past research has shown that older naked mole-rats appear to have all the signs of high levels of oxidative stress, but are largely unaffected by it.
Naked mole-rats (NMRs) are eusocially organized in colonies. Although breeders carry the additional metabolic load of reproduction, they are extremely long-lived and remain fertile throughout their lifespan. This phenomenon contrasts the disposability theory of aging stating that organisms can invest their resources either in somatic maintenance, enabling a longer lifespan, or in reproduction, at the cost of longevity. Here, we present a comparative transcriptome analysis of breeders vs. non-breeders of the eusocial, long-lived NMR vs. the polygynous and shorter-lived guinea pig (GP).
Comparative transcriptome analysis of tissue samples from ten organs showed, in contrast to GPs, low levels of differentiation between sexes in adult NMR non-breeders. NMRs show functional enrichment of status-related expression differences associated with aging. Lipid metabolism and oxidative phosphorylation - molecular networks known to be linked to aging - were identified among most affected gene sets. Remarkably and in contrast to GPs, transcriptome patterns associated with longevity are reinforced in NMR breeders.
Our cross-species analysis revealed that the liver of NMRs possesses three major characteristics compared to GP: (i) lower rate of mitochondrial respiration, due to reduced protein levels of complex I; (ii) higher reliance on fatty acids for energy production, deriving from increased abundance of enzymes responsible for lipid turnover; and (iii) increased expression of detoxifying enzymes.
Naked mole-rats have a very low metabolic rate, which reaches only 40% of the value predicted for a mammal in relation to body mass. They further have a very poor ability of thermoregulation and one of the lowest body temperatures of 32°C known among mammals. These traits likely serve as energy-saving adaptations to their arid environment. An inverse relationship between body temperature and expected lifespan has been reported, which suggests a contribution of the low body temperature of NMR to their longevity. These adaptations, as well as their high resistance to hypoxia, may account for a large proportion of the unique metabolic differences of NMR compared to other mammals.
Consistent with the established and published knowledge on NMR phenotypes at old age, we have shown a clear impact of aging on the NMR liver proteome that negatively affects the abundance of proteins involved in lipid metabolism and detoxification processes. The same pathways are similarly affected with aging also in mice and humans. Our observations support the notion of an extremely low, but detectable, rate of aging in NMRs.
Two major questions arise from our work: how NMRs have evolved their particular liver metabolism, and how does this contribute to the extreme longevity of these animals? Multiple studies have previously linked the composition of the mitochondrial respiratory chain to lifespan extension in multiple species. Similarly, lipid homeostasis and signaling has been linked to health and longevity, and changes in lipid metabolism have been shown to mediate the positive effects of anti-aging dietary interventions. Our data show that in both NMR and human liver, there is a progressive decline of enzymes responsible for fatty acid turnover. These alterations might contribute to changes in energy metabolism that favor the accumulation of adipose tissue and increased inflammation at older age.
From a mechanistic point of view, it is conceivable that adaptation to the particular ecosystem of NMRs has selected for characteristics of energy metabolism that in turn enabled extreme longevity via activation of stress pathways. Among these, the NFE2L2 pathway, which controls the expression of many of the detoxifying enzymes that we found increased in NMR vs. GP, was shown to have enhanced activity in NMR. The activities of the same pathways tend to decline during aging, as shown here by the decline of their target genes in both NMR and humans and in different model organisms. It is therefore tempting to speculate that their higher basal activity in the NMR might contribute to its enhanced stress resistance and ultimately delay the aging process.