Naked mole-rat (Heterocephalus glaber) is a unique species for the study of aging. Unlike other rodents, this animal is distinguished by the exceptional longevity and can live more than 30 years. This month, BMC Biology published two articles of scientists from the Leibniz Institute on Aging, which present transcriptomic and proteomic data from naked mole-rats and shed light on the mechanisms of aging.
In the first study [1], the relationship between reproduction and lifespan was studied. According to the well-known theory of aging, called disposable soma theory, frequent reproduction spends a large part of energy resources at the expense of maintaining organism viability, and hence leads to a shortening of lifespan. Surprisingly, breeding eusocial naked mole-rats live longer than non-breeders. To elucidate the molecular basis of this phenomenon, a comparative transcriptome analysis was carried out for 10 tissues of breeding and non-breeding (isolated from the population) naked mole-rats. Guinea pigs (Cavia porcellus) were used as a contrasting rodent model.
Naked mole-rat males and females which did not participate in reproduction had similar phenotypes and showed slight differences in their transcriptomes. However, once they started reproduction sex-specific changes in gene expression patterns became significant.
As naked mole-rat is a eusocial animal, isolated individuals (non-breeders) experienced a social stress and had significant differences in pathways associated with endocrine regulation. Moreover, sexual maturation caused detectable changes in the expression of pro-longevity genes. Indeed, according to evolutionary theories of aging, eusocial animals with active reproduction score advantages and are characterized by extended life- and healthspan, which should be regulated by appropriate changes at the molecular level.
To a large extent, differences in gene expression between long-lived breeding naked mole-rats and non-breeders, as well as short-lived guinea pigs, were associated with lipid metabolism (upregulated) and oxidative phosphorylation providing mitochondrial respiration (downregulated). These two ways are closely related to aging. Additionally, transcriptomic changes were observed for other genes. For example, the gene TMEM8C associated with muscle regeneration was more activated in naked mole-rats compared with guinea pigs. This may be a molecular basis for the slow muscle loss of aged naked mole-rats.
Dr Martin Bens commented: "Deeper investigations of naked mole-rat transcriptome data can help us understand how sexual maturation is regulated. This could potentially help us better understand sexual maturation in humans, where the onset of puberty varies between individuals and is influenced by a variety of factors such as stress and nutrition. Variations in puberty onset have implications for the risk for diseases such as breast cancer or cardiovascular diseases. Our data may help identify targets to mitigate these variations." [2]
The second study [3] was aimed to reveal determinants of longevity by using integrated approach that includes proteome and transcriptome analysis. Comparison of transcriptomes and proteomes of naked mole-rats and guinea pigs established that most of adaptations to local ecosystems are manifested through changes in gene expression and translate into variation in proteins.
Just like the researchers stated in the previous article, analysis of liver samples of naked mole-rats and guinea pigs showed significant differences in lipid metabolism and mitochondrial respiration. In naked mole-rats, the level of mitochondrial respiratory chain components was reduced, while enzymes that involved in utilization of fatty acids were increased. Thus, these long-lived rodents redistribute energy balance from the lower intensity of mitochondrial respiration to energy production due to the turnover of fatty acids. Such changes can be energy-saving adaptation of naked mole-rats, which are characterized by a low metabolic rate.
In addition, liver samples of naked mole-rats were characterized by high activity of enzymes involved in detoxification and maintenance of redox homeostasis (in particular, enzymes that are targets of the transcription factor NFE2L2).
The authors of this article analyzed aging-related changes in liver proteomes of the studied rodents. Old naked mole-rats showed age-associated molecular alterations typical for many other kinds, such as an increase of immune response-related proteins, inflammation markers, and an accumulation of extracellular matrix proteins. It is interesting to note that proteins decreased their activity during aging of naked mole-rats (for example, proteins participating in fatty-acid beta-oxidation and detoxification of xenobiotics) had higher levels in livers of young individuals compared to guinea pigs. The contrary was observed for proteins that increased expression upon aging.
It must be noted that the molecular changes appeared during aging of naked mole-rats are similar to humans, indicating a probable similarity of basic longevity mechanisms of these two species. For example, the age-dependent reduction in the level of enzymes that provide fatty acid turnover can lead to a disruption of energy metabolism, accumulation of adipose tissue, and chronic inflammation in old individuals. At the same time, decrease in the level of a number of detoxification enzymes (for example, cytochrome P450s, glutathione S-transferases, and UDP-glucuronosyltransferases) reduces viability in the old age.
Dr Alessandro Ori commented: "We found that naked mole-rat livers have a unique expression pattern of mitochondrial proteins that result in distinct metabolic features of their mitochondria, including an increased capacity to utilize fatty acids. We were also able to show that similar molecular networks are affected during aging in both naked mole-rats and humans, which suggests that there may be a direct link between these networks and the longevity of these species, both of which would be expected to have much shorter lives based on their body mass." [2]
References:
- 1. Bens M. et al. Naked mole-rat transcriptome signatures of socially suppressed sexual maturation and links of reproduction to aging. BMC Biol. 2018; 16(1): 77. doi: 10.1186/s12915-018-0546-z.
- 2. Naked mole-rats defy conventions of aging and reproduction.
- https://www.biomedcentral.com/about/press-centre/science-press-releases/naked-mole-rat
- 3. Heinze I. et al. Species comparison of liver proteomes reveals links to naked mole-rat longevity and human aging. BMC Biol. 2018; 16 (1): 82. doi: 10.1186/s12915-018-0547-y.
Naked mole-rat transcriptome signatures of socially suppressed sexual maturation and links of reproduction to aging | BMC Biology
Abstract
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 disposable soma 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. After transition into breeders, NMR transcriptomes are markedly sex-specific, show pronounced feedback signaling via gonadal steroids, and have similarities to reproductive phenotypes in African cichlid fish, which also exhibit social status changes between dominant and subordinate phenotypes. Further, 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 results provide comprehensive and unbiased molecular insights into interspecies differences between NMRs and GPs, both in sexual maturation and in the impact of reproduction on longevity. We present molecular evidence that sexual maturation in NMRs is socially suppressed. In agreement with evolutionary theories of aging in eusocial organisms, we have identified transcriptome patterns in NMR breeders that—in contrast to the disposable soma theory of aging—may slow down aging rates and potentially contribute to their exceptional long life- and healthspan.
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Species comparison of liver proteomes reveals links to naked mole-rat longevity and human aging | BMC Biology
Abstract
Mammals display a wide range of variation in their lifespan. Investigating the molecular networks that distinguish long- from short-lived species has proven useful to identify determinants of longevity. Here, we compared the livers of young and old long-lived naked mole-rats (NMRs) and the phylogenetically closely related, shorter-lived, guinea pigs using an integrated omics approach. We found that NMR livers display a unique expression pattern of mitochondrial proteins that results in distinct metabolic features of their mitochondria. For instance, we observed a generally reduced respiration rate associated with lower protein levels of respiratory chain components, particularly complex I, and increased capacity to utilize fatty acids. Interestingly, we show that the same molecular networks are affected during aging in both NMRs and humans, supporting a direct link to the extraordinary longevity of both species. Finally, we identified a novel detoxification pathway linked to longevity and validated it experimentally in the nematode Caenorhabditis elegans. Our work demonstrates the benefits of integrating proteomic and transcriptomic data to perform cross-species comparisons of longevity-associated networks. Using a multispecies approach, we show at the molecular level that livers of NMRs display progressive age-dependent changes that recapitulate typical signatures of aging despite the negligible senescence and extraordinary longevity of these rodents.
