Abstract
The naked mole-rat (Heterocephalus glaber) is characterized by a more than tenfold higher life expectancy compared to another rodent species of the same size, namely, the laboratory mouse (Mus musculus). We used mass spectrometric metabolomics to analyze circulating plasma metabolites in both species at different ages. Interspecies differences were much more pronounced than age-associated alterations in the metabolome. Such interspecies divergences affected multiple metabolic pathways involving amino, bile and fatty acids as well as monosaccharides and nucleotides. The most intriguing metabolites were those that had previously been linked to pro-health and antiaging effects in mice and that were significantly increased in the long-lived rodent compared to its short-lived counterpart. This pattern applies to α-tocopherol (also known as vitamin E) and polyamines (in particular cadaverine, N8-acetylspermidine and N1,N8-diacetylspermidine), all of which were more abundant in naked mole-rats than in mice. Moreover, the age-associated decline in spermidine and N1-acetylspermidine levels observed in mice did not occur, or is even reversed (in the case of N1-acetylspermidine) in naked mole-rats. In short, the present metabolomics analysis provides a series of testable hypotheses to explain the exceptional longevity of naked mole-rats.
Highlights
AND DISCUSSION biological and chronological time can be dissociated to some extent by experimental manipulation, aging appears to be the most important risk factor for the deterioration of normal physiological functions and the manifestation of organ-specific or systemic pathologies, physical and mental decadency, and eventual death [1,2,3].Trans-species differences in the metabolomePlasma samples from post-adolescent young (1-1.5 months), intermediate (6-10 months) and mature/old (20 months) mice were compared to plasma specimens fromOne species that – to a certain degree – escapes from the rule that natural life expectancy declines with body mass is the naked mole-rat (Heterocephalus glaber)
Cardiac functions are well preserved in aged naked mole-rats [8], cognitive functions do not decline with age and the NMR brain seems to be naturally protected from neurodegenerative processes [9], and very little pathologic alterations have been found in the kidneys of aged naked mole-rats [10]
Our present work reveals important differences in the metabolism between two species differing in their natural lifespan, namely, short-lived mice and longlived naked mole-rats
Summary
Biological and chronological time can be dissociated to some extent by experimental manipulation, aging appears to be the most important risk factor for the deterioration of normal physiological functions and the manifestation of organ-specific or systemic pathologies, physical and mental decadency, and eventual death [1,2,3]. The lysine degradation product 5aminovaleric acid present a reduced abundance in NMR compared to mice (Figure 3e) This metabolite is correlated positively with breast cancer risk in women [16]. Bile acid supplementation has been shown to promote longevity in yeast [29,30], and supplementation with cholic acid increases longevity in short-lived progeroid mice [19] This suggests a possible link between bile acid metabolism and the exceptional longevity of naked mole-rats. Spermidine and N1 acetylspermidine declined in aging mice, but remained at high levels in aging naked mole-rats (Figure 7c, d), echoing an abundant literature showing that spermidine supplementation promotes longevity in mice and other model organisms [35,36,37,38] and that increased nutrient uptake of spermidine reduces cardiovascular and cancer-related mortality in humans [39,40,41]
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