Naked mole-rats live something like ten times longer than similarly sized mice, show few signs of aging until very late life, and are near immune to cancer. These two species are used as models by researchers to try to understand how, in detail, differences in metabolism can lead to the observed large differences in life span across mammalian species. Since metabolism is ferociously complex, this is very much a work in progress; in the grand scheme of things, only small inroads and starting points have been established. I fully expect investigations of the detailed interactions of metabolism and aging to be ongoing and nowhere near complete thirty years from now, when rejuvenation therapies based on repair of the well-known root causes of aging are a going concern. While it is of course the right thing to do to attempt to fully understand metabolism, this work is not the fast path to new medical technologies that will have significant impacts on human health and longevity.
Although 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. One 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). Although this rodent has a similar size as the laboratory mouse (Mus musculus), it lives 10-20 times longer without showing any visible signs of aging. Furthermore, the naked mole-rat can live for over 32 years in captivity, without facing any increased age-related risk of mortality, challenging Gompertz's mortality law, and thus establishing the naked mole-rat as a non-aging mammal.
Not only naked mole-rats can live an extremely long life, but they also show a remarkably long healthspan associated with almost no decline in physiological or biochemical functions for more than 20 years. For example, cardiac functions are well preserved in aged naked mole-rats, cognitive functions do not decline with age and the naked mole-rat brain seems to be naturally protected from neurodegenerative processes, and also very little pathologic alterations have been found in the kidneys of aged naked mole-rats. In addition, typical signs of aging, such as loss of fertility, muscle atrophy, bone loss, changes in body composition or metabolism are mostly absent in the naked mole-rats. Finally, the incidence of age-related diseases such as cancers or metabolic disorders is extremely low in the naked mole-rat.
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 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.