Digging into the metabolome: What the naked mole rat can teach us about rodent longevity

Research in model organisms has taught us a great deal about the fundamental biology of aging. Our belief in the value of such studies—specifically, the idea that we can learn about human aging by studying longevity in smaller, shorter-lived species— is predicated on the idea of evolutionary conservation: in organisms related by common descent, similar genes do similar things for similar reasons. According to this logic, if a pathway extends lifespan in a mouse, it’s at least worth checking to see if it has similar effects in larger mammals (like us).

But what can we learn from animals with unconventional life cycles? Suppose, for example, that we knew of a species with an exceptional lifespan for its body size. One might seek to identify the differences between that species and shorter-lived species, and then hypothesize that at least some of those features were responsible for the enhanced longevity. However, if the species in question also has an unusual natural history, implying very different selective pressures over the course of its evolution, it might be difficult to parse out which differences are related to lifespan.

This issue confronts one of the most fascinating models for the study of aging: the naked mole rat*, Heterocephalus glaber, a small rodent that can live more than 30 years and (at least by one definition) does not age. Specifically, H. glaber exhibits a rare feature known as negligible senescence: a lack of increase in the mortality rate as a function of time. Adult naked mole rats manifest no age-related decline in physiological functions, rarely develop cancer, and are no more likely to die at 20 years of age than at 5. Naked mole rats express high levels of stress-response gene, including those encoding DNA repair factors and protein chaperones, and it is tempting to speculate that these (or other) distinctive cellular and molecular characteristics of this species hold the secret to long life.

Unfortunately from the standpoint of evolutionary conservation, and the logic outlined in the first paragraph of this piece, naked mole rats are just plain weird. They are finely adapted to their subterranean lives, are capable of withstanding hypoxia for long periods of time, and regulate their body temperatures very differently than other mammals—they’re not quite cold-blooded per se, but they are thermolabile, and can tolerate dramatic swings in core temperature in response to changing environmental conditions. Moreover

Consequently, one is left wondering whether any given distinct property of naked mole rats relative to (e.g.) mice is related to extended lifespan, or simply an adaptation to their unusual life cycle. Similarly, it is conceivable that even the bona fide causal pro-longevity mechanisms in this species only function against the backdrop of the idiosyncratic features that have emerged over millions of years of divergent evolution. Simply put, then: Can we learn about the fundamental biology of mammalian aging, in a general sense, by studying one bizarre mammal?

Happily, based on a new paper from Shelley Buffenstein’s lab (which administers the largest naked mole rat colony in the US and possibly the world, and which recently relocated to the aging research company Calico), the answer appears to be at least a qualified yes.

The authors examined the plasma metabolome (the signature of small molecules in the circulating blood) in naked mole rats, reasoning that prolongevity cellular behaviors would manifest as differences in the metabolic profile. The plasma metabolome is advantageous for studies of this type because it integrates the biochemical activities of many cell types in many tissues, along with dietary conditions and overall health status. Moreover, it can be measured relatively non-invasively, requiring only a conventional blood sample.

The metabolite concentrations in mole rat plasma mirrored changes observed in other rodents subjected to life-extending interventions, such as methionine restriction in rats and calorie restriction or genetic dwarfism in mice. Some of the measurements were even reminiscent of the differences between young and old humans. Together, these findings imply that the pro-longevity cellular maintenance pathways that can be activated by nutritional or environmental signals in all mammals are simply always turned on in mole rat, and that the lifelong activation of these pathways is responsible for this species’ unusual longevity.

Moreover, the results address the question I raised above regarding the suitability of mole rat as a model system in biogerontology. Despite the dramatic differences between the natural histories of mole rats and other rodents, it seems clear that at least some of the key pro-longevity mechanisms are conserved, even extending to primates. Therefore, we should be able to identify lifespan-extending interventions by searching for conditions that make mice—or at least their plasma—look more mole rat–like.

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Lewis et al. “A window into extreme longevity; the circulating metabolomic signature of the naked mole-rat, a mammal that shows negligible senescence.” GeroScience 2018 Apr 20 1–17 (epub ahead of print). DOI: 10.1007/s11357-018-0014-2

 

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* Which, for the record, is neither a mole nor a rat.

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