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Opportunities for new insight into aging from the naked mole-rat and other non-traditional models

Non-traditional model organisms can facilitate discovery when their natural properties provide insight into biological mechanisms that are invariant across standard-use lab species. Long-lived naked mole-rats provide such insights for healthy aging.

Model organisms catalyse biomedical research, allowing scientists to investigate mechanisms and test interventions with expediency and rigor. Selection of an appropriate model organism requires the complex consideration of many factors that balance ease-of-use against biological relevance. The past century has witnessed a consolidation of biomedical research efforts into a small number of standard model species. While beneficial in terms of an ever-expanding array of experimental tools and knowledge for these organisms, this trend has sidelined the question of biological relevance. In many research fields, these preordained choices are adequate to address most scientific questions, but this may not necessarily hold true for studies addressing the biology of aging.

Modern aging research focuses primarily on four model organisms: yeast (Saccharomyces cerevisiae), nematodes (Caenorhabditis elegans), fruit flies (Drosophila melanogaster) and mice (Mus musculus). While evolutionarily distant, all of these standard models share an important feature for the study of aging: as each individual gets older, its health declines and its probability of dying increases, ultimately limiting its potential longevity. The short lifespans of these organisms permit rapid examination of the mechanisms leading to these functional declines, facilitating discovery of compensatory interventions1. The hope is that at least some of these findings will ultimately lead to innovations to delay or abrogate human aging.

While useful in these ways, use of standard models neglects an alternative path to the discovery of age-compensating interventions: learning by example. None of the standard organisms possess the ability that we humans wish to attain: sustained physiological maintenance and good health until exceptionally old ages. As a species, humans are extremely long-lived for our body size, with lifespans far exceeding those of other primates and larger mammals2. As such, our human physiology already seemingly surpasses standard models in terms of resistance to the inevitable age-related decline. Interventions that improve longevities of these standard models may only allow them to ‘catch up’ with humans and may not provide any additional advantage. Supporting this premise, none of the longevity-extending interventions found for mice have extended this short-lived species’ lifespan even close to its allometrically predicted (that is, maximum lifespan estimate based on animal size) limit of six years. Further, to date, none of these interventions have yet been successfully applied to humans1.

Even when scientifically sound and relevant to humans, the deep study of mechanisms of decline that pervades the aging field can be misleading, as it provides no pattern for successful compensation. Telomeres provide an example of this pitfall: the shortening of the ends of chromosomes undeniably leads to cellular senescence, a phenomenon that is associated with broad physiological decline3. However, a naïve approach to addressing this mechanism of decline — supplementing telomere-maintaining enzymes — leads to an unfortunate side effect: widespread cancer3. Put another way, it is easier to break a system than to build one. Standard models have been most useful when the biology under investigation was already found within the organism and could be readily disrupted or purified. Such has been the case in many Nobel Prize-winning studies where the mechanism of action has been investigated in depth (for example, the study of apoptosis using C. elegans). There is, however, also modern precedence for seeking out off-the-beaten-path model organisms when the relevant biologies of standard models are lacking. For example, the unusual regenerative capacity of the axolotl Ambystoma mexicanum has led to its use in determining mechanisms of limb regeneration.

Within the field of aging, several organisms exhibit notable properties that make them attractive examples of ‘successful’ slow-aging models. In some cases, specific ecophysiological characteristics imply that these organisms have found solutions to problems that humans may experience with advancing age or in diseased states. These include apparent cancer resistance of horses and elephants4, tolerance by diving mammals and birds of recurring bouts of ischemia/reperfusion without the accrual of oxidative tissue damage5, and the absence of obesity-induced insulin resistance as well as bone loss and kidney disease exhibited by hibernating bears6. In other cases, the organism simply lives much longer than can reasonably be expected. These include the immortal jellyfish (Turritopsis nutricula), the ocean quahog (Arctica icelandica) and the little brown bat (Myotis brandtii)2. While either of these qualifying features — age-related disease resistance or exceptional longevity — can provide motivation for studying an unusual organism, they must be considered against the unusual efforts that are required to make these species or their biological specimens amenable to laboratory experimentation. Public resources and technologies commonly available for traditional models may initially be lacking for these species, adding difficulty to the initiation of experiments, and aging research would benefit from publicly available resources or services to work with non-traditional models. The long lives of these organisms need not be of concern: fundamental aspects of biology that preserve homeostasis and facilitate their longevity will certainly be active at arbitrary ages. Nonetheless, a species’ overall power as a laboratory model, along with its relevance to human biology, must be critically considered.

The naked mole-rat (Heterocephalus glaber), a mouse-sized rodent, stands out as an especially powerful model of successful aging because it is known to fulfill both criteria for interest (Fig. 1). It exhibits exceptional resistance to many particular forms of stress and disease: cancer, hypoxia, cardiovascular disease and reproductive senescence among them4,7,8,9,10. Unlike humans and mice, naked mole-rats also show resistance to non-pathological cardiovascular deterioration with advancing years and with unchanged diastolic function, blood pressure and vascular stiffness11. Similarly, naked mole-rats maintain body composition, bone quality and mineral density throughout their long lives and show no signs of a decline in fertility or metabolic rate well into their third decade7,8. In addition, its overall lifespan extends far beyond what would be allometrically predicted for a rodent of its size12. As a species, the naked mole-rat seems to provide a counterexample to the inevitability of mammalian aging. At ages far beyond their expected lifespans given their body size or the timing of early developmental milestones, naked mole-rats fail to exhibit either any meaningful changes in physiological health or demographic mortality8,12. Thus, they provide a proof-of-concept that age-related health decline is avoidable in mammals.

Fig. 1: A photograph of a 37-year-old naked mole-rat.
figure1

Ben Passarelli, Calico Life Sciences, LLC.

This breeding male exemplifies some of the attractive features of his species as a model of healthy aging: exceptional longevity given his body size (52.3 g), and maintenance of body composition, reproductive capability, activity levels and resistance to age-related diseases.

The biological adjustments required to prevent age-associated decline in naked mole-rats are likely complex, and they emerged from a multi-million-year evolutionary process in which many orthogonal aspects of biology were also modified. Naked mole-rats have numerous qualities that make them unique. Most notably, they exhibit a unique eusocial structure in which reproduction is restricted to only one breeding female within a large family group, with the majority of animals within the colony reproductively suppressed. They also maintain many pedomorphic or fetal-like traits well into adulthood, including lung structure and expressed hemoglobin type13. Also, their immune system stands out for its lack of natural killer cells and a greater reliance on myeloid-based innate immunity14. Discernment between relevance and irrelevance of unique physiology to the phenotype of interest is a common challenge when seeking insight from non-standard model organisms. But it is also the motivation to develop these atypical species as fully fledged biomedical models: through rigorous direct experimentation, the underlying and medically pertinent mechanisms of their unique biology can be discovered. For example, detailed study of the naked mole-rat tumor suppressor protein, p53, suggests that its unusual stability and constitutive nuclear localization may facilitate this species’ resistance to cancer, enhance its genomic stability and prolong its longevity15.

Preventing adverse effects of aging in humans poses numerous difficult challenges, including both understanding the causes of decline and conceiving of effective strategies to mitigate those harbingers of aging. But whatever complicated balance of modifications across multiple physiological systems are necessary to achieve this feat in a mammal, they have already been accomplished by nature through millions of years of evolutionary experimentation in our fellow mammal: the naked mole-rat. Whatever detrimental side effects arose from life-extending mutations have been resolved by compensatory adaptations during the course of evolution. The biology of naked mole-rats thus contains a blueprint for how to stave off the myriad of adverse effects of aging in mammals. The high-risk and technological challenges of working with an unusual laboratory species is mitigated by the high reward of gaining access to such a blueprint. Clearly, the naked mole-rat embodies a successful conquest of aging in mammals. In our own human species’ quest to conquer the ills of aging, we would be wise to follow in the footsteps of the naked mole-rat.

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Acknowledgements

We gratefully acknowledge support from Calico Management, and in particular D. Botstein and C. Kenyon, to undertake studies using this model. We also appreciate the care of our colony by M. Smith and her team of caretakers, as well as the scientists who have worked with us in our quest to elucidate previously unknown mechanisms naked mole-rats employ to beat the vagaries of aging.

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R.B. and G.R. discussed and planned this Comment. The first draft was written by R.B. and edited by G.R.

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Correspondence to Rochelle Buffenstein.

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G.R. and R.B. are both employees at Calico Life Sciences, LLC.

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Buffenstein, R., Ruby, J.G. Opportunities for new insight into aging from the naked mole-rat and other non-traditional models. Nat Aging 1, 3–4 (2021). https://doi.org/10.1038/s43587-020-00012-4

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