Written by Elise Hebert '24
Edited by Wonjin Ko '26
A female naked mole rat. Flickr user Jedimentat44, 2011, hosted on Wikimedia Commons.
Beneath the soil of the Eastern African grasslands, a strange creature toils away, building sprawling societies in underground tunnels. They’re nearly blind, insensitive to acid [1], resistant to cancer [2], and can survive 18 minutes completely deprived of oxygen [3]. They organize themselves around a single queen, who produces all the colony’s young, and suppresses reproduction in the other females [4]. But they’re not insects. They’re naked mole rats, and they’re mammals like us.
This year, new research revealed yet another way that naked mole rats subvert our expectations of mammalian biology.
In some ways, these odd little animals remain familiar. They’re closely related to the ordinary rats found in sewers and scientific laboratories the world over, and like them, they share many developmental pathways, body functions, and genes with us humans. They even have hair - it’s just hard to see, clustered in sensory whiskers. But where common rats traverse both the surface and the underground with equal enthusiasm, naked mole rats are entirely adapted to burrowing life. Their tunnels are their whole world. Working for three years in naked mole rat habitat, one group of researchers caught only 9 individuals on the surface [5].
For scientists interested in human health, the naked mole rat’s combination of strange adaptations and familiar underpinnings makes them an enticing study animal. Their cancer resistance and unusual longevity are certainly enviable traits - they can live for 30 years, or up to 10 times the lifespan of a typical lab rat! With such lofty prospects involved, most researchers have ignored that other mole rat hallmark, the colonial reproduction, brushing over the subject for its “limited biomedical translatability” [2]. But recently, it’s become clear that this world of queens and daughters may hold an important secret of its own.
This February, the journal Nature Communications published the latest discovery by a team of researchers working under Professor Ned J. Place at Cornell University and Assistant Professor Miguel Angel Brieño-Enríquez at the University of Pittsburgh School of Medicine. For this group, the mystery started with a simple question: How do mole rat queens keep up with the strenuous demands of exclusive motherhood for 30 years?
Most female mammals live their reproductive lives in a finite time window - a fact that us humans often find ourselves intimately aware of. Early in embryonic development, a protected group of stem cells, the primordial germ cells, migrate to the tissues that will one day become ovaries or testes. These cells will divide to give rise to eggs and sperm, and eventually, to the next generation. In males, the descendants of the primordial germ cells can keep on dividing forever, producing an endless supply of sperm, but in females, they use themselves up in one burst of division before the new individual is even born. We arrive with all the eggs we’ll ever have.
And so, with no fresh new eggs available, a female mammal has limited time to use them, before they’re gone for good. The infamous “biological clock” is ticking. For humans, menopause typically occurs when we have somewhere around 500 eggs left [6]; for short-lived mice, fertility starts to drop off at 9 months of age [7]. But naked mole rats live multiple decades, and never experience a decline in fertility. A queen will continue to breed until the day she dies, potentially spawning thousands of pups.
Brieño-Enríquez and the rest of Place’s team may have uncovered why. Closely examining naked mole rat ovaries, they found that in these animals, eggs are not stockpiled during early embryonic development. In fact, the primordial germ cells only started dividing into eggs after birth, and remained active, though less so, even in 3-month-old animals, still dividing. The team had previously spotted germ cell clusters in the mature ovary while counting eggs, but this was the first evidence of continuing division [8].
A self-renewing supply of eggs could help naked mole rats cope not just with their unusual longevity, but with the drama of their colonial life. Though subordinate naked mole rats live under the reproductive control of the queen, her hold is not unbreakable. And when an upset rocks the colony, some subordinate - any one of them - must be ready to take her place. The Cornell University group compared the ovaries of subordinates and newly “crowned” ex-subordinates - all 3-year-old adults this time - and found primordial germ cells alive and well in them, too. In the ex-subordinate, these cells flickered with genetic markers of proliferation, and divided happily in a petri dish. The new queen was well equipped to mother a colony [9].
In the ovary of a 3-year-old naked mole rat, living primordial germ cells - dyed red - are clearly visible. From Brieño-Enríquez et al 2023, fig. 8.
In all mammals, newly-produced eggs enter a state of suspended animation, locked partway through their final cell division until they’re fertilized. In this state, the cell’s chromosomes are held in a delicate and precarious position, linked together. With time, the ties holding them begin to break down, and this may be one of the factors that causes egg viability to decrease for older humans [10]. However, the whole process is difficult to study because it happens internally and starts when we’re only embryos. In naked mole rats, however, new eggs continue to appear and enter suspended animation into adulthood. This might allow the rodents to rise to queendom at any stage of their lives, and it might also allow scientists to get a closer look at the roots of reproductive longevity than ever before [9].
As humans, we don’t live in colonies with queens, but we do live in an aging population: according to the World Health Organization, by 2030, one in six people will be 60 years old or over [11]. For the medical scientists of today, uncovering mechanisms to prolong health is a high priority, and this, of course, includes reproductive health. Naked mole rats, adapted for longevity, already make a valuable model, and no doubt will continue to offer insight, and to overturn assumptions on how mammals function and evolve [12].
They may be weird and unglamorous, and they may spend their lives digging in the dirt, but we could all stand to learn a thing or two from the naked mole rat.
References
[1] Smith ES, Omerbašić D, Lechner SG, Anirudhan G, Lapatsina L, Lewin GR. The molecular basis of acid insensitivity in the African naked mole-rat. Science. 16 Dec 2011 [cited 11 Apr 2023];334(6062):1557-60. DOI: 10.1126/science.1213760.
[2] Smith ES, Schuhmacher LN, Husson Z. The naked mole-rat as an animal model in biomedical research: current perspectives. Open Access Animal Physiology. 11 Aug 2015 [cited 11 Apr 2023];2015(7):137-148. DOI: 10.2147/OAAP.S50376.
[3] Park TJ, Reznick J, Peterson BL, Blass G, Omerbašić D, Bennett NC, Kuich PH, Zasada C, Browe BM, Hamann W, Applegate DT. Fructose-driven glycolysis supports anoxia resistance in the naked mole-rat. Science. 21 Apr 2017 [cited 11 Apr 2023];356(6335):307-11. DOI: 10.1126/science.aab3896.
[4] Buffenstein R, Amoroso V, Andziak B, Avdieiev S, Azpurua J, Barker AJ, Bennett NC, Brieño‐Enríquez MA, Bronner GN, Coen C, Delaney MA. The naked truth: a comprehensive clarification and classification of current ‘myths’ in naked mole‐rat biology. Biological Reviews. 3 Sep 2021 [cited 11 Apr 2023];97(1):115-40. DOI: 10.1111/brv.12791.
[5] Braude S, Holtze S, Hildebrandt T, Koch R. Naked mole‐rats do not disperse or deliver pups in correlation with moon phase. African Journal of Ecology. 10 Feb 2020 [cited 11 Apr 2023];58(3):592-5. DOI: 10.1111/aje.12721.
[6] Depmann M, Faddy MJ, Van Der Schouw YT, Peeters PH, Broer SL, Kelsey TW, Nelson SM, Broekmans FJ. The relationship between variation in size of the primordial follicle pool and age at natural menopause. The Journal of Clinical Endocrinology & Metabolism. 1 Jun 2015 [cited 11 Apr 2023];100(6):E845-51. DOI: 10.1210/jc.2015-1298.
[7] Findlay JK, Hutt KJ, Hickey M, Anderson RA. How is the number of primordial follicles in the ovarian reserve established?. Biology of reproduction. 1 Nov 2015 [cited 11 Apr 2023];93(5):111, 1-7. DOI: 10.1095/biolreprod.115.133652.
[8] Place NJ, Prado AM, Faykoo-Martinez M, Brieño-Enriquez MA, Albertini DF, Holmes MM. Germ cell nests in adult ovaries and an unusually large ovarian reserve in the naked mole-rat. Reproduction (Cambridge, England). 2021 Jan [cited 11 Apr 2023];161(1):89. DOI: 10.1530/REP-20-0304.
[9] Brieño-Enríquez MA, Faykoo-Martinez M, Goben M, Grenier JK, McGrath A, Prado AM, Sinopoli J, Wagner K, Walsh PT, Lopa SH, Laird DJ. Postnatal oogenesis leads to an exceptionally large ovarian reserve in naked mole-rats. Nature Communications. 21 Feb 2023 [cited 11 Apr 2023];14(1):670. DOI: 10.1038/s41467-023-36284-8.
[10] Jones KT. Meiosis in oocytes: predisposition to aneuploidy and its increased incidence with age. Human reproduction update. 14 Dec 2007 [cited 11 Apr 2023];14(2):143-58. DOI: 10.1093/humupd/dmm043.
[11] World Health Organization. Fact Sheets: Ageing and Health [Online]. 1 Oct 2022 [cited 11 Apr 2023]. Available from: https://www.who.int/news-room/fact-sheets/detail/ageing-and-health.
[12] Buffenstein R. Negligible senescence in the longest living rodent, the naked mole-rat: insights from a successfully aging species. Journal of Comparative Physiology B. 8 January 2008 [cited 11 Apr 2023];178:439-45. DOI: 10.1007/s00360-007-0237-5.