Due to their long life expectancy, naked mole rats are particularly suitable for researching mechanisms that maintain cellular function and slow aging. If these mechanisms could be solved, then the results could be relevant for humans aging and the development of cancer. An international study involving the University of Veterinary Medicine Vienna (Konrad Lorenz Institute for Ethology; KLIVV) is now providing important new insights into how adult stem cells affect long-term tissue maintenance using naked mole rats and their intestinal tract.
Naked mole rats (Heterocephalus glaber) are very special mammals. The animals, which are a maximum of 15 centimeters in size, live in large underground burrows and colonies of up to 300 animals in the semi-deserts of East Africa and are the only species of the genus Heterocephalus. Not only are they extremely social, their life expectancy is also unusually long and significantly exceeds that of other rodents. Because of this property, they offer scientists a unique opportunity to explore how evolution has influenced adult stem cell (ASC) activity and tissue function as life expectancy increases.
In mammals and other multicellular organisms, long-term maintenance of tissue homeostasis requires strict regulation of adult stem cell activity to ensure efficient repair and regeneration. In high-turnover mammalian tissues such as the intestine, the balance is controlled primarily by the continuous division and differentiation of the ASC and the subsequent cell death (apoptosis) of the mature cells. The longer survival of ASCs puts them at increased risk of mutations and reduces their fitness, which is evident in aging and in diseases such as cancer.
Intestinal tract with numerous cellular peculiarities
With this in mind, the scientific team examined the intestinal tract of naked mole rats and compared their intestinal ASCs (Lgr5+) with those of mice and humans. Study co-author Dustin J. Penn from the Vetmeduni's KLIVV said: “In vivo, we found an expanded pool of Lgr5+ cells in naked mole-rats. These cells exhibit slower division rates compared to those of wild house mice, specifically at the crypt base (Lgr5+CBC), but have a similar turnover to human Lgr5+CBC cells. Instead of entering quiescence (G0), naked mole rat Lgr5+CBC cells reduce their division rates by prolonging the G1 and/or G2 phases of the cell cycle.”
In addition, the researchers observed a higher proportion of differentiated cells in naked mole rats, which provide the intestinal mucosa with better protection and function. “The intestinal mucosa of naked mole rats is able to efficiently detect any chemical imbalance in the intestinal environment and trigger a robust pro-apoptotic, anti-proliferative response within the stem/progenitor cell zone,” explains study co-author Dustin J. Penn from the KLIVV at the Vetmeduni.
Less cancer: Evolutionary adaptations reduce the incidence of age-related diseases
Their study characterizing the intestinal tract of naked mole rats adds to the growing body of evidence that these remarkable animals have evolved unique adaptations that enable long-term maintenance of tissue homeostasis and, as a secondary consequence, reduce the incidence of age-related diseases such as cancer. The development of a greater reserve of ASC in all tissue types in naked mole rats facilitates efficient maintenance of the tissue in an environment of high oxidative and mechanical stress, reduces the likelihood of fixation of deleterious mutations due to increased selection against deleterious variants, and slows the clonal expansion that occurs in aging can be observed. The lower ASC division rates in the gut of naked mole-rats – as in humans – also likely prevent proliferative exhaustion of ASCs, which is necessary for a longer life expectancy.
The article “Adult stem cell activity in naked mole rats for long-term tissue maintenance” by Shamir Montazid, Sheila Bandyopadhyay, Daniel W. Hart, NanGao, Brian Johnson, Sri G. Thrumurthy, Dustin J. Penn, Bettina Wernisch, Mukesh Bansal , Philipp M. Altrock, Fabian Rost, Patrycja Gazinska, Piotr Ziolkowski, Bu'Hussain Hayee, Yue Liu, Jiangmeng Han, Annamaria Tessitore, Jana Koth, Walter F. Bodmer, James E. East, Nigel C. Bennett, Ian Tomlinson and Shazia Irshad was published in Nature Communications.
Scientific Article