The lowly naked mole rat is in the news again. I talked about the little critter in my in my February 2009 post Animal models of aging – the African naked mole rat. I said “This little critter is the size of a tiny mouse but lives about eight times longer. Living up to 28 years, it is the longest-living rodent. Its secret to longevity is not known but there are clues. For example they are very cool, they can all but shut down their metabolism, and they spend a great deal of their life sleeping. Surprisingly, the markers of oxidative damage in these tiny rats exceed those of mice when they are relatively young. However the rate of accrual of oxidative damage in these rats does not appear to markedly ramp up with age as it does with mice. They change very little as they age and females more than 20 years old can give birth. It seems that the mole rat has a powerful long-lived antioxidant defense system which mice do not have.”
The news items that surfaced yesterday reported on work by Vera Gorbunova and her team at the University of Rochester and included a nice story in the New York Times entitled The Life Span of a Rodent May Aid Human Health. Even apart from their longevity these little naked mole rat critters are fascinating. They cannot see and spend their entire lives underground. They “live in large colonies, presided over by a queen, in which only the queen and a few privileged males breed while the rest of the colony—all members of the same family—work together to raise young and maintain the colony. Wild colonies range in size from 20 to 300 individuals, with an average colony consisting of 75 individuals(ref).” They have a very hierarchical social system with the queen at the top, then her favorite mates, ranging down to the workers. She is extremely bossy. They dig extensive tunnels looking for tubers which they share for food with other members of their colony. Besides dead reckoning, they use the earth’s magnetic field to help them navigate underground, at least for longer distances(ref). A colony of naked mole rats can build a system of tunnels stretching up to two or three miles in cumulative length. “Ensconced in the arid soils of Africa, these three-inch-long creatures must continually dig tunnels in search of sporadic food supplies and evade the deadly jaws of snakes(ref).” If you are interested in learning more about their lifestyle, you can check the article The Naked Truth about Mole-Rats.
Physically, the naked mole rats are quite unique. Apparently they have no pain sensors on their skins and use their fang-like teeth to dig their tunnels. Their large, protruding teeth are used to dig, and their lips are sealed just behind the teeth to prevent soil from filling their mouths while digging(ref).” They look a little like tiny walruses. “They have little hair (hence the common name) and wrinkled pink or yellowish skin. — The naked mole rat is well adapted for the limited availability of oxygen within the tunnels that are its habitat: its lungs are very small and its blood has a very strong affinity for oxygen, increasing the efficiency of oxygen uptake. It has a very low respiration and metabolic rate for an animal of its size, about 2/3 that of a mouse of the same size, thus using oxygen minimally. In long periods of hunger, such as a drought, its metabolic rate can be reduced by up to 25 percent(ref).”
“Some of the “hottest” research on naked mole rats today concerns senescence, or aging. Naked mole rats in the lab have reached up to 28 years of age. And it’s not just the controlled environments of their captivity that are doing this. –Braude has observed mole rats in the wild that are 17 years and older. But these are the breeders. Lab researchers didn’t realize that in the wild workers only live two or three years(ref).”
Though there are many interesting things about these little beasties, let me get down to the questions of why they live so long and what might be the lessons for us. To start, there are two clues from my previous post on them:
1. Naked mole rats go inactive for periods and turn their metabolism way down.
2. Naked mole rats have a powerful long-lived antioxidant defense system which mice do not have.
The next point is based on the research reported yesterday:
3. Naked mole rats never get cancers.
Despite their very long lives which provide plenty of time for their cells to grow cancerous, naked mole rat have never been found with tumors of any kind. A report just published in The Proceedings of the National Academy of Sciences, Hypersensitivity to contact inhibition provides a clue to cancer resistance of naked mole-rat, suggests why. “Here we show that naked mole–rat fibroblasts display hypersensitivity to contact inhibition, a phenomenon we termed “early contact inhibition.” Contact inhibition is a key anticancer mechanism that arrests cell division when cells reach a high density. In cell culture, naked mole–rat fibroblasts arrest at a much lower density than those from a mouse. — We demonstrate that early contact inhibition requires the activity of p53 and pRb tumor suppressor pathways. Inactivation of both p53 and pRb attenuates early contact inhibition. Contact inhibition in human and mouse is triggered by the induction of p27/Kip1. In contrast, early contact inhibition in naked mole–rat is associated with the induction of p16(INK4a).”
In essence, the observed results were that expression of p16(INK4a) “makes the cells “claustrophobic,” stopping the cells’ proliferation when too many of them crowd together, cutting off runaway growth before it can start. The effect of p16 is so pronounced that when researchers mutated the cells to induce a tumor, the cells’ growth barely changed, whereas regular mouse cells became fully cancerous(ref).” [I have discussed p16(INK4a) at some length in my treatise and in this blog(ref), a tumor suppressor protein also very active in humans. But nowhere previously have I seen any discussion of p16(INK4a) making cells claustrophobic. Apparently this does not happen in humans where weaker contact inhibition is instead triggered by p27/Kip1.] In any event, whether or not contact resistance is the central element, naked mole rats have an incredibly effective defense against cancers.
Finally, to top it off, it is believed that
4. Naked mole rats body cells express telomerase.
In 2006 the same lead researcher, Vera Gorbunova, studied small rodents to see how their telomerase expression varied. She “investigated 15 rodents from across the globe to determine what level of telomerase activity each species expressed, to see if there were some correlation she could find. — The species ranged from tiny field mice to the 100-pound capybara from Brazil. Lifespans ranged from three years for the mice, to 23 or more for common backyard squirrels(ref).” She found the smaller the critters the higher degree of expression of telomerase – presumably also in the naked mole rat. Her results were published in the paper Telomerase activity coevolves with body mass, not lifespan where she concludes “Here we show that telomerase activity does not coevolve with lifespan but instead coevolves with body mass: larger rodents repress telomerase activity in somatic cells. These results suggest that large body mass presents a greater risk of cancer than long lifespan, and large animals evolve repression of telomerase activity to mitigate that risk.” Of course, we are like very large rodents in the respect that telomerase activity in our somatic cells is very repressed.
These studies provide interesting insights and food for speculation. First of all, for my readers who see telomerase activation as a one-track approach to life extension, telomerase expression by itself does not correlate with lifespan. Second, it could well be that the message of the naked mole rat is that a combination of a very powerful anti-cancer defense with activated telomerase might lead to significantly greater longevity. That, by the way, has been my personal view for some time now. In my treatise I have written “I speculate that protection against carcinogenesis in the course of such telomerase stimulation can probably be achieved through strengthening of apoptotic mechanisms such as P53, P16 and P21. Credence is given to this view by a very recent finding that mice which possess extra copies of both telomerase-creating and antitumor genes live 26% to 40% longer than their normal cohorts(ref).” Both the Lifestyle Regimen and the Supplement Regimen in my anti-aging firewall program suggest numerous provisions for the avoidance of cancers. The treatise contains an extensive discussion of telomerase activation and the supplement regimen suggests use of a telomerase activator.