SAN ANTONIO, Texas ( Ivanhoe Newswire) - Getting old and getting cancer are two things a lot of people worry about and a lot of scientists are trying to fight. Now, some unique critters could be the key to preventing both.
Are you worried about getting old? How about cancer? What if you were agile enough to do things well into your nineties and your body was cancer resistant? The secrets to those possibilities could be inside naked mole rats.
In the basement lab of the UT Health Science Center are about 2,500 of them. Doctor Rochelle Buffenstein is studying the critters. Based on their size, they should only live about six years, but they live to 35 and are highly active until they're 25.
"Which would be equivalent to a human at the age of about 90 maintaining good health and good function," Dr. Rochelle Buffenstein, a professor at UT Health Science Center, told Ivanhoe.
Based on our size, Buffenstein said we should only live to 40.
"Humans and naked mole rats live between four and five times as long as they should," Dr. Buffenstein said.
Unlike the rodents, we get cancer.
"We've never seen a single tumor in our colony," Dr. Buffenstein said.
While most mice die from tumors, researchers painted the mole rats' skin with carcinogens and no tumors developed. They even took out their cells and manipulated them to get cancer. Buffenstein said we share 178 unique gene families with mole rats. The key is to find the pathways that make the rats age better and stay cancer-free, then find a way to modify human genes to do the same. The doctor said her goal isn't to help humans live hundreds of years but a healthy life for at least 95 years rather than 60.
Doctor Buffenstein believes she's getting close to finding the pathways that could help her figure out why the mole rats age so well and don't develop cancer, but, translating the findings to help humans could take a lot longer.
BACKGROUND: Dr. Rochelle Buffenstein of the Barshop Institute for Longevity and Aging Studies is a native of Zimbabwe (then Rhodesia) who was educated largely in South Africa. She trapped many of the naked mole rats she studies herself and then brought the whole colony along when she moved to the United States.
Naked mole rats are the source of great interest in an area of study called "comparative gerontology" or "comparative biology of aging." In short: Usually, you can make a reasonably accurate prediction of how long a mammal will live based on its size. The larger the mammal, the longer it lives. But there are outliers, and naked mole rats are a notable exception. They're about the same size as mice, which live up to 4 years. Naked mole rats live 30 years or more, and maintain surprisingly good health throughout. (Source: University of Texas Health Science Center San Antonio)
THE RESEARCH: Comparative biology of aging highlights those unusual species that are not only able to live considerably longer than expected on the basis of their body size but also maintain good health until very late in life. A key focus of the research undertaken in the Buffenstein lab addresses the cellular and molecular mechanisms that the longest-lived rodent, the naked mole-rat uses to thwart the aging process and maintain cancer-free good health well into their third decade of life. In particular, researchers currently are using a genomic and metabolomics approach to address the underlying mechanisms that facilitate the maintenance of protein stability and genomic integrity in rodents of disparate longevity. (Source: University of Texas Health Science Center San Antonio)
NAKED MOLE RAT FACTS:
Despite their names, naked mole rats are neither moles nor rats (nor are they totally hairless). They are more closely related to porcupines and guinea pigs.
Naked mole rats live in the horn of Africa and are native to Somalia, Ethiopia and Kenya.
Soldier mole rats defend the colony from both predators—mostly snake—and foreign mole rats, which they identify as foreign by their odor.
The queen isn't born a queen. She's a female who has fought her way to the top.
A colony of naked mole rats can consist of 20 to 300 individuals. Their underground territory can be as large as six football fields. (Source: smithsonianmag.com)
Rochelle Buffenstein Ph.D, a professor at the UT Health Science Center, talks about how mole rats could solve two medical mysteries.
Why study mole rats?
Dr. Buffenstein: Naked mole-rats are very interesting animals from the perspective of aging, although they're the size of a mouse, that lives only a maximum of 3-4 years, they live thirty two years, which is an extraordinary long length of time for an animal this size. They live about four to five times longer than expected on the basis of body mass. We feel that an animal that lives such a long time might tell us secrets about how to age slowly and how to age well. What's really interesting about these animals is that not only do they live thirty two years but they maintain high levels of activity well into old age. They maintain activity, they maintain body composition, and they maintain every aspect of physiological function for at least twenty five years, which would be equivalent to a human at the age of about ninety maintaining good health and functionality.
It would be equivalent to an older adult in good health?
Dr. Buffenstein: Most people by the time they are forty show declines in bone health, declines in glucose handling, and declines in fat tolerance and at least in the case of females a decline in fertility. These animals can breed throughout their long-lives. They don't show menopause so we're very interested in understanding how they're able to maintain good reproductive health well into old age. They maintain every aspect of their biochemistry (e.g. protein levels, enzyme function) at the same high levels that you see in a young animal. Whereas in mice, by the time they're twelve months of age, which is twenty five percent of their lifespan, you're already seeing a steep decline in many aspects of their physiology and biochemistry.
What's the lifespan of mice?
Dr. Buffenstein: The most a mouse lives is four years, that's the record.
They're the same size, so what's the difference?
Dr. Buffenstein: One of the key things that we think is responsible for their extreme longevity is that they have remarkable resistance to cancer. We've never seen a single tumor in our colony and most mice die of cancer. The cancer kills them usually when they're older than two years. One of the big studies we're doing is trying to understand how these animals are able to protect against cancer, even though they naturally have very high levels of oxidative damage. This is a very strange finding in these animals, which surprised me greatly, as we would predict that an animal that lives a long time has mechanisms in place to prevent oxidative stress, because the oxidative stress theory of aging suggests that as you get older it's oxygen that does you in. It causes damage to proteins, to lipids, to DNA and these then impair the normal functionality of those proteins and you see the decline in function or the onset of frailty that characterize aging. Our first study that we did with regards to aging is we looked at oxidative damage and oxidative stress in these animals. The suite of antioxidant defense mechanisms these animals have is really unremarkable. They are exactly the same as the mouse. The levels of reactive oxygen species or free radicals they produce also seems to similar to that of the mouse. Much to our surprise we found that they have really high levels of oxidative damage even at a young age. An animal that is six months old has more oxidative damage than a two year old mouse, and yet it's able to live another thirty one and a half years with that kind of damage whereas the mouse can't. These animals defy or challenge this key dogmas of aging. Despite having this high level of oxidative damage, they are able to maintain both genomic and protein integrity and thereby maintain an extended healthspan. We're basically focusing on both those different topics looking at how do they maintain their proteins and good function throughout their long live and how do they maintain their genomic integrity until they die. We've had some very interesting findings. For instance we found that their cells are very resistant to any kind of toxin. Clearly they have mechanisms in place to resist toxins or to detoxify those kind of agents. We found with their proteins if you take the proteins and you subject them to unfolding stressors like urea or high temperatures, the proteins don't seem to unfold, they have mechanisms, most likely heat shock proteins, in place to maintain good protein health. Proteosome activity, the cellular machinery that degrade damaged proteins, is really high in these animals so they're able to efficiently remove damaged proteins and thereby high quality proteins throughout their long life. I think that's a very important component.
How could this help you unlock the keys to aging and helping people never get cancer?
Dr. Buffenstein: We know that every organism shares most fo their genetic makeup. Naked mole-rats have several genes that are naturally overexpressed or uniquely modified to alter their functionality and many of these are known to play an important role in cancer protection. We're getting a good handle that there are certain stress pathways that are primed in these animals to rapidly respond to toxins or carcinogens, neutralize these and thereby prevent cancer initiation. Other genes may be overexpressed that block the inflammatory responses known to promote tumor formation and progression. If we can modify those kind of genes and their level of expression in humans or employ different different stimulants to upregulate these so that they too counteract cancer initiation and progression and improve mechanisms of cancer prevention. By understanding what those mechanisms are, and what they do, we can apply these in translational research to improve mechanisms of cancer protection, that's our goal. We've now recently sequenced the naked mole-rat genome and found for the most part, their genes are identical to both mice and humans, which is exactly what you would expect, naked mole-rats are not from outer space but African underground inhabitants. We did find there were a hundred and seventy eight gene families which were uniquely shared amongst humans and naked mole-rats and were not found in mice, even though mice are closer relatives to naked mole-rats than humans obviously are. We're focusing on those hundred and seventy eight genes that they share in common because humans also are an extremely long lived animal and maybe these are key longevity assurance genes so that these may be tweaked to be even more effective in protecting genomic integrity.
What do you mean by same pathways?
Dr. Buffenstein: I mean a whole lot of different chemical signaling pathways in the body that tell you you're having to deal with a stress now, and this is what you need to detoxify that stress or to neutralize it to up regulate molecular chaperones to protect your proteins so that they don't completely unfold and things like that.
There might be something a little bit off on us that is on in them that is making them so resistant to cancer?
Dr. Buffenstein: Absolutely. What's been interesting is, we've got lots of keys why these animals are living a long time. The first one was their resistance to any kind of toxin, their resistance to gamma radiation. We've gamma radiated animals and years later we see they still haven't developed cancers although we would anticipate they would. We've seen that they don't get Alzheimer's, they have beta amyloid in their brains because they live a long enough time for it to accumulate. We're trying to get a handle on every physiological system, from brain aging to heart aging to normal chemical aging in every single tissue. We see in every single system they are primed to not show those age-dependent changes that we get in humans and other animals. Clearly it has to be a very generic and global mechanism that they're using in every system, so that they can survive and can live a long time. For if any one system were to break down it would impact on their longevity and for animals to live a long time every system has to be functioning properly. That way these animals can maintain good health and a good quality of life, which in essence is what we are trying to simulate. We don't think people can live 500 years and even if they could we would not want to. Rather we would like to live a healthy life for at most of our lifespan and not have to contend with pain associated with age-dependent diseases such as osteoarthritis, or other age-associated frailty. These animals appear able to do that, they maintain really good health until about twenty five years and only then we start seeing this steep decline in muscle mass or levels of activity. Because everybody is eventually going to die what we would really want to do is , and be able to do the things you enjoy well into old age and thereby have a good quality of life. This is really what we want.
How do you compare a twenty five year old mole-rat to a ninety year old person? Are we still talking someone who could go out and run marathons and act like they're twenty?
Dr. Buffenstein: That's what we would like. To answer your question from a much more simplistic point of view, we know from comparative biology that every single feature in biology scales for body size. The bigger you are, the bigger your brain is and the bigger your eye will be, and the longer you live. You don't live longer just because you've got big eyes or longer legs that can run away from predators, it seems that there is an inherent scaling of every body function with average species body size. This relationship is often referred to as the mouse to elephant curve. For example as a species gets larger heart rate declines and metabolic rate per gram of body mass declines. Many of these equations have been carefully worked out to help predict what these variables should be. Most animals live about as long as predicted on the basis of body size, and as such they have a longevity quotient (the ratio of the observed lifespan over that predicted on the basis of body size) of one. Nevertheless there are a few animals that are considered very long lived for their body size. The two species that are the greatest outliers from the allometric relationship between body size and maximum lifespan are humans and naked mole-rats. Both humans and naked mole-rats live between four and five times as long as they are expected to. Both naked mole-rats and humans are extremely long lived for their body size and both show a very much delayed aging profile. Humans shouldn't live more than forty years and by thirty years human bone quality has already declined, activity levels have changed and there are many other age-associated physiological changes that are evident in a thirty to forty year old healthy human. In the case of mole-rats you don't see any of those changes until they are at least seventy five percent through their maximum lifespan, whih would be equivalent to a 90 year old human maintaining the kind of functionality seen in a 20 year old.. And that to me is where you get that good quality of life.
How close are we to unlocking that pathway?
Dr. Buffenstein: I think we're getting closer. I think there are many interesting studies that are on the burner at the moment. One of the key studies that ought to yield important insights is elucidating the mechanisms leading to stress resistance and maintenance of protein and genomic integrity. I think we're seeing some evidence of where that's going but I think we're quite a ways still from translation. Hopefully in my lifetime but who knows.
FOR MORE INFORMATION, PLEASE CONTACT:
Will Sansom Executive Director of Media Communications The UT Health Science Center at San Antonio (210) 567-2579 firstname.lastname@example.org
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