The Latest Update on Naked Mole Rat Cancer Immunity

Naked mole rats are exceedingly long lived in comparison to similarly sized rodents, and furthermore appear to be immune to cancer. A number of researchers are engaged in uncovering the reasons why the species has these characteristics. On the longevity front, differences in the composition of vulnerable cell membranes is one candidate, making cells more resistant to the more important forms of oxidative damage to protein machinery that accumulate over time. Cancer immunity on the other hand seems to be connected to the p16 gene and cellular reactions to overcrowding:

Like many animals, including humans, the mole rats have a gene called p27 that prevents cellular overcrowding, but the mole rats use another, earlier defense in gene p16. Cancer cells tend to find ways around p27, but mole rats have a double barrier that a cell must overcome before it can grow uncontrollably.

Neighboring species of blind mole rat may also be immune to cancer, but appear to have evolved a different mechanism to achieve the same end.

The modern research community being what it is, I expect that the years ahead hold a lot more work on the cancer angle than on aging and longevity. There is much more money in cancer research, and it is actually possible in the present regulatory environment to take new discoveries straight into development and clinical trials. No such luck for potential ways to treat aging: the FDA doesn't recognize aging as a disease, and therefore there is no path to gaining approval for a way to treat aging. Hence there is little funding for research like that organized by the SENS Research Foundation, aimed at plausible near future paths to human rejuvenation.

In investigating naked mole rat cancer immunity researchers are following the normal script, which is to find any important part of the biological mechanisms of interest - such as by removing genes until they find one that is necessary for the process to work - and then from that starting point move along the chains of protein interactions in an effort to understand how it all fits together. So starting from p16, researchers have moved on to identify a role for hyaluronan. The full paper isn't open access, unfortunately, but the publicity materials give a fair overview:

Biologists Identify the Chemical Behind Cancer Resistance in Naked Mole Rats

[Researchers] discovered that these rodents are protected from cancer because their tissues are very rich with high molecular weight hyaluronan (HMW-HA). The biologists' focus on HMW-HA began after they noticed that a gooey substance in the naked mole rat culture was clogging the vacuum pumps and tubing. They also observed that, unlike the naked mole rat culture, other media containing cells from humans, mice, and guinea pigs were not viscous. [They] identified the substance as HMW-HA, which caused them to test its possible role in the naked mole rat's cancer resistance.

When HMW-HA was removed, the cells became susceptible to tumors, confirming that the chemical did play a role in making naked mole rats cancer-proof. [The] team also identified the gene, named HAS2, responsible for making HMW-HA in the naked mole rat. Surprisingly, the naked mole rat gene was different from HAS2 in all other animals. In addition naked mole rats were very slow at recycling HMW-HA, which contributed to the accumulation of the chemical in the animals' tissues.

[Previously researchers] showed that the p16 gene in naked mole rats stopped the proliferation of cells when too many of them crowd together. In their latest work, the two biologists identified HMW-HA as the chemical that activates the anti-cancer response of the p16 gene.

The next step will be to test the effectiveness of HMW-HA in mice. If that test goes well, [researchers] hope to try the chemical on human cells. "There's indirect evidence that HMW-HA would work in people. It's used in anti-wrinkle injections and to relieve pain from arthritis in knee joints, without any adverse effects. Our hope is that it can also induce an anti-cancer response. We speculate that naked mole rats have evolved a higher concentration of HA in the skin to provide skin elasticity needed for life in underground tunnels. This trait may have then been co-opted to provide cancer resistance and longevity to this species."

A little early to be seeking out and stockpiling hyaluronan, I think - unless you have an aggressive cancer, in which case it doesn't seem like there's all that much to lose given the present safety profile. There are all sorts of reasons why hyaluronan may not have the same effect in anything other than naked mole rats: if the presence of hyaluronan is unusual in this species, then why not the reaction to it as well? So wait for the mouse studies before getting excited.

A reader was kind enough to dig up a few interesting papers on hyaluronan from past years and send over the links earlier today. The stem cell biology connection is interesting in connection with naked mole rat longevity, but that's really just speculation on my part:

Comments

The NM-rat's hyaluronan may have additional effects besides preventing cancer.

It appears that this intercellular glue protects stem cell niches and may pace cells' progression from stemness to senescence, e.g., see -

Hyaluronan Regulates Cell Behavior: A Potential Niche Matrix for Stem Cells
http://www.hindawi.com/journals/bcri/2012/346972/
Hyaluronan preserves the proliferation and differentiation potentials
of long-term cultured murine adipose-derived stromal cells
http://www.ncku.edu.tw/~biotech/teacher/L.H.%20Huang_mark/29.pdf
Hyaluronan: from extracellular glue to pericellular cue
http://www.nature.com/nrc/journal/v4/n7/authors/nrc1391.html

Posted by: Lou Pagnucco at June 20th, 2013 11:20 AM

According to a 2010 paper: Abnormal Glucose Tolerance in the Longest Lived Rodent, the Naked Mole-rat. A new Model for Longevity and Diabetes Research by Stephen Santos, "Diabetes has not been shown in NMRs. They have low fasting blood glucose levels, abnormal Glucose Tolerance Test readings, abnormal pancreas arrangement, and unmeasureable insulin levels." Day (1950, 1952) showed that hyaluronic acid plays an important part in the resistance of connective tissue to the flow of fluid through it, and these diffusion studies showed that glucose is one of the metabolites blocked by HMW-HA, so HA may only be acting to restrict metabolite flow into tissue culture cells to prevent cancer induction. Metabolic studies of Naked Mole Rats Glucose Tolerance demonstrate abnormal pancreas arrangement and unmeasureable insulin levels. NMR's are extremely sensitive to exogenous insulin. It is common knowledge that cancer cells exhibit accelerated glycolysis and are often dependent on insulin so mechanically blocking glucose could prevent cancer induction. These animals appear to normally have a fatty-acid-based metabolism that is not hospitable to cancer cell growth.

Posted by: Victor Walker at June 25th, 2013 6:20 AM

I believe that with genetic engineering, we may be able to copy the p16 gene from the naked mole rat, as well as increase the amount of hyaluronan. Although i do believe that this should be tested on mice first, IF all goes well, We could have cancer immune humans. A downside of this would be the structural component of the hyaluronan. Because hyaluronan also holds the rats tissue and other parts together, it may mess up the organisation and structure of the internal human body.

As far as treating ageing, There are currently studies of how to increase the amount of an enzyme called telomerase in the human body. unlike humans, Lobsters contain high amounts of this enzyme.

Posted by: Chad at April 5th, 2014 1:10 PM

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