Naked mole rat genome may point way to long, healthy life
By David Brown,
The upside is you live a ridiculously long and healthy life, can’t develop cancer, feel very little pain, never get lonely and have great skin right to the end.
The downside is you breathe stinky air, rarely go outside, tend to get cold, don’t see well, live in a monarchy and can’t count on having sex. (Also, you’re a naked mole rat.)
How this collection of traits and behaviors came to exist in a strange rodent found only in the Horn of Africa has been a mystery. Now biologists have a tool for unraveling it — and what they find may one day prove useful to human medicine.
A team of 36 scientists working on three continents published the genome Wednesday of the naked mole rat, the latest and perhaps most exotic organism to have its entire DNA sequence transcribed.
“It’s a treasure-trove for cancer and Alzheimer’s research. It’s got so much information that we can now go and mine to test all kinds of theories about aging and disease,” said Rochelle Buffenstein, a researcher at the University of Texas Health Science Center in San Antonio who participated in the project.
“Having the genome raises the possibility of finding treatments that may prevent cancer in people and possibly even extend life span,” said Vera Gorbunova, a cell biologist and mole rat researcher at the University of Rochester, who was not involved in the work.
Mole rats are hairless, buck-toothed rodents four inches long that live in underground colonies in arid sections of Kenya, Ethiopia, Somalia and Eritrea. Their social structure is the mammalian equivalent of an ant colony. There’s a queen who takes two or three male consorts and is the only female to reproduce. She lords over the rest of the realm — which can be as large as 200 animals — so that the other females cease ovulating and the males give up.
Mole rats can survive in environments low in oxygen (as little as 8 percent as opposed to 21 percent in the atmosphere) and laden with ammonia and carbon dioxide. Unlike other mammals (but like reptiles), they have a hard time regulating their body temperature. They have to move toward the warmer upper reaches of the burrow or huddle with their brethren when they get cold.
But their most unusual features are extreme longevity and apparently complete resistance to developing cancer.
Naked mole rats can live more than 25 years; mice live about four. Buffenstein said she has never found a malignant tumor in a mole rat in her 30-year-old colony, which has 2,000 animals. In a recent experiment, a group of mole rats had patches of skin painted with a chemical carcinogen at a dose 1,000 times stronger than what causes skin cancer in mice. None developed tumors.
A study published in 2009 found that naked mole rats had a molecular anticancer mechanism not present in mice or people. But a first look at the species’ full complement of 22,561 genes shows that’s just the beginning.
There are changes in genes involved in maintaining telomeres, the “tails” of chromosomes that determine how long a cell lives. There are changes in genes involved in marking damaged proteins for destruction. There’s an increase in “chaperone” genes that keep proteins folded into their right shapes. There are genes that appear to let the animals maintain stem cells in their tissues longer than other rodents.
The study looked at 54 human brain genes that become less or more active as a person ages. In the mole rat, 30 of those genes remain stable throughout life, and two others change their activity in a direction opposite to what occurs in human brains.
Mole rats have 96 gene families unique to the species. Interestingly, they and humans also share 178 gene families that neither mice nor other rats have.
“Now we have to go back and study each one of these in detail,” said Vadim N. Gladyshev, a researcher at Harvard Medical School who headed the project and whose report appears in the journal Nature.
In many cases, the unusual features of the naked mole rat genome make perfect sense.
The species lacks many genes associated with vision, although it still has ones that allow it to perceive light. Genes involved with setting circadian rhythms based on daylight and darkness are gone. A gene that regulates Substance P — a protein involved in the perception of pain caused by caustic chemicals — is very different. That presumably allows the animals to tolerate breathing air loaded with ammonia from their urine.
They also lack many bitter-taste receptors. Buffenstein said that probably makes underground tubers, a staple of the mole-rat diet, more palatable. Many of those roots are loaded with bitter, plant-protecting compounds.
On the other hand, they appear to have genetic enhancement of sweet receptors. This doesn’t surprise the Texas researcher.
“My colonies go absolutely nuts for sweet things,” she said.