Exception to Several Theories of Aging – Why Do Naked Mole Rats Live So Long?

Naked mole-rats (Heterocephalus glaber) are rodents found in the hot tropical regions of the Horn of Africa. When he first described a naked mole-rat in 1842, the famous German naturalist Eduard Rüppell suspected he had encountered a diseased specimen—because the animal had no fur and permanently protruding teeth. Only after several more specimens had been collected did it become apparent that their weird appearance, variously described as resembling saber-toothed sausages or miniature walruses, was normal.
Naked mole-rats live in a maze of underground tunnels that may extend more than a mile in length and as deep as 8 feet beneath the soil surface. Their burrows contain both nest chambers, tended by sterile worker animals, and several toilets, which the animals use religiously to avoid contamination of their living space. To locate the roots, tubers, and small onion-like bulbs they eat, mole-rats must dig through the soil, expanding their tunnels using their chisel-like, ever-growing incisor teeth. They occasionally make an opening to the outside world to kick excavated soil to the surface, where it forms small volcano-shaped mounds—the only aboveground signs of the vast colonies below. Given this strictly subterranean existence, it is not surprising that naked mole-rats have evolved a set of characteristics highly suited to life in dark, dank burrows.

This is how the naked mole rat’s colony looks like. This excellent review in The Scientist by Thomas Park and Rochelle Buffenstein illustrates the complicated lives of these outstanding hairless animals: how they live under the ground in Africa, how they have the breeding Queen and worker-animals (just like the honey bees), how they don’t feel certain kinds of pain, how they are resistant to the lack of oxygen and toxic amounts of carbon dioxide in the air. But the coolest thing about the naked mole rats is that they basically live 9 times more than “they should”:

Although naked mole-rats are the size of a mouse, weighing only about 35–65 grams, in captivity these rodents live 9 times longer. With a recorded maximum lifespan of 32 years, they are the longest-lived rodents known. And remarkably, they appear able to maintain good health for most of their lives. At an age equivalent to a human age of 92 years, naked mole-rats show unchanged levels of activity and metabolic rate, as well as sustained muscle mass, fat mass, bone density, cardiac health, and neuron number.

So not only they are exceptionally long-lived, they are also very active and healthy even in the old age.

Somehow they delay the onset of aging and compress the period of decline into a small fraction of their overall lifespan.

They also have no cancer.

Naked mole rates are exceptions to several theories of aging. For example, the free radical theory states that aging happens, because of the extensive cellular damage from reactive oxygen species. However, naked mole rats show very high levels of oxidative damage from these free radicals and still their cells are perfectly functioning for years and years. Another hypothesis claims that aging is due to shortening of telomeres – DNA molecules caps, that shorten every time a cells undergoes division. Yet the naked mole rat has relatively short telomeres. Also the telomerase, protein that lengthens telomeres, is not really active in naked mole rats’ cells. So telomere maintenance is unlikely to explain the outstanding longevity in these animals.

So what are the reasons for these almost “magical” properties of the naked mole rat? Park and Buffenstein note:

1. Naked mole-rat tissues are better able to recognize abnormal cells, neutralize their tumorigenic properties, and repair their DNA. Should that fail, the cells are ushered into programmed cell death pathways.  This means that errors in the DNA are constantly and effectively repaired or removed, before they give rise to cancer.

2. Many gene families in the mole-rat genome are involved in DNA repair and detoxification processes, and the expression of these genes remains unchanged as the animals age. So, stress resistance genes work perfectly well into the old age.

3. Proteasomes are more abundant and more efficient in degrading the damaged proteins within the cells. Same thing with autophagy – it occurs at a twofold greater rate in naked mole-rat cells than those of the mouse. These two enchanted mechanisms of cellular cleaning resist damage from toxins, heavy metals and DNA-damaging agents. In simple words: better housekeeping means longer life.

This supermodel for research is being studied only in a couple of labs in the world. This is such a shame. I wish more researchers included naked mole rats in their experiments. I wish there were more money for research in naked mole rats, because they may hold the keys to our understanding of the mechanisms responsible for life extension.

New DNA Repair Process Discovery May Lead to Human Life Extension

A key component of aging is the accumulation of errors in cells genetic’ genetic code or DNA. Once enough errors accumulate, the cell makes faulty proteins leading to irreparable cell damage and death, or in some cases cancer.

In a new study published in the Journal of Biological Chemistry researchers discovered that DNA acetylation governs DNA replication and repair. This process adds acetyl groups to DNA segments which then determines what path of DNA doubling that segment will take.

Cells are known to use a high fidelity yet high energy consuming path for DNA that encodes for proteins.  A low cost yet lower fidelity pathway is used for non protein encoding segments of DNA. The acetylation process just identified tells the cell which repair process the section of DNA should undergo.

Once the process of DNA acetylation can be exploited and applied at will it is possible to ensure cells have very low DNA error rates and thus live longer.

“Our research is in the very early stages, but there is great potential here, with the capacity to change the human experience,” said Robert Bambara, Ph.D., chair of the Department of Biochemistry and Biophysics at the University of Rochester Medical Center and leader of the research. “Just the very notion is inspiring.”

Though exciting it could take a while before this research leads to human lifespan extension.

“The translational rate is becoming better and better. Today, the course between initial discovery and drug development is intrinsically faster. I could see having some sort of therapeutic that helps us live longer and healthier lives in 25 years,” said Bambara.

Source (Eureka Alert)

Scientists Discover New Way to Detect and Fix DNA Damage

Researchers at Vanderbilt University, Pennsylvania State University and the University of Pittsburgh have discovered a new mechanism that detects and repairs a more common form of DNA damage called alkylation.
In a typical day, about one million bases in the DNA of a human cell are damaged. These lesions are caused by a combination of normal chemical activity within the cell and exposure to radiation and toxins coming from environmental sources including cigarette smoke, grilled foods, UV rays and industrial waste. These lesions cause structural damage to the DNA molecule, and can dramatically alter the cell’s way of reading the information encoded in its genes. Luckily, repairing damage and maintaining the integrity of its DNA is one of the cell’s highest priorities. 

As cells age however, the DNA repair process can no longer keep up with ongoing DNA damage. The cell then suffers one of three possible outcomes:
* An irreversible state of dormancy, known as senescence (http://en.wikipedia.org/wiki/Senescence)
* Cell suicide, also known as apoptosis (http://en.wikipedia.org/wiki/Apoptosis) or programmed cell death
* Cancer
When cells become senescent, alterations in their gene regulation cause them to function less efficiently, which inevitably causes disease. The DNA repair ability of a cell is vital to its normal functioning and to the health and longevity of the organism. Many genes that are shown to influence lifespan are associated with DNA damage repair and protection.

“There is a general belief that DNA is ‘rock solid’ – extremely stable,” said Brandt Eichman (http://structbio.vanderbilt.edu/faculty/eichman.php), associate professor of biological sciences at Vanderbilt, who directed the project. “Actually DNA is highly reactive,” he was quoted as saying.
According to the Vanderbilt study, when a DNA base becomes alkylated, it forms a lesion that distorts the shape of the molecule enough to prevent successful replication. Human cells contain a single glycosylase (http://en.wikipedia.org/wiki/DNA_glycosylase), named AAG that repairs alkylated bases. It’s specialized to detect and delete “ethenoadenine” bases, which have been deformed by combining with highly reactive, oxidized lipids in the body.

“It’s hard to figure out how glycosylases recognize different types of alkylation damage from studying AAG since it recognizes so many. So we have been studying bacterial glycosylases to get additional insights into the detection and repair process,” said Eichman.
That is how they discovered the bacterial glycosylase AlkD with its unique detection and deletion scheme. “All the known glycosylases work in basically the same fashion: hey flip out the deformed base and hold it in a special pocket while they excise it. AlkD, by contrast, forces both the deformed base and the base it is paired with to flip to the outside of the double helix.”

“Understanding protein-DNA interactions at the atomic level is important because it provides a clear starting point for designing drugs that enhance or disrupt these interactions in very specific ways,” says Eichman. “So it could lead to improved treatments for a variety of diseases, including cancer.”

So there is a vast body of evidence that correlates DNA damage to death and disease. As indicated by the findings of the Vanderbilt study, increasing the activity of some DNA repair enzymes could cause a decrease in the rate of cell damage which would result in adding many healthy and disease-free years to our aging population.
Read about the DNA Repair study: (http://news.vanderbilt.edu/2010/10/newly-discovered-dna-repair-mechanism/)

Maria Konovalenko 
SCIENCE FOR LIFE EXTENSION FOUNDATION 
http:/mariakonovalenko.wordpress.com/ 
maria.konovalenko@gmail.com