Tag Archives: naked mole rat

Do Model Animals Tell Us Anything about Human Aging?

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I wrote a tiny report on the pluses and minuses of using model  animals in aging research.

Using model animals in gerontological studies has yielded an enormous wealth of useful information about the mechanisms of human aging and longevity. Animal models were crucial in identifying the conserved pathways that regulate human aging. Model organisms are fundamental for aging research, because there are serious limitations of using human subjects, such as the length of lifespan, genetic heterogeneity and vast differences in environmental influences. The shape of survival curves represents the health of the organism over time. Model organisms display significantly different lifespans, however the survival curves resemble those of humans quite remarkably. Despite this general similarity in the way we describe aging between humans and model animals, there are some distinct differences (Mitchell, Scheibye-Knudsen, Longo, & de Cabo, 2015). For instance, increasing Sir2 gene expression in yeast (Kaeberlein, McVey, & Guarente, 1999), nematodes (Tissenbaum & Guarente, 2001), and flies (Rogina & Helfand, 2004) boosts animal longevity. A small molecule called resveratrol was found to activate Sir2 and its mammalian ortholog SIRT1 (Howitz et al., 2003). Resveratrol extends lifespan of mice fed a high-fat diet (Baur et al., 2006), however it failed to have a beneficial longevity effect in mice on a standard diet (Pearson et al., 2008). This example highlights the fact that we cannot simply transfer the results of longevity interventions to humans and expect the same efficacy as in invertebrate models.

Everyday the researchers are broadening the understanding of human biology of aging with the help of various model systems. Each of them has its advantages and drawbacks. Let’s take a look at what those are for the most widely used animal models.

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Genome of Long-Lived Brandt’s Bat Sheds Some Light to Its Exceptional Longevity

Brandt's bat

 

Congratulations to my colleague, Dr. Alexey Moskalev, who, with collaboration with Dr. Vadim Gladyshev, published this awesome paper on genetic basis of exceptional longevity of the Brandt’s bat. This is an amazing animal – it lives up to more than 40 years of age, but weighs only 4-8 grams. A tiny “centenarian” creature. It lives in caves, sleeps during the day, echolocates and hibernates during winter. Every trait has its genetic background. The authors tried to decipher the background of the bat’s longevity.

The most important thing that they found was that Brandt’s bat has altered growth hormone and insulin growth factor 1 signaling (GH/IGF1). This signaling is reduced, there is a kind of dysfunction, that contributes to the animal’s longevity along with the adaptations like hibernation and low reproduction rate. There are other interesting findings. For example, olfactory function is also reduced in these amazing animals. It’s interesting, because olfactory system plays a role in regulating longevity. For example, if you put drosophilas on a restricted diet, they start to live longer, but if you let them smell food, then life extension effect goes away.

I think that this work is crucial, because if we are able to identify the genes that are responsible to exceptional longevity in species like naked mole rats, whales and rougheye rockfish, we’d be able to find the way to alter the activity of those longevity genes in our bodies, for example, pharmacologically. Eventually this will lead to creating life extension therapies that would make us live longer, healthier and happier lives.

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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.

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The main question in Biogerontology

mechanisms of aging, white-footed mouse, lab mouse, mice, aging, fight aging, aging research, biogerontology, funding, stress resistance, oxidative stress, George Sacher, long-lived animals, negligible senescence, naked mole rat
There’s this quite simple idea: to take two species similar in size and basic biology, but having a substantial difference in longevity, and figure out what’s the reason for this difference. What are the distinctions in the mechnisms of aging and stress resistance? It’s desirable to carry out this work in various species. However, not a lot of people are excited about this simple idea. Even the genome of the famous naked mole rat has not been sequenced yet, although many people believe it’s got “negligible” senescence.

For now all that we have is negligible funding of evolutionary-comparative biology of aging. Moreover, previously obtained results are put into cold storage.

In 1962 George Sacher began laboratory breeding of wild-caught house mice (Mus musculus) and white-footed mice (Peromyscus leucopus) trapped near the Argonne Laboratory site in northeast Illinois. The maximal lifespan of the white-footed mouse turned out to be more than 8 years, contrary to 3,5 years in either wild-caught or laboratory house mice. Sacher’s laboratory publiched about a dozen papers comparing house and white-footed mice, as did Ron Hart’s laboratory in the National Center for Toxicological Research.

There’s no need to say that George Sacher was given grants mostly for works in the area of radiological protection, and aging research was mostly funded by means of the lab’s own resources.

Since the beginning of the 1980s research was just middling, but still something was found out.

Below are some data from the works of Ungvary et al. and Labinskyy et al. Basicly this table shows the major known differences between the species. The autors claim that these data correspond with the oxidative stress theory of aging.

mechanisms of aging, white-footed mouse, lab mouse, mice, aging, fight aging, aging research, biogerontology, funding, stress resistance, oxidative stress, George Sacher, long-lived animals, negligible senescence, naked mole rat
Still a lot of questions can be addressed to the white-footed mouse. For example, what is the destinction in the stress resistance mechanisms? What’s with its regeneration capacity? What if we compare it with the naked mole rat? And here comes the main question in Biogerontology. Why is the research into the fundamental mechanisms of aging so scarcely funded?

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