Benjamin Button Jellyfish

I enjoy reading the New York Times so much. Especially when they write about various aspects of aging. This article got my attention, because is even better, it’s about immortality and fighting aging. You have probably heard about the immortal  jellyfish, Turritopsis dohrnii, that instead of dying goes back in time and renews itself to become young again. It’s fascinating. It could give us the clues to make a human being immortal, however I quote:

 You might expect that, having learned of the existence of immortal life, man would dedicate colossal resources to learning how the immortal jellyfish performs its trick. You might expect that biotech multinationals would vie to copyright its genome; that a vast coalition of research scientists would seek to determine the mechanisms by which its cells aged in reverse; that pharmaceutical firms would try to appropriate its lessons for the purposes of human medicine; that governments would broker international accords to govern the future use of rejuvenating technology. But none of this happened.

And this is not the most surprising thing! Do you know how many researchers in the world culture the immortal jellyfish in a lab? Just one. I found this really shocking. There’s only one guy, a Japanese professor Dr. Shin Kubota, who has been keeping a population of  Turritopsis dohrnii in a lab, carefully looking after them and studying them. I believe he is one of the most amazing researchers in the world, because he studies the jelly fish to solve the problem of aging and become immortal. I quote him:

The immortal medusa is the most miraculous species in the entire animal kingdom, I believe it will be easy to solve the mystery of immortality and apply ultimate life to human beings.

That’s the spirit! I believe Dr. Kubota needs all the help in the world to figure out what it is exactly that makes the immortal jelly fish be able to reverse its age backwards. It’s such a shame that he has got no money and no help at all to conduct this kind of research. I understood from the article that other than funding Dr. Kubota needs a molecular biologist and a geneticist to collaborate with to decipher those rejuvenation mechanisms. Anyone interested? Any volunteers? Do I need to say that this is probably the most important research in the history of mankind?

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.

Aging of Stem Cells

Continuing the series of charts describing the mechanisms of aging. Here you can download the pdf the chart about aging of stem cells. Take a look at how telomere shortening, oxidative stress and impaired stem cell niche regulation influences our stem cells: reduces the number of dormant stem cells, reduces their engrafting capacities and leads to aberrant, meaning improper, differentiation.

Telomeres and Aging Chart

I love charts, because it’s a great way to explain complex biological processes. This chart shows what happens when our telomeres shorten. And the beauty of this series of charts created by Dr. Alexei Moskalev is that we added the definitions of biological phenomena to make the illustrations easier to understand. You are most welcome to download the pdf of the telomeres and aging chart here.

Senescent Cells Removal Alleviates Age-Related Pathologies

Getting rid of senescent cells improves health in mice. In the picture we can see two mice of the same age, however one of them has lordokyphosis (the obvious problem with the spine), sarcopenia (loss of muscle mass), cataracts and other age-related pathologies. The other one has got its senescent cells removed by the group of researchers led by Darren J. Baker and Jan M. van Deursen at the Mayo Clinic in Rochester, Minnesota. Senescent cells are the aged cells that stopped dividing, but still secreting tons of various molecules into their environment. A lot of those molecules are harmful. The hypothesis expressed by Dr. Judith Campisi was that these senescent cells contribute to aging processes in our tissues and are the cause of aging and pathologies. In the paper published in Nature Journal the link between the presence of senescent cells and age-related diseases was established. Researchers took a rapidly aging strain of mice and genetically changed them in a way to be able to selectively kill these senescent cells that expressed the p16Ink4a gene by triggering apoptosis (cell suicide). Senescent cells were removed only from the skeletal muscles, fat tissue and lens. As a result there was a significant reduction in aging pathologies in these tissues. Unfortunately, there was no difference in life span, but researchers believe it was because the main reason of death in this strain is heart failure. Senescent cells were not removed from the arteries walls and cardiac muscles, so this may be the reason why both groups of mice live the same amount of time. It would be very interesting to see if lifespan will be increased if researchers remove senescent cells from all of the tissues.

Read the story about senescent cells removal in NY Times

Read the original paper

The Most Important Scientific Discovery of the Year

Our body is constantly being stressed. There’s nothing new about it and everybody seems to understand what it means. But I’d like to clarify what stress is from the biological point of view. The term stress stands for the negative effects including oxidation of macromolecules with free radicals, inflammation and infections, lack of nutrients, increase or decrease in temperature, light regime disturbance, impact of ionizing radiation. It all leads to damage on molecular and tissue levels. Our body has got the mechsnisms that protect us from this damage. It’s the mechanisms of stress resistance: DNA repair (the glossary is below), autophagy, proteasome activity, xenobiotic detox systems and anti-oxidant systems, heat shock factors, LON mitochondrial protease, methionine sulfoxide reductase, neuroendocrinological regulation of homeostasis.

A paper of extreme importance for fighting aging came out in the Nature journal on Thursday. A research group from Buck Institute lead by Professor Gordon Lithgow was able to prolong life of nematodes by 78% by adding one compound to the worms’ diet – a dye Thioflavin T. The authors showed that the effect of the dye was due to activation of stress resistance mechanisms, which lead to significant increase in median (60%) and maximum lifespan (43-78%). Thioflavin T is used to mark the amyloid protein aggregates in Alzheimer’s disease. Dr. Lithgow’s group showed that this compound regulates protein homeostasis, which leads to life extension in nematodes and improvement of their health later in life. The effect of Thioflavin T depends on autophagy, proteasomal functions, heat shock factor-1 (HSF-1) and transcription factor SNK-1. Both of these proteins play a role in response to stress in nemamtodes: HSF-1 triggers the production of heat shock proteins and SNK-1 takes part in neutralizing oxidative stress. So, Thioflavin T intensificates cellular stress response by activating signaling pathways dependant on HSF-1 and SNK-1, which lealds to misfolded protein stabilization and increased longevity.

This article proves the possibility to prolong life by activating stress resistance using chemical compounds simply added to the diet. There’s also some research where the positive effect on longevity was achieved by mutations in genes governing stress resistance. For example, the work of Dr. Alexey Moskalev, where they activated the DNA repair gene GADD45 and extended maximum lifespan of drosophilas by 77%. Right now it is necessary to identify the chemicals that would activate GADD45 genes in humans and develop drugs based on these compounds.

I’d like to highlight the need of creation of a new class of drugs – geroprotectors. Their distinctive feature is that not so much they will cure the already manifested diseases, as they will prevent them. And the most important part is that geroprotectors will extend our lives. In order for these drugs to be created it is necessary to fund research on activation of stress resistance genes and clinical trials of chosen chemical activators. Again, I’d like to stress that it is time to start clinical trial of geroprotectors.

Glossary:

DNA repair – restoration of damaged DNA structures

Autophagy – process of digestion of cellular components, including damaged proteins and organelles, in lysosomes

Proteasome – protein complex that degrades proteins in the end of their life cycle

Xenobiotics – foreign chemical compaound for an organism, like antibiotics

Heat shock proteins – class of protection proteins, which expression is increased upon high temperature or other stresses

LON Mitochondrial protease – enzyme that cleaves oxidized proteins in the mitochondrial matrix

Methionine sulfoxide reductase – enzyme that restores the oxidized proteins structure by turning methionine sulfoxide into methinine

Neuroendocrinal regulation of homeostasis – maintaining the equilibrium of the internal environment of the organism via the vegetative nervous and endocrine systems

HSF-1 – heat shock factor-1, triggers synthesis of heat shock proteins as a response to ovarious types of stress

Transcription factors – regulatory proteins that control the transfer of the information from the DNA to the mRNA molecules that recognize their target genes by binding to specific fragments of DNA

SNK-1 – transcription factor in nematodes that participates in protection from the oxidative stress

Hormesis: How Harmful Can Be Beneficial

Hormesis is the stimulating effect of moderate stress – low doses of toxins, temperature, radiation and other stressors that are toxic in larger doses. Moderate stresses are known to slow down the processes associated with aging and to increase life span. The author is Professor Alexey Moskalev.

Download the Hormesis chart in pdf

Melanie Swan: A summary of important themes in aging research

Melanie Swan, MBA, is an Affiliate Scholar of the IEET – The Institute for Ethics and Emerging Technologies. Ms. Swan is a science generalist, hedge fund manager, and founder of citizen science organization DIYgenomics. She serves as a researcher and advisor to foundations, government agencies, corporations, and startups, and is active in the community promoting science and technology. Her life mission is to impact millions of people by facilitating the widespread deployment of beneficial high-impact science and technology.

Melanie recently summarized some important themes in aging research that were discussed at the second Bay Area Aging Meeting:

Processes work in younger organisms but not in older organisms

A common theme in aging is that processes function well in the first half of an organism’s life, then break-down in the second half, particularly the last 20% of the lifespan. In one example, visualizations and animations were created from the 3D tissue-sectioning of the intestine of young (4 days old) and old (20 days old) C. elegans. In the younger worms, nuclei and cells were homogenous and regularly spaced over the course of the intestine running down the length of the worm. In older worms, nuclei disappeared (an initial 30 sometimes ultimately dropped to 10), and the intestine became twisted and alternately shrunken and convoluted due to DNA accumulation and bacterial build-up.

Discovery of molecular switch could help reduce risk of type 2 diabetes

In a study that could have major implications for the treatment of type 2 diabetes, a team of researchers from the Harvard School of Public Health have discovered a molecular switch that can turn off cellular mechanisms that protect against aging and metabolic dysfunctions.

The team reported in the journal Cell Metabolism that the SMRT protein accumulates more on older cells. This increases the effects of oxidative stress on the cells’ mitochondria, which are responsible for the energy production and metabolic functions of cells. This damage increases the likelihood of developing type 2 diabetes. Additionally, SMRT turns off the production of other proteins that protect against oxidative stress and promote the burning of fat.

“This finding is significant since increased oxidative stress, coupled with reduced metabolic function, contributes to the aging process and the development of age-related metabolic diseases,” said lead researcher Reilly Lee.

Lee added that while much more research is necessary for scientists to gain a full understanding of the process, it could be a target of medications that reduce the risk of type 2 diabetes and other metabolic problems.

Read more about the study and the Molecular switch that contributes to the cellular aging process

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

The FDA Needs to Rethink Aging

I wanted to share an interesting perspective by statistician Gary Liberson, PhD. He recently published some valid points on the present system of FDA licensing and the difficulty that companies face in finding an economic justification for longevity research without seeking a specific disease.

According to Liberson, the problem lies with the FDA approval system that requires a pharmaceutical company show three things: (1) a mechanism of action (i.e., identify why a drug works), (2) safety and (3) efficacy in managing a measurable biologic end point associated with a disease. This last condition, according to Liberson is a  problem.