Tag Archives: regeneration

SENS5 Conference on Aging and Regenerative Therapies was Fantastic

And here’s why. I wrote some notes about the talks I found interesting. The ones that I haven’t listed were also very exsiting.

1. Bio-electrospraying is a novel method of forming an engineered organ

Dr. Suwan Jayasinghe from the University College London shared the successful work of his scientific group in electrospraying cells to form viable structures. The common methods of creating biological scaffolds with living cells are ink jet printing and electrospraing. Dr. Jayasinghe explained that bio-electrospraying is a quite promising new methods, not only because it doesn’t damage the cells, but also becuase it allows to manipulate with cell drops of smaller diameter than the regular ink jet printing. This technique can be used to produce seeded scaffolds for artificial organ creation and trating damaged or diseases organs, like for example, the heart.

2. Liver regeneration

Dr. Shay Soker from the Wake Forest Institute for Regenerative Medicine pointed out the necessity of creation of artificial organs. Aging, trauma and immune strikes cause severe health problems. We can treat them with organ transplantation, but it’s a zero-sum game. The demand on new organs is huge and growing, but the number of donor organs is tiny. There’s an option – bionic limbs, for instance, but masines wear out too. The better solution is to grow organs from the patient’s own cells.

Organs consist of cells and scaffolds. Scaffolds must:

1. Support 3D structure

2. Mimic the microenvironment

decellularization provides good scaffolds that retain the archtecture of the organ with its blood vessels including the tiny capillaries. Dr. Soker tolld the audience about the seccess in regenerating the miniature liver. They took livers from rats, ferrets and pigs, decellularized them and analyzed the obtained scaffolds. The vasculature was intact. The extracellular matrix proteins, such as collagen 1, 3, 4, laminin and fibronectin, were present. Seeding with cells was done through central and portal veins. Interestingly, seeded scaffolds have anti coagulating features. Researchers were also excited to see that cells can find their own niches. Endothelial cells go to vessels and hepatic cells go to parenchyma. The engineered livers were functional. Urea and albumin were secreted. This is an important step towards human liver regeneration.

3. Lung engineering

Dr. Laura Niklasson from Yale University is working on lung engineering. Human lung is an extremely complicated organ. There’s 23 generations of branching of airways, they are up to 200 microns in diameter. 70 square meters for gas exchange. More than 100 million air sacks all together. Engineered lung must have right mechanical properties, autologous cells, adequate surface area for gas exchange and adequate barrier to prevent flooding of airways with blood constituents after implantation.

Researchers used donor lung scaffolds. They took rat lungs, decellularized them and repopulated with pulmonary cells. The cells were semigeneic, that means they were almost genetically identical rat cells. The lung was cultured in a bioreactor. Besearchers were breating the lung during culturing. They used perfusion system of culture. They seeded pulmonary epithelium and vascukar endothelium cells. When Dr. Niklasson examined the integrity of blood vessels, it was ok. But some of elastin was stil present. And that’s bad so far. Also some of the air sacks got infused with staining, so the result is not perfect just yet. It seems like there are local instructions in the matrix that tell the cells where to land. Endothelial cells form a very dense population in vessels.

Scientists implanted engineered half lung in a rat. It was 95% as efficient as a native lung in terms of gas exchange. But in several hours they got trombosis. Also they saw a little bit of blood cells in airways, so the barrier was not perfect. After being improved this technique can be used to engineering human lungs.

4. Generation of functional thymus ex vivo

John Jackson gave a beautiful overview of thymic involution and told us about the ongoing experiments in the Wake Forest Institute for Regenerative Medicine on thymus engineering.

 

5. Zscan4 gene may provide immortality to stem cells

Dr. Minoru Ko is studying immortality of stem cells in the National Institute on Aging. Embryonic stem cells are remarkable, because they are pluripotent, they have self renewal, immortality and genome stability. Immortality is the ability to defy cellular senescence and undergo more than 250 doublings without undergoing crisis or transformation.

Researchers used embryogenomics and systems biology approach to identify differential gene expression in preimplantation embryos and other kinds of cells. They ruled out that the most interesting gene is Zscan4. It is expressed in 5% of the cells in the embryo, it can be turned on and off, but it’s crucial for proliferative potential. Knock down of Zscan4 leads to ES culture crisis by day 8. They have massive karyotype problems, but this can be alleviated. Telomere shortening is one of the mechanisms for karyotype deterioration in Zscan4-knockdown embryonic stem cells. When they turned off telomerase and overexpressed Zscan4, they still could see telomere elongation.

It was telomerase independent telomere elongation.

This gene is colocalized with meiosis-specific homologous recombination proteins on telomeres. Zscan4 may be the master gene that provides immortality among other things in embryonic stem cells. That’s the hypothesis. Researchers can accelerate Zscan4 cycle. Maybe it’s active at first and the cell is an embryonic stem cell, but over time its expression deminishes. But then at some point of time Zscan4 kicks in again and restores things back to normal. Maybe if we can accelerate Zscan4 cycles we could increase proliferative potential of stem cells. Zscan4 expressed constantly blocks proliferation of cells. You need to have it oscilating to keep cells proliferating.

6. Non-aging regeneration system in the brain

I personally found the talk by Dr. Charles Greer the most fascinating one. Aparently, there is a subsytem in our brain that is constantly regenerating. The rate and quality of this regeneration process doesn’t decline with age. It’s the oldfactory system. Sensory neurons in olfactory system die every 6-8 weeks. Neurogenesis is constant. New neurons come from the subventricular zone. It’s like a river of migrating neurons to olfactory bulb. The number of newly formed neurons a day is amazing – 10,000.

Vascular organization is the framework of migration. If we turn off VEGF with siRNA then there will be no migration. There are no changes in size of glomeruli with aging. Cell number, cell dencity doesn’t go down with aging too. The question is why is this system so special? What factors play the role in maintaining such an exeptional regenerative capacity thoughout life?

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Poll – How Much Sleep is Good for You?

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Age-related regeneration decline conundrum

Over a 16-year period, Panagiotis Tsonis at the University of Dayton, Ohio, and colleagues removed the lenses of six Japanese newts (Cynops pyrrhogaster) 18 times. After each excision, the lenses regenerated. They did so not from remaining lens tissue, but from pigment epithelial cells in the upper part of the iris. There was no documented decline in regenerative capacity neihter due to aging, nor to repetition.

The paper published in Nature Communications reports: “In addition, despite beliefs that aged animals regenerate less efficiently than young ones (also discussed by Darwin), our experiments show that this is not the case in the newt. As regenerative medicine has entered a new era, the knowledge that aged tissues possess robust regenerative capabilities should provide the impetus to identify mechanisms underlying this capacity in the newt and compare them with strategies being employed to promote mammalian regeneration, such as the creation of iPS cells.”

Unfortunately, the authors don’t discuss possible mechanisms underlying such an extraordinary capacity. This absolutely has to be studied, because these mechanisms, when identified, may shed light at how we can manipulate mammalian and human cells in order to trigger at least somewhat similar effects. I find restoration of own regenerative capacity to be a very potent way of extending our lives, therefore this work in newts and other animals with fantastic regenerative abilities has to be continued and multiplied. Any ideas about how this may be done are welcome.

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Expert on Cellular and Organ Aging: “The Body’s Ability to Dispose of Cell Debris Could Extend Life.”

One of the main goals of my blog is to keep readers aware of important research and discoveries in the field of life extension, longevity and anti-aging. To that end, we have been following the work of Dr. Ana Maria Cuervo (www.einstein.yu.edu/cuervo), a molecular biology professor at the Albert Einstein College of Medicine and would like to provide some details into her important research and recent findings.
According to Cuervo, “the current challenges in the field of aging are two-fold: To continue and complete the molecular dissection of the factors that contribute to aging and to promote the translation of these novel findings into interventions to improve the health-span of the aging human population”.

Dr. Cuervo identified certain defects that lead to decreased activity of Chaperone-Mediated Autophagy (CMA) (www.einstein.yu.edu/cuervo/chaperone.htm) with age and how to correct and improve cellular function. Dr. Cuervo theorized that the decrease of Autophagy could be a determining factor in why some older organisms are unable to fight off cell abnormalities. Her research looked at the breakdown of the various autophagic pathways as the body ages and if restoring these pathways would jumpstart normal cellular activity. CMA is involved in at least 30% of the body’s cell degradation processes and upon studying this pathway, Cuervo determined that the LAMP-2A protein acts as a vital receptor in the pathway.

In recent experiments, livers in genetically modified mice 22 to 26 months old (the equivalent of octogenarians in human years), that were injected with the LAMP-2A protein, cleaned blood as efficiently as those in animals a quarter their age! By contrast, the livers of normal mice in a control group began to fail. While her paper didn’t show increased survival rates among the mice, Dr. David le Couteur (http://ichal06.longevity-international.com/cms/details.asp?NewsID=281), a leading Australian ageing researcher and Professor of Geriatric Medicine at the University of Sydney, says the paper was a major breakthrough and that Cuervo’s data definitely demonstrated improved survival rates. “She has single-handedly shown that lysosome function is a crucial part of the ageing process,” he says. Cuervo has also shown, he says, the critical role the lysosomal receptor molecules play in keeping the liver clean of damaged proteins.

Cuervo’s findings suggest that therapies for boosting protein clearance might help stave off some of the declines in function that accompany old age. This is especially positive news for those suffering from Alzheimer’s, Parkinson’s and Huntington’s disease as Dr. Cuervo has linked these diseases to a toxic buildup from mutated proteins possibly due to a breakdown in autophagy.

Dr. Cuervo is also working with pharmaceutical companies to identify drugs that will turn receptors on, or make them more active. Cuervo believes maintaining efficient protein clearance may improve longevity and function in all the body’s tissues. “The benefits of restoring the cleaning mechanisms found inside all cells could extend far beyond a single organ”, says Cuervo. “If the body’s ability to dispose of cell debris within the cell were enhanced across a wider range of tissues, she says, it could extend life as well”.

Read more about chaperone-mediated autophagy and the published research findings of Dr. Ana Maria Cuervo:http://www.nature.com/nm/journal/v14/n9/full/nm.1851.html

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

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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

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Main questions of Biology of Aging

main questions of biology of aging, problem, question, negligible senescence, aging, fighting aging, mechanisms of aging, neurogenesis, inflammation, regeneration, stress response, anti-aging, oncogenesisHere
are the main questions in the Biology of Aging. I suggest that the specialists
should extend the list of questions. And maybe, formulate the problems in more
detail. Everybody is welcome to express their opinion and suggest some
answers.

1. What are the mechanisms responsible for the differences in life expectancy within one species and between species?
2. Why do experimental impacts, like caloric restriction, delay the
onset of a number of age-related physiological and pathological changes
and increase the average and maximal life span in animals?
3. What is the relationship between aging and pathology?
4. At what stage of evolution did aging emerge?
5. How did the mechanisms of aging and anti-aging evolve?
6. What are the mechanisms of relationship between aging of an organism and aging on cellular level?
7. What is the reason for the existence of species with negligible aging?
8. How are reproduction and lifespan interrelated?
9. What is aging?
10. Why is there a decline in regenerative potential of an organism over time?
11. What is the role of epigenetic regulation during aging?
12. What is the role of inflammation in aging processes?
13. What is the role of genomic instability in aging processes?
14. What interventions in aging processes could extend the maximal lifespan of model animals and humans?
15. What is the effect of aging on the cells’ and organisms’ energy supplies and vica versa?
16. What is the role of the neuroendocrinal system in the regulation of aging processes?
17. What is the distinction of centenarians as compared to the whole population?
18. How relevant to humans are the results of life extension research on model animals?
19. What is essential for creating the unified synthetic theory of aging?
20. How did animals with negligible senescense evolve?
21. What are the factors influencing differences in the rate of aging among individuals?
22. What are the mechanisms of aging in cancer cells?
23. What is the relationship between aging and oncogenesis?
24. When does aging begin in humans?
25. When do manifestations of aging begin?
26. What are the molecular biological mechanisms of regeneration during sleep?
27. What is necessary for the creation of an exhaustive list of biomarkers of aging?
28. Can neurogenesis be stimulated?
29. What are the mechanisms of how higher nervous system activity influences the mechanisms of aging?
30. What are the factors defining the rate and efficiency of stress responses?

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“Magical” regeneration in MRL mice

I just couldn’t walk past this article in PNAS about the miracles that happen to one strain of lab mice – MRL. These guys can fully close ear holes made for labeling purposes in order to mark a mouse for its whole life;  in these animals the holes turn out to be just temporary. The wounds close without scarring, and brand new cartilage, derma, epidermis and hair are formed. And the rest rest of the mice could wear earrings, if only there were any animal jewellery!

Another striking thing is that this feature was noticed 9 years ago, when the same group of researches published a paper telling how MRL mice can heal wounds on their hearts, leaving hardly any scars. As early as in 2001, it was shown that these mice can heal themselves from myocardial infarction after-effects in 60 days. But for some reason the molecular mechanisms underlying these miracles haven’t been studied until now. So, here they are.

MRL mice, mouse, regeneration, regenerative capacity, ear hole closure, scar, p21, DNA damage, p53, G2/M, molecular mechanisms of regeneration, wound healing, healing, regenerative, cell cycle

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