A Johns Hopkins University biologist has led a research team reporting progress in understanding the shape-shifting ways of stem cells, which have vast potential for medical research and disease treatment.

In a research paper published in Cell Reports on Oct. 13, Xin Chen, an associate professor of biology in the university’s Krieger School of Arts and Sciences, and her six co-authors report on how stem cells are affected by their immediate surroundings. The scientists found that an enzyme present in the spot where stem cells are found can help nurture a greater abundance of these cells by sustaining them in their original state, and by promoting other cells to lose their specialized traits and transform into stem cells.

The results show that the enzyme aminopeptidase in the stem cell niche?in this case, the area where stem cells are found in the testicular tissue in fruit flies?plays a role in both of these functions. How the niche itself plays this role, however, remains unclear.

That the enzyme in that spot promotes more specialized cells to become like stem cells “suggests that this change of cell fate needs cues from where stem cells normally reside, but not randomly,” said Chen, the principal investigator. “These results have medical implications because if this cell fate change could happen randomly, it may lead to diseases such as cancers.”

That’s because there’s a delicate balance to be struck in managing the proliferation of undifferentiated stem cells in tissue, Chen said. Too few can cause tissue deterioration, too many can promote tumors.

The study focused on fruit flies in part because they share with humans about three-quarters of the genes that cause disease, making them a fine research model. The work on this paper focused on the testis because stem cells are found there in both fruit flies and humans.

Stem cells are found in humans in an array of tissues, including skin, blood vessels, teeth, heart, brain, and liver.

Because they can develop from their original state into specialized or differentiated cells, stem cells have long held out the promise of being used to replace damaged organs and muscle. Stem cells have been used to treat illness in limited ways for decades, including transplantation from bone marrow.

However, their application could be much wider with reliable techniques to control how they take on specialized functions, how they can revert to their stem state, and in some instances, how they proliferate in their original state to form potentially dangerous tumors.

One question now is whether the activity of the niche and of the enzyme reported in this research can be harnessed to manipulate stem cells to differentiate in useful ways. There’s a lot of work yet to be done, Chen said.

“How cells become different, it’s very important to understand that,” Chen said.

Chen’s six collaborators on this paper were Cindy Lim, who earned her doctorate at Johns Hopkins and now works for the U.S. Food and Drug Administration; Lijuan Feng of the Johns Hopkins University Department of Biology; Shiv Gandhi and Sinisa Urban of the Howard Hughes Medical Institute, Department of Molecular Biology and Genetics at the Johns Hopkins University School of Medicine; and Martin L. Biniossek and Oliver Schilling of the Institute of Molecular Medicine and Cell Research at the University of Freiburg.

Researchers in Melbourne and Brisbane have successfully grown a human ‘mini-kidney’ from stem cells.

Published in the journal Nature, the results have significant implications for medical research, as the mini-organ mimics normal kidney development.

It means laboratory-grown kidneys can be used for drug testing and potentially the bioengineering of replacement kidneys for patients with renal failure as they can be grown from any person using cells such as skin or blood.

It also opens the door for cell therapy and other new treatments for kidney disease – not to mention giving researchers a chance to grow ‘kidney models’ to learn more about how the human kidney forms normally.

“For us it’s a pretty exciting advance,” said stem cell biologist Melissa Little, of the Murdoch Childrens Research Institute.

“This organ is making its own blood vessels, it’s making it’s own tubules for filtering and cleaning the blood, so it’s really a very complex structure,” she said of the kidney, which was observed three weeks after creation.

An author on the paper, Professor Little said it was equally important to learn how healthy and diseased kidneys functioned but that ethical reasons often limited research on human kidneys. Instead mice were used. However, she said while the mouse kidney was similar to humans, it was structurally different.

“Now for the first time we have a chance to ask what is different between a human and a mouse kidney because we don’t study human kidneys for obvious reasons,” she said. “From a research point of view it is going to tell us a great deal more than we knew before.”

About half the children with kidney disease had inherited the condition via a genetic mutation. Being able to grow a kidney using a patient’s stem cells meant a diseased kidney could be grown to test a patient’s response to treatment before drugs were administered.

The breakthrough follows Professor Little’s team’s first creation of a mini-kidney in 2013, which was able to form two cell-types.

This kidney, grown in collaboration with colleagues from Melbourne University and the University of Queensland, is different. No longer than a centimetre, it features up to 12 types of cell normally found in the human body making it equivalent to a foetal kidney. An adult kidney has around 20 cell types and is the size of a large softball.

It was also created using stem cells made from adult skin, rather than embryonic stem cells which were used in the 2013 kidney.

Following an exhaustive, ten-year effort, scientists at the Buck Institute for Research on Aging and the University of Washington have identified 238 genes that, when removed, increase the replicative lifespan of S. cerevisiae yeast cells. This is the first time 189 of these genes have been linked to aging. These results provide new genomic targets that could eventually be used to improve human health. The research was published online on October 8th in the journal Cell Metabolism.

“This study looks at aging in the context of the whole genome and gives us a more complete picture of what aging is,” said Brian Kennedy, PhD, lead author and the Buck Institute’s president and CEO. “It also sets up a framework to define the entire network that influences aging in this organism.”

The Kennedy lab collaborated closely with Matt Kaeberlein, PhD, a professor in the Department of Pathology at the University of Washington, and his team. The two groups began the painstaking process of examining 4,698 yeast strains, each with a single gene deletion. To determine which strains yielded increased lifespan, the researchers counted yeast cells, logging how many daughter cells a mother produced before it stopped dividing.

“We had a small needle attached to a microscope, and we used that needle to tease out the daughter cells away from the mother every time it divided and then count how many times the mother cells divides,” said Dr. Kennedy. “We had several microscopes running all the time.”

These efforts produced a wealth of information about how different genes, and their associated pathways, modulate aging in yeast. Deleting a gene called LOS1 produced particularly stunning results. LOS1 helps relocate transfer RNA (tRNA), which bring amino acids to ribosomes to build proteins. LOS1 is influenced by mTOR, a genetic master switch long associated with caloric restriction and increased lifespan. In turn, LOS1 influences Gcn4, a gene that helps govern DNA damage control.

“Calorie restriction has been known to extend lifespan for a long time.” said Dr. Kennedy. “The DNA damage response is linked to aging as well. LOS1 may be connecting these different processes.”

A number of the age-extending genes the team identified are also found in C. elegans roundworms, indicating these mechanisms are conserved in higher organisms. In fact, many of the anti-aging pathways associated with yeast genes are maintained all the way to humans.

The research produced another positive result: exposing emerging scientists to advanced lab techniques, many for the first time.

“This project has been a great way to get new researchers into the field,” said Dr. Kennedy. “We did a lot of the work by recruiting undergraduates, teaching them how to do experiments and how dedicated you have to be to get results. After a year of dissecting yeast cells, we move them into other projects.”

Though quite extensive, this research is only part of a larger process to map the relationships between all the gene pathways that govern aging, illuminating this critical process in yeast, worms and mammals. The researchers hope that, ultimately, these efforts will produce new therapies.

“Almost half of the genes we found that affect aging are conserved in mammals,” said Dr. Kennedy. “In theory, any of these factors could be therapeutic targets to extend healthspan. What we have to do now is figure out which ones are amenable to targeting.”

The human cerebral cortex contains 16 billion neurons, wired together into arcane, layered circuits responsible for everything from our ability to walk and talk to our sense of nostalgia and drive to dream of the future. In the course of human evolution, the cortex has expanded as much as 1,000-fold, but how this occurred is still a mystery to scientists.

Now, researchers at UC San Francisco have succeeded in mapping the genetic signature of a unique group of stem cells in the human brain that seem to generate most of the neurons in our massive cerebral cortex.

The new findings, published Sept. 24 in the journal Cell, support the notion that these unusual stem cells may have played an important role in the remarkable evolutionary expansion of the primate brain.

?We want to know what it is about our genetic heritage that makes us unique,? said Arnold Kriegstein, MD, PhD, professor of developmental and stem cell biology and director of the Eli and Edyth Broad Center of Regeneration Medicine and Stem Cell Research at UCSF. ?Looking at these early stages in development is the best opportunity to understand our brain?s evolution.?

Building a Brain from the Inside Out

The grand architecture of the human cortex, with its hundreds of distinct cell types, begins as a uniform layer of neural stem cells and builds itself from the inside out during several months of embryonic development.

Until recently, most of what scientists knew about this process came from studies of model organisms such as mice, where nearly all neurons are produced by stem cells called ventricular radial glia (vRGs) that inhabit a fertile layer of tissue deep in the brain called the ventricular zone (VZ). But recent insights suggested that the development of the human cortex might have some additional wrinkles.

In 2010, Kriegstein?s lab discovered a new type of neural stem cell in the human brain, which they dubbed outer radial glia (oRGs) because these cells reside farther away from the nurturing ventricles, in an outer layer of the subventricular zone (oSVZ). To the researchers? surprise, further investigations revealed that during the peak of cortical development in humans, most of the neuron production was happening in the oSVZ rather than the familiar VZ.

oRG stem cells are extremely rare in mice, but common in primates, and look and behave quite differently from familiar ventricular radial glia. Their discovery immediately made Kriegstein and colleagues wonder whether this unusual group of stem cells could be a key to understanding what allowed primate brains to grow to their immense size and complexity.

?We wanted to know more about the differences between these two different stem cell populations,? said Alex Pollen, PhD, a postdoctoral researcher in Kriegstein?s lab and co-lead author of the new study. ?We predicted oRGs could be a major contributor to the development of the human cortex, but at first we only had circumstantial evidence that these cells even made neurons.?

Outsider Stem Cells Make Their Own Niche

In the new research, Pollen and co-first author Tomasz Nowakowski, PhD, also a postdoctoral researcher in the Kriegstein lab, partnered with Fluidigm Corp. to develop a microfluidic approach to map out the transcriptional profile ? the set of genes that are actively producing RNA ? of cells collected from the VZ and SVZ during embryonic development.

They identified gene expression profiles typical of different types of neurons, newborn neural progenitors and radial glia, as well as molecular markers differentiating oRGs and vRGs, which allowed the researchers to isolate these cells for further study.

The gene activity profiles also provided several novel insights into the biology of outer radial glia. For example, researchers had previously been puzzled as to how oRG cells could maintain their generative vitality so far away from the nurturing VZ. ?In the mouse, as cells move away from the ventricles, they lose their ability to differentiate into neurons,? Kriegstein explained.

But the new data reveals that oRGs bring a support group with them: The cells express genes for surface markers and molecular signals that enhance their own ability to proliferate, the researchers found.

?This is a surprising new feature of their biology,? Pollen said. ?They generate their own stem cell niche.?

The researchers used their new molecular insights to isolate oRGs in culture for the first time, and showed that these cells are prolific neuron factories. In contrast to mouse vRGs, which produce 10 to 100 daughter cells during brain development, a single human oRG can produce thousands of daughter neurons, as well as glial cells?non-neuronal brain cells increasingly recognized as being responsible for a broad array of maintenance functions in the brain.

New Insights into Brain Evolution, Development and Disease

The discovery of human oRGs? self-renewing niche and remarkable generative capacity reinforces the idea that these cells may have been responsible for the expansion of the cerebral cortex in our primate ancestors, the researchers said.

The research also presents an opportunity to greatly improve techniques for growing brain circuits in a dish that reflect the true diversity of the human brain, they said. Such techniques have the potential to enhance research into the origins of neurodevelopmental and neuropsychiatric disorders such as microcephaly, lissencephaly, autism and schizophrenia, which are thought to affect cell types not found in the mouse models that are often used to study such diseases.

The findings may even have implications for studying glioblastoma, a common brain cancer whose ability to grow, migrate and hack into the brain?s blood supply appears to rely on a pattern of gene activity similar to that now identified in these neural stem cells.

?The cerebral cortex is so different in humans than in mice,? Kriegstein said. ?If you?re interested in how our brains evolved or in diseases of the cerebral cortex, this is a really exciting discovery.?

The study represents the first salvo of a larger BRAIN Initiative-funded project in Kriegstein?s lab to understand the thousands of different cell types that occupy the developing human brain

?At the moment, we simply don?t have a good understanding of the brain?s ?parts list,?? Kriegstein said, ?but studies like this are beginning to give us a real blueprint of how our brains are built.?

After sequencing the genome of flatworms (Macrostomum lignano), researchers from Cold Springs Harbor Laboratory (CSHL) have concluded that it can regenerate parts of its entire body ? with the exception of its brain. According to the scientists, this has potential applications in stem cell research.

“This and other regenerating flatworms have the same kind of pathway operating in stem cells that is responsible for their remarkable regenerative capabilities.” Gregory Hannon, a CSHL professor, said in a news release. “As we started to try to understand the biology of these stem cells, it very quickly became clear that we needed information about the genetic content of these organisms.”

As certain species grow, base cells called stem cells develop into many different cell types. They also act as an internal repair system, dividing and replenishing other cells as needed, similar to how flatworms regenerate body parts that are injured.

Hannon was studying an important pathway in mammalian reproductive tissues when M. lignano caught his eye. When his researchers took a closer look, they found that the flatworm had a very complex genome with repetitive elements, which made it hard to assemble. This required the use of long-read, or high-quality, sequencing technology.

“At the genomic level it has almost no relationship to anything else that’s ever been sequenced. It’s very strange and unique in that sense,” notes Michael Schatz, a CSHL associate professor.

“The worms are just like floating sacks full of stem cells, so they’re very easily accessible,” said Kaja Wasik, the study’s lead author who conducted the work as a Ph.D. student in Hannon’s lab. “From what we looked at, it looks like many of the developmental pathways that are present in humans are also present in the worms, and we can now study whether they potentially could be involved in regeneration.”

M. lignano aids in stem cell researcher because it is small, has simple tissues, is transparent and uses sexual reproduction, the researchers noted. Sequencing the flatworm’s genome is a stepping stone in understanding exactly how its cells are able to regenerate.

Their findings were recently published in the journal Proceedings of the National Academy of Sciences.

Possible stem cell therapies often are limited by low survival of transplanted stem cells and the lack of precise control over their differentiation into the cell types needed to repair or replace injured tissues. A team led by David Mooney, a core faculty member at Harvard?s Wyss Institute, has now developed a strategy that has experimentally improved bone repair by boosting the survival rate of transplanted stem cells and influencing their cell differentiation. The method embeds stem cells into porous, transplantable hydrogels.

In addition to Mooney, the team included Georg Duda, a Wyss associate faculty member and director of the Julius Wolff Institute for Biomechanics and Musculoskeletal Regeneration at Charit? ? Universit?tsmedizin in Berlin, and Wyss Institute founding director Donald Ingber. The team published its findings in today?s issue of Nature Materials. Mooney is also the Robert P. Pinkas Family Professor of Bioengineering at the Harvard John A. Paulson School of Engineering and Applied Sciences.

Stem cell therapies have potential for repairing many tissues and bones, or even for replacing organs. Tissue-specific stem cells can now be generated in the laboratory. However, no matter how well they grow in the lab, stem cells must survive and function properly after transplantation. Getting them to do so has been a major challenge for researchers

Mooney?s team and other researchers have identified specific chemical and physical cues from the stem cell niche (the area in which stem cells survive and thrive with support from other cell types and environmental factors) to promote stem cell survival, multiplication and maturation into tissue. Whereas chemical signals that control stem cell behavior are increasingly understood, much less is known about the mechanical properties of stem cell niches. Stem cells like those present in bone, cartilage, or muscle cultured in laboratories, however, have been found to possess mechanosensitivities, meaning they require a physical substrate with defined elasticity and stiffness to proliferate and mature.

?So far these physical influences had not been efficiently harnessed to propel real-world regeneration processes,? said Nathaniel Huebsch, a graduate student who worked with Mooney and who is the study?s first author. ?Based on our experience with mechanosensitive stem cells, we hypothesized that hydrogels could be leveraged to generate the right chemical and mechanical cues in a first model of bone regeneration.?

Two water-filled hydrogels with very different properties are the key to the Mooney team?s method. A more stable, longer-lasting ?bulk gel? is filled with small bubbles of a second, so-called ?porogen? that degrades at a much faster rate, leaving behind porous cavities.

By coupling the bulk gel with a small ?peptide? derived from the extracellular environment of genuine stem cell niches, and mixing it with a tissue-specific stem cell type as well as the porogen, the team can create a bone-forming artificial niche. While the bulk gel provides just the right amount of elasticity plus a relevant chemical signal to coax stem cells to proliferate and mature, the porogen gradually breaks down, leaving open spaces into which the stem cells expand before they naturally migrate out of the gel structure altogether to form actual mineralized bone tissue.

In small-animal experiments conducted so far, the researchers show that a void-forming hydrogel with the correct chemical and elastic properties provides better bone regeneration than transplanting stem cells alone. Of further interest, the maturing stem cells deployed by the hydrogel also induce nearby native stem cells to contribute to bone repair, further amplifying their regenerative effects.

?This study provides the first demonstration that the physical properties of a biomaterial can not only help deliver stem cells but also tune their behavior in vivo,? said Mooney. ?While so far we have focused on orchestrating bone formation, we believe that our hydrogel concept can be broadly applied to other regenerative processes as well.?

The collaborative, cross-disciplinary work was supported by the Harvard University Materials Research Science and Engineering Center (MRSEC), which is funded by the National Science Foundation (NSF).

?This is an exquisite demonstration of MRSEC programs? high impact,? said Dan Finotello, program director at the NSF. ?MRSECs bring together several researchers of varied experience and complementary expertise who are then able to advance science at a considerably faster rate.?

New research has shown for the first time that the part of the brain used for learning, memory and mental health is smaller in people with unhealthy diets.

The results of the study by researchers at Deakin University and the Australian National University (ANU) suggest that older Australians with unhealthy diets have smaller hippocampi – the hippocampus is a part of the brain believed to be integral to learning, memory and mental health. It has also shown that older people with healthier diets have larger hippocampi.

Associate Professor Felice Jacka, lead author of the study and researcher with Deakin University’s IMPACT Strategic Research Centre in Geelong, said that as the negative impact of unhealthy foods on the waistline of the population grows, so does the evidence suggesting that our brain health is also affected.

“It is becoming even clearer that diet is critically important to mental as well as physical health throughout life,” Associate Professor Jacka said.

“We’ve known for some time that components of diet, both healthy and unhealthy, have a rapid impact on aspects of the brain that affect hippocampal size and function, but up until now these studies have only been done in rats and mice. This is the first study to show that this also appears to be the case for humans.”

The researchers used magnetic resonance imaging to measure the size of hippocampi (there are two in the brain ? left and right) in Australian adults aged 60-64 years and participating in the PATH study – a large longitudinal study of ageing conducted at the ANU. They also measured the participants’ regular diets and took into account a range of other factors that could affect the hippocampus.

The results of the study, now published in the international journal BMC Medicine, suggest that older adults who eat more unhealthy foods, such as sweet drinks, salty snacks and processed meats, have smaller left hippocampi. It also shows that older adults who eat more nutrient-rich foods, such as vegetables, fruits and fish, have larger left hippocampi. These relationships existed over and above other factors that may explain these associations, such as gender, levels of physical activity, smoking, education or depression itself.

These findings have relevance for both dementia and mental health, Associate Professor Jacka said.

“Mental disorders account for the leading cause of disability worldwide, while rates of dementia are increasing as the population ages,” she said.

“Recent research has established that diet and nutrition are related to the risk for depression, anxiety and dementia, however, until now it was not clear how diet might exert an influence on mental health and cognition.

“This latest study sheds light on at least one of the pathways by which eating an unhealthy diet may influence the risk for dementia, cognitive decline and mental disorders such as depression and anxiety in older people.

“However, it also points to the importance of diet for brain health in other age groups. As the hippocampus is critical to learning and memory throughout life, as well as being a key part of the brain involved in mental health, this study underscores the importance of good nutrition for children, adolescents and adults of all ages.”

Why do some people remain healthy into their 80s and beyond, while others age faster and suffer serious diseases decades earlier? New research led by UCLA life scientists may produce a new way to answer that question and an approach that could help delay declines in health.

Specifically, the study suggests that analyzing intestinal bacteria could be a promising way to predict health outcomes as we age.

The researchers discovered changes within intestinal microbes that precede and predict the death of fruit flies. The findings were published in the open-source journal Cell Reports.

“Age-onset decline is very tightly linked to changes within the community of gut microbes,” said David Walker, a UCLA professor of integrative biology and physiology, and senior author of the research. “With age, the number of bacterial cells increase substantially and the composition of bacterial groups changes.”

The study used fruit flies in part because although their typical life span is just eight weeks, some live to the age equivalent of humans’ 80s and 90s, while others age and die much younger. In addition, scientists have identified all of the fruit fly’s genes and know how to switch individual ones on and off.

In a previous study, the UCLA researchers discovered that five or six days before flies died, their intestinal tracts became more permeable and started leaking.

In the latest research, which analyzed more than 10,000 female flies, the scientists found that they were able to detect bacterial changes in the intestine before the leaking began. As part of the study, some fruit flies were given antibiotics that significantly reduce bacterial levels in the intestine; the study found that the antibiotics prevented the age-related increase in bacteria levels and improved intestinal function during aging.

The biologists also showed that reducing bacterial levels in old flies can significantly prolong their life span.

“When we prevented the changes in the intestinal microbiota that were linked to the flies’ imminent death by feeding them antibiotics, we dramatically extended their lives and improved their health,” Walker said. (Microbiota are the bacteria and other microorganisms that are abundant in humans, other mammals, fruit flies and many other animals.)

Flies with leaky intestines that were given antibiotics lived an average of 20 days after the leaking began — a substantial part of the animal’s life span. On average, flies with leaky intestines that did not receive antibiotics died within a week.

The intestine acts as a barrier to protect our organs and tissue from environmental damage.

“The health of the intestine — in particular the maintenance of the barrier protecting the rest of the body from the contents of the gut — is very important and might break down with aging,” said Rebecca Clark, the study’s lead author. Clark was a UCLA postdoctoral scholar when the research was conducted and is now a lecturer at England’s Durham University.

The biologists collaborated with William Ja, an assistant professor at Florida’s Scripps Research Institute, and Ryuichi Yamada, a postdoctoral research associate in Ja’s laboratory, to produce an additional group of flies that were completely germ-free, with no intestinal microbes. Those flies showed a very dramatic delay in intestinal damage, and they lived for about 80 days, approximately one-and-a-half times as long as the animal’s typical life span.

Scientists have recently begun to connect a wide variety of diseases, including diabetes and Parkinson’s, among many others, to changes in the microbiota, but they do not yet know exactly what healthy microbiota look like.

“One of the big questions in the biology of aging relates to the large variation in how we age and how long we live,” said Walker, who added that scientific interest in intestinal microbes has exploded in the last five years.

When a fruit fly’s intestine begins to leak, its immune response increases substantially and chronically throughout its body. Chronic immune activation is linked with age-related diseases in people as well, Walker said.

Walker said that the study could lead to realistic ways for scientists to intervene in the aging process and delay the onset of Parkinson’s disease, Alzheimer’s disease, cancer, stroke, cardiovascular disease, diabetes and other diseases of aging — although such progress could take many years, he said.

Other co-authors of the research are Matteo Pellegrini, professor of molecular, cell and developmental biology and co-director of UCLA’s Institute for Quantitative and Computational Biosciences, postdoctoral scholars Anna Salazar and Anil Rana, graduate students Jeanette Alcaraz and Marco Morselli, and researcher Sorel Fitz-Gibbon, all of UCLA; and Michael Rera, a former UCLA postdoctoral scholar.

Age defying species such as the giant red sea urchin, the painted turtle, the naked mole rat and the bowhead whale may begin teaching us how to extend our own lives. All these species stand out because they exhibit negligible senescence, the ability to grow older without suffering functional declines or any age-related increase in mortality. Apparently, these species have something we lack. This something, according to a new study, is gene network stability.

A stabilized gene network promotes longer lifespan. The new data is consistent with Dr. Villeponteau’s model that keeping the optimal gene network at youth from drifting with age generates longer life. Likewise, interventions that nudge gene expression back to that of the youthful gene network reverses aging. That is the goal with all the Life Code products, particularly Stem Cell 100 and Stem Cell 100+.

The new study was undertaken by scientists from the biotech company Gero in collaboration with Robert J. Shmookler Reis, Ph.D., a professor of geriatrics at the University of Arkansas. Dr. Shmookler Reis enjoys the distinction of having extended by a factor of 10 the lifespan of the nematode Caenorhabditis elegans.

These scientists noticed that in long-lived animals, negligible senescence is accompanied by exceptionally stable gene expression. And stable gene expression, they reasoned, could be attributed to gene network repair systems. To test this idea, the scientists devised a mathematical model of a genetic network. This model not only managed to account for the age-independent mortality exhibited by long-lived animals, it also identified gene network parameters that influence longevity. These parameters include effective gene network connectivity, effective genome size, proteome turnover, and DNA repair rate.

The scientists published their findings August 28 in the journal Scientific Reports, in an article entitled, ?Stability analysis of a model gene network links aging, stress resistance, and negligible senescence.? This article argues that under a very generic set of assumptions, there exist two distinctly different classes of aging dynamics.

?If the repair rates are sufficiently high or the connectivity of the gene network is sufficiently low, then the regulatory network is very stable and mortality is time-independent in a manner similar to that observed in negligibly senescent animals,? wrote the authors. ?Should the repair systems display inadequate efficiency, a dynamic instability emerges, with exponential accumulation of genome-regulation errors, functional declines and a rapid aging process accompanied by an exponential increase in mortality.?

The authors added that the onset of instability depends on the gene-network properties only, irrespective of genotoxic stress levels. Essentially, instability can be viewed as being hard-wired in the genome of the species.

Nonetheless, the authors said that their model implies many possibilities to stabilize a regulatory network and thus extend lifespan. Some of these possibilities, in fact, have already been exploited by nature, accounting for some of the lifespan increases observed to have occurred in evolution. For example, a model parameter that the authors call the coupling rate can be adjusted by increasing or decreasing the degree of gene network connectivity.

A biological embodiment of this parameter is the degree to which the nuclear envelope reduces the effective interactions between the genes and the cellular environment. Once the nuclear envelope became available, organisms that used it enjoyed a dramatic increase in complexity and life expectancy.

Such observations have implications for potential life-extending interventions. For example, experimental reduction of the network connectivity by silencing of kinase cascades involved in regulation of transcription factors leads to a dramatic effect on the lifespan in C. elegans (up to a 10x lifespan extension by a single mutation).

The relation between stresses, stress resistance, and aging, the authors explained, can also account for the way damage to gene regulation from stresses encountered even at a very young age can persist for a very long time and influence lifespan. Such effects, the authors believe, indicate that further research into the relation between gene network stability and aging will make it possible to create entirely new therapies with potentially strong and lasting effect against age-related diseases and aging itself.