DNA Sequences That Change During Aging May Contribute To Age-Related Brain Defects

More evidence for adult somatic cells displaying genetic variability, both over time in one cell, and from cell to cell. Thus the idea of a single genome for an individual is misguided; there are many genomes in an individual and those genomes change in time.

In a journal article published in Nature Neuroscience, CSHL Associate Professor Joshua Dubnau, PhD and colleagues show that so-called “jumping genes,” or transposons, increase in abundance and activity in the brains of fruit flies as they age. Originally discovered at CSHL by Professor Barbara McClintock, a Nobel Laureate, while working on maize (corn) in the 1940s, transposons are typically repeat DNA sequences that insert themselves into the DNA of an animal or plant.

The term “jumping genes” comes from the fact that when activated these gene segments can reinsert themselves, or transpose, into another part of the genome. In the course of doing so they are thought to either provide variations in genetic function or, especially in the germline, induce potentially fatal disruptive defects.

The results in his team’s new paper, Dubnau proposes that a transposon activation may be responsible for age-related neurodegeneration as well as the pathology seen in some neurodegenerative disorders.

However, his studies so far don’t address whether transposons are the cause or an effect of aging-related brain defects. The next step will be to activate transposons by genetically manipulating fruit flies and ask whether they are a direct cause of neurodegeneration.

Reference: http://www.nature.com/neuro/journal/v16/n5/full/nn.3368.html

Pluripotent Stem Cell Discovered in Adult Tissue

A new study by Dr. Thea Tisty, PhD at UCSF describes rare somatic cells from human breast tissue that exhibit extensive lineage plasticity, and thus appear to be pluripotent adult stem cells. Previously, only embryonic stem cells were thought to be pluripotent. As Ron Leuty described in the San Francisco Business Times, "A new type of stem cell, discovered by UCSF researchers, may open new possibilities for fixing damaged parts of the body while sidestepping the politically and morally thorny issues surrounding embryonic stem cell research."

Some religious organizations oppose embryonic stem cell research because they consider embryos, a small cluster of cells that fit on the tip of a pin, to be human life. As a result, conservative, anti-abortion lawmakers have largely seized on those concerns to block federal funding for research of embryonic stem cells.  The newly discovered endogenous pluripotent stem cells (ePS) described by Dr Tisty obviate these religious and moral problems.

Further, unlike iPSCs or parthenogenetic stem cells, the ePS cells are genetically and epigenetically stable and mortal, which means they will stop growing over time, thus reducing the risk of cells becoming rogue and morphing into cancer tumors.

The discovery by Dr Tisty opens a new path for exploration in the quest to develop stem cell therapies.

S2RM Technology Versus iPSC, Parthenogenetic, And Other Stem Cell Therapeutic Technologies

The unique nature of the stem cell released molecules technology (SRM Technology^TM) centers on the identification, selection, culture, and stimulation of the appropriate stem cells, and then the capture of those molecules released from the stem cells. In this manner, proprietary and patent-pending technology is used in the BioRegenerative Science (BRS) laboratory to capture what the stem cells normally release in the body. This is a systems based approach where, instead of a reductionist approach where one or two molecules are used for treatment, all of the molecules from the stem cells act together as they normally do in order to deliver the emergent properties of the system of all molecules. Further, BRS uses a technology that mimicks the manner in which the body heals itself whereby two or more types of stem cells become resident at the site of injury, and the two types of stem cells release their molecules into the tissue in concert, producing an emergent, synergistic healing effect. The use of two or more stem cell types to produce the SRM is known as BRS' S²RM Technology.^TM

The S²RM Technology, exclusively used by BioRegenerative Sciences, has the advantage compared to other stem cell technologies of capturing a full and natural complement, or "system," of known molecules. This full complement of captured molecules from stem cells are subsequently injected into, or topically applied to, the patient in a precise dosing schedule to begin the systems-based regenerative process. Examples of topical S²RM Technology^TM procedures include dry eye therapy, and lower extremity diabetic ulcer wound therapy where treatment is easily and most effectively delivered topically to the affected site. Injectable or ingestible S²RM Technology^TMis used in procedures for Central Nervous System (CNS) and other organ diseases where the molecules cannot be delivered as a simple topical.

The BRS “Intelligent Molecules” Expression System employs a proprietary manufacturing process that allows the production of a wide variety of soluble and properly folded proteins and signaling molecules from multiple stem cell types important to immune modulation, and tissue repair and regeneration. The advantages of the process are in the production of biologically active proteins, exosomes, and signaling molecules, developing a “systems therapeutic” yielding a combination of many molecules, that act at multiple targets, resulting in a synergistic therapeutic with emergent therapeutic value. Furthermore, the production of the SRM (stem cell released molecules) does not require downstream solubilization, refolding, or other processes. Additionally, the process offers reduced purification requirements and lower production costs than other pharmacological and biological processes. The production of a therapeutic with a multitude of molecules represents a multi-targeted, systems biology approach to designing and manufacturing therapeutics. In the BRS “Intelligent Molecules” Expression System, multiple stem cell types are used to express SRM and thus the term “S²RM^TM” is used to denote that two or more types of stem cells are used to produce a synergistic effect. The combination of stem cells used to develop each therapeutic depend on the condition being treated, and the type of tissue underlying the condition. Included in the S²RM^TM is the BRS Exosome Delivery System that drives the active molecules through the layers of tissue into the target site, effectuating regeneration and repair in all damaged tissue regardless of the depth or remoteness of the target.

Unlike other so-called stem cell therapeutics, such as iPSCs and parthenogenetic stem cells, which are artificially induced "stem cells," and suffer from genetic and epigenetic programming errors, the adult stem cells in S²RM^TM Technology are genetically and epigenetically normal. Further, the production of some "stem cell" therapeutics does not allow the molecules to be completely processed in the cell and allow for proper post-translational modifications. That is, the S²RM^TM Technology allows the stem cells to fully process the molecules to the point of exosome production and release, including complete post-translational modification with resultant normal molecular folding characteristics and moiety construction. Other production techniques that are faster and less expensive, such as harsh cellular extraction methods with incomplete post-translational modification, result in incomplete molecules with errors such as 3-dimensional misfolding and moiety deletions, and cellular packaging errors. Thus, unlike iPSCs and parthenogenetic "stem cells" that don't produce the complete set of the natural molecules of a stem cell and also fail to complete the full assembly of each of the molecules, the true adult stem cells in S²RM Technology display correct genetic and epigenetic coding, with complete post-translational modifications and molecular packaging to produce a natural and full complement of molecules with complete post-translational modifications and hence full efficacy and a natural safety profile.

S2RM is a registered trademark of BRS, Inc.

Caloric Reduction Enhances Stem Cell Function

Calorie reduction (CR) extends life span and ameliorates age-related pathologies in most species studied, yet the mechanisms underlying these effects remain unclear. A number of studies have shown that CR acts in part by enhancing the function of tissue-specific stem cells. Even short-term CR significantly enhances stem cell availability and activity, as observed in muscle tissue.

In the intestine, Paneth cells, a key constituent of the stem-cell (ISC) niche that reside adjacent to stem cells, augment stem-cell function in response to calorie restriction. Calorie restriction acts by reducing mechanistic target of rapamycin complex 1 (mTORC1) signalling in Paneth cells, and the ISC-enhancing effects of calorie restriction can be mimicked by rapamycin.

These studies indicate that metabolic factors play a critical role in regulating stem cell function and that this regulation can influence the efficacy of recovery from injury and the engraftment of transplanted cells.

Decreased calorie ingestion, without malnutrition, extends lifespan and promotes healthy aging in many animals and is, at least partially, attributed to enhanced stem cell function.

Nature (2012) doi:10.1038/nature11163
Cell Stem Cell. 2012 May 4;10(5):515-9.

Short Telomere Length Linked To Risk Of Dying

The protective caps on the ends of chromosomes called telomeres may portend a higher risk of death. A new, large study,The Genetic Epidemiology Research on Adult Health and Aging (GERA), reports data on telomere lengths and genotypes of over 675,000 SNPs for each of 100,000 subjects.

Telomeres prevent a chromosome’s DNA from being eaten away or damaged. Previous studies have shown that telomeres shorten with age and have linked short telomeres with several diseases. However no one has previously reported whether  truncated telomeres cause health problems or are a side effect of aging and poor health.

To better understand, researchers at Kaiser Permanente and the University of California, San Francisco measured telomere length in 110,266 people in northern California. The participants were part of an ongoing project that explores links between genetics and health. This study is the largest ever to examine the role of telomeres in health.

The 10 percent of people with the shortest telomeres had a more than 20 percent higher risk of dying than people with longer telomeres, reported November 8 at the annual meeting of the American Society of Human Genetics. The study suggests that once your telomeres become critically short, your risk of dying increases. The increased death risk is about the same as for people who drink 20 to 30 alcoholic beverages per week or smoke for 20 to 30 years.  The increased risk is small, but significant.

Telomeres do shorten with age, the study confirms, but men older than 75 and women over age 80 tended to have longer telomeres than their slightly younger counterparts. The result seems counterintuitive, and does not mean that telomeres start to grow in length once people reach a certain age. Rather, the finding probably means that people with shorter telomeres died before they reached those ripe old ages and the survivors are those that carry longer telomeres.

African-Americans tended to have longer telomeres than European-Americans, Latinos or Asians, the researchers found. The reason for that difference is not clear. As expected, people who smoked or drank heavily were more likely to have shorter telomeres, and higher levels of education were associated with longer telomeres. Other studies have linked exercise with longer telomeres, but Dr. Schaefer, the PI, and her colleagues found no such association.

One of the study’s findings is rather puzzling: Higher body mass index, or BMI, was associated with longer telomeres.  Although a high BMI is not healthy, more work will be needed to understand the relationship between body size and telomere length.

While the study is important, over reaching conclusions should not be drawn given the study used the biomarker of telomeres taken from saliva samples. Telomeres from cells in other parts of the body, something hard to sample in human studies such as this one, will be one, amongst other additional studies that are required to better understand telomeres in aging and health.

Transposable RNA Elements Control Gene Expression And May Lead To Speciation

Numerous studies over the past decade have elucidated a large set of long intergenic noncoding RNAs (lincRNAs) in the human genome. Research since has shown that lincRNAs constitute an important layer of genome regulation across a wide spectrum of species. However, the factors governing their evolution and origins remain relatively unexplored. One possible factor driving lincRNA evolution and biological function is
transposable element (TE) insertions. In a study at Harvard and MIT, led by Drs. David Kelley, Ph.D. and John Rinn, Ph.D., they comprehensively characterize the TE content of lincRNAs relative to genomic averages and protein coding transcripts.

Dr Kelley and Dr Rinn realized that the movement within the genome of transposable elements can be considered a mutation, and wondered if this mutation has evolutionary consequences. They think it does because when they looked at the relation between such elements and lincRNA genes, they found a number of patterns. First, lincRNAs are much more likely to contain transposable elements than protein-coding genes. More than 83% do so, in contrast to only 6% of protein-coding genes. Second, those transposable elements are particularly likely to be endogenous retroviruses, rather than any of the other sorts of transposons. Third, the TEs are usually found in the bit of the gene where the process of copying RNA from the DNA template begins, suggesting the TEs are involved in switching genes on or off. And fourth, lincRNAs containing one particular type of endogenous retrovirus are especially active in pluripotent stem cells, the embryonic cells that are the precursors of all other cell types. That datum suggests these lincRNAs have a role in the early development of the embryo.

Previous work suggests lincRNAs are also involved in creating the differences between various sorts of tissue, since many lincRNA genes are active in only one or a few cell types. Given that their principal job is regulating the activities of other genes, this makes sense. Even more pointing, studies of lincRNA genes from species as diverse as people, fruit flies and nematode worms, have found they differ far more from one species to another than do protein-coding genes. The lincRNA are, in other words, more species specific. And that suggests they may be more important than protein-coding genes in determining the differences between those species.

What seems to be happening is that endogenous retroviruses are jumping around in an arbitrary way within the genome. Mostly, that will, in evolutionary terms, be either harmless or bad. Occasionally, though, a retrovirus lands in a place where it can change the regulation of a lincRNA gene in a way beneficial to the organism. Such variations are then spread by natural selection in the way that any beneficial mutation would be. But because the variation affects developmental pathways and tissue types, and thus a creature’s form, rather than just a simple biochemical pathway, that could encourage the formation of a new species.

Epigenome: The DNA Methylome Helps Predict Aging

The epigenome, which is the set of modifications to DNA other than changes in the sequence of DNA, is associated with aging. The ability to measure human aging from molecular profiles has practical implications in many fields, including disease prevention and treatment, forensics, and extension of life. Although chronological age has been linked to changes in DNA methylation, the methylome has not yet been used to measure and compare human aging rates. Researchers at UCSD (Hannum et al, 2012), have built a quantitative model of aging using measurements at more than 450,000 CpG markers from the whole blood of 656 human individuals, aged 19 to 101. This model measures the rate at which an individual’s methylome ages, which we show is impacted by gender and genetic variants. They also show that differences in aging rates help explain epigenetic drift and are reflected in the transcriptome. They also show how their aging model is upheld in other human tissues and reveals an advanced aging rate in tumor tissue. The model highlights specific components of the aging process and provides a quantitative readout for studying the role of methylation in age related disease.