Cellular differentiation is the process by which stem cells and other progenitor cells divide to form specialized cell populations - of which there are a great many different types in the body. Much of stem cell research to date has been focused on finding out how to first obtain stem cells and then differentiate them to form specific desired types of specialized cell. This has been a challenging process, but advances in biotechnology are making it easier and less costly as the years go by.

Cells are programmable machinery; it seems to be the case that any given type of cell holds the potential to produce any other type of cell, if researchers just understood the right chemical and genetic cues and instructions. Thus in addition to the work of reverting specialized cells into stem cells, and differentiating stem cells into desired specialized cells, there is also the possibility of achieving transdifferentiation - converting one type of cell directly into another without passing through a stem cell stage.

In recently reported research, researchers are making inroads in converting various types of cell in the pancreas - which offers the possibility of a fairly direct path towards providing new beta cells to diabetes patients:

While the current standard of treatment for diabetes - insulin therapy - helps patients maintain sugar levels, it isn't perfect, and many patients remain at high risk of developing a variety of medical complications. Replenishing lost beta cells could serve as a more permanent solution, both for those who have lost such cells due to an immune assault (Type 1 diabetes) and those who acquire diabetes later in life due to insulin resistance (Type 2).

"Our work shows that beta cells and related endocrine cells can easily be converted into each other," said study co-author Dr. Anil Bhushan, an associate professor of medicine in the endocrinology division at the David Geffen School of Medicine at UCLA and in the UCLA Department of Molecular, Cell and Developmental Biology.

It had long been assumed that the identity of cells was "locked" into place and that they could not be switched into other cell types. But recent studies have shown that some types of cells can be coaxed into changing into others - findings that have intensified interest in understanding the mechanisms that maintain beta cell identity.

This is as much the age of controlling cells as it is the age of biotechnology. Researchers are presently building the foundation for complete control over the component machinery of the human body. Along the way to that goal lies the production of ever more effective general repair kits for all forms of damage that originate in missing or damaged cell populations - including one portion of aging itself.

Mitochondria are the cell's roving herd of bacteria-like power plants, and the damage they suffer in the course of their operation is strongly implicated as a contributing cause of aging. Here researchers show that calorie restriction appears to boost the rate at which new mitochondria are spawned: "mice with increased respiratory rates and reduced energetic conversion efficiency due to spontaneously uncoupled mitochondria lived longer than their counterparts. Indeed, different uncoupling strategies were able to extend lifespan in models ranging from yeast to mammals. ... uncoupling could be an approach to promote lifespan extension due to its ability to prevent the formation of reactive oxygen species (ROS). Indeed, mild mitochondrial uncoupling is a highly effective intervention to prevent the formation of ROS ... CR also increases the number of functional respiratory units (mitochondrial biogenesis) [and researchers] demonstrated that mitochondrial biogenesis was essential for many beneficial effects of dietary limitation in mice. ... We recently demonstrated that murine lifespan can be extended by low doses of the mitochondrial uncoupler 2,4-dinitrophenol (DNP) in a manner accompanied by weight loss, lower serological levels of glucose, insulin and triglycerides as well as a strong decrease in biomarkers of oxidative damage and tissue ROS release. Similar effects have been repeatedly reported using CR diets ... Based on the similarities between these two interventions, we hypothesized that DNP treatment could also lead to enhanced mitochondrial biogenesis. In this manuscript, we measured the effects of DNP treatment and CR on mitochondrial biogenesis and associated pathways. We observed that both DNP and CR increase mitochondrial biogenesis, [confirming] that signaling events in both treatments converge."

Link: http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0018433

A fairly long open access commentary on metformin and its effects on slowing aging in mice: "A recent study [may] certainly establish that metformin should be defined as geroprotective or gerosuppressant rather than bona fide [calorie restriction mimetic]. Long-living female mice from the outbred SHR strain were fed metformin in drinking water beginning at 3, 9 or 15 months of age and they were then analyzed for reproductive aging, mean and maximal lifespan and incidence of malignant tumors ... In female SHR mice, [researchers] now confirm that metformin treatment, if started early in life, notably increases by 21% the mean lifespan of tumor-free mice. In contrast, if started late in life, metformin treatment appears to significantly reduce (by 13%) the mean lifespan of tumor-free mice. ... It is perhaps relevant to note that, if started early in life, metformin treatment decreased the risk of death compared to the control group whereas similar treatment with metformin at older ages did not affect the relative risk of death in SHR female mice. Metformin's ability to increase the mean lifespan of tumor-free mice while simultaneously decreasing the risk of death in an age-related manner somewhat recapitulate metformin's ability to reduce cancer incidence among type 2 diabetic individuals."

Link: http://www.impactaging.com/papers/v3/n4/full/100316.html

What is the Vegas Group initiative setting out to achieve, in a nutshell? I'm still working on that short explanation, but here is one attempt at it. Thanks to the present regulatory situation in the US - where aging is not recognized as a disease, and therefore no therapy for aging can be legally developed - there are any number of potentially useful biotechnologies presently languishing without further development. These are methods and techniques shown to extend life in mice or repair and reverse specific biochemical aspects of aging, but for which there is no further funding for clinical development. Nothing may be happening for these technologies in the US, but there are active biotechnology and medical development communities in other parts of the world who are not so encumbered by local regulation: many of the developed Asia-Pacific countries, for example. What the Vegas Group initiative ultimately aims to do is build a bridge between these undeveloped technologies and the developers who could bring them into the clinic for human use.

How will that bridge be built? I believe that the growing garage biotechnology and DIYbio communities will play a pivotal role in the US - validating, documenting, and lowering the cost for overseas ventures to pick up and further develop longevity therapies. From my perspective then, the very earliest actions for the first Vegas Group volunteers involve building the foundations for a repository of how-to documentation: guides that clearly explain how the garage biotechnology community could validate and further develop the best and latest techniques in longevity science.

At the outset this is less a matter of writing documents and more a matter of figuring out a sustainable process and organizational structure - the business of freelance writing is much akin to herding cats even when money is involved.

So I can envisage a guiding council of advisors putting together a plan for the hierarchy of topics they would like to see in the Vegas Group codex, from basic methods in biotechnology through to best attempt reverse engineering of things we know to be possible and that have been published: such as Cuervo's work on restoring youthful levels of autophagy, or protofection to replace mitochondrial DNA. The end result of that process might look something like a distillation of Fight Aging! mixed with the very elegant materials produced by the Science for Life Extension Foundation.

Codex project volunteers would then run an ongoing process of hiring post-graduates and interested researchers to write, and passing the results to starving authors who improve the output to a quality suitable for the open biotechnology community. There would of course be some back and forth between the post-graduates and the starving authors in order to reduce the inevitable translation errors, but I see this as a viable way to produce a body of knowledge that is sufficiently good to begin with - not perfect, not even necessarily very good, but sufficient.

I mentioned rejuvenation of autophagy above as one of the possible projects for documentation, and at present, the Vegas Group discussion list is focused on mitochondrial protofection - and we could certainly use another life science volunteer or two to help lay out the skeleton for full documentation, or work on one of the other potential projects. If you're interested, come on over and join in.

Some of the other possible projects that have been mentioned or came to mind include the following:

1) LysoSENS

LysoSENS isn't an established methodology, but it is an ongoing research program that aims to find bacterial enzymes capable of breaking down harmful aggregates that build up with age. This is a matter of synthesizing the chemicals to be broken down, digging up some dirt from likely locations, culturing bacteria, and matching them up against your unwanted chemicals to see if you have a hit. This seems like an excellent project for DIYbio enthusiasts - someone is going to find an existing bacterial strain containing enzymes that can be adapted to safely destroy lipofuscin in human cells, and there's no reason that person has to be working in an institutional establishment.

2) Manufacturing Targeted Mitochondrial Antioxidants

A number of research groups have been publishing in recent years on ingested targeted mitochondrial antioxidants that appear to slow aging in mice. It seems a viable sophisticated garage or shared lab-space chemistry experiment to replicate their published work, and then a biotech experiment to validate your synthesized antioxidants in cell cultures.

3) Upregulation of PEPK-C

This is a manipulation of gene expression show to increase longevity in mice. As gene engineering goes, this is about as straightforward as it is going to get - which is to say still a fair hurdle for the garage biotech community to work towards - a single gene altered, and an impressive result. Managing to document the process sufficiently well to recreate this intervention in cell cultures would be, I think, a real showpiece for a laboratory cooperative.

Now all of these items, when carried out as projects, can be expected to sit atop a pyramid of supporting techniques and documentation, some of which will be common to many different projects. Producing that material sufficiently well will, I think, help in the growth of the garage biotechnology and DIYbio communities. Documentation is key for newcomers and recruitment, and you can never have too much of it.

A study of markers of oxidative stress in centenarians: "Human longevity is a complex phenotype that is determined by environment, genetics, and chance. Understanding the mechanisms by which aging leads to longevity, particularly healthy longevity would be of enormous benefit to our aging population. Unfortunately, most research on human aging has focused on phenomenological description of age-related diseases, and much less is known about the mechanisms of aging itself. Among the most promising theories about how and why we age is the Free Radical Theory, initially proposed by Denham Harman in 1956. Harman proposed that oxygen radicals produced during aerobic respiration induce oxidative damage in DNA, cells, tissues, and organisms that lead to aging and death. ... Harman hypothesized, based on observations of enzymatic redox chemistry, that oxygen radical generation occurs in vivo and that mechanisms exist to protect against such damage. Mitochondria were later found to be a principal source of these oxygen radicals ... Okinawa has among the world's longest-lived populations but oxidative stress in this population has not been well characterized. ... The low plasma level of [oxidized lipids] in Okinawan centenarians, compared to younger controls, argues for protection against oxidative stress in the centenarian population and is consistent with the predictions of the Free Radical Theory of Aging."

Link: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3068305/

An open access paper: "Aging is the single most important risk factor in human disease in developed countries but when it comes to research on prevention or cures, aging is seldom taken into account. Nevertheless if aging is a significant contributor to age-related conditions, we would hope that an understanding of aging mechanisms could prompt the design of rational therapies. Moreover, if aging causes multiple diseases then it is reasonable to think that pharmacological agents that slow aging could be also effective in preventing or slowing a wide spectrum of diseases. ... Protein aggregation is a hallmark of aging and several age-related pathologies, collectively known as conformational diseases (CD). This similarity strongly suggests a crosstalk between aging and disease. Although it is not clear how protein aggregation occurs, dramatic alterations in the balance of protein synthesis, protein folding and protein degradation (together representing 'protein homeostasis') are likely to play important roles in this process. As a consequence, modified proteins tend to accumulate into soluble oligomers and insoluble aggregates that may actively influence cell function. Neurodegenerative diseases are arguably the best studied CD and the aberrant aggregation of several insoluble molecules [has] long been associated with the development of these pathologies. ... The general picture that that has emerged is that conformationally-altered proteins escape the surveillance of repair and degradation systems, form aggregates, and this process contributes to aging; aging could be therefore a manifestation of a loss in protein homeostasis. This then prompts the question: to what extent could chemical modulation of protein aggregation alter the rate of aging? Furthermore, would such an intervention influence disease pathology? In a recent publication, we addressed this issue by identifying small molecules able to slow protein aggregation in the C. elegans model. We were then able to directly assess the degree to which protein aggregation influences normal aging rates."

Link: http://www.impactaging.com/papers/v3/n4/full/100317.html

LysoSENS is the SENS Foundation initiative to build a platform for medical bioremediation capable of breaking down the damaging byproducts of metabolism that build up in old cells and degrade their ability to recycle garbage. The short of is that we know that out there somewhere are bacteria that can eat these compounds, such as the lipofuscin that contributes to many age-related conditions. There is no buildup of prominent components of lipofuscin in graveyards, for example - so something is consuming it. That bacterial something will be armed with enzymes, biological knifes and saws that might be turned into a therapy to destroy lipofuscin if identified and introduced into the human body.

You might recall that the early LysoSENS volunteers ran a contest for soil samples from obscure locations back in 2006, the better to get a good mix of bacterial origins for analysis.

The search for bacterial enzymes that can safely attack lipofuscin in the body presently gets the lion's share of research funding at the SENS Foundation, and, appropriately, they are hiring in the Bay Area, California:

SENS Foundation is hiring for our research center located in Mountain View, CA. We are seeking a team lead for our LysoSENS project, which contains both intra- and extramural components.

Qualified candidates will have an MS, or Ph.D. in the chemical/biological sciences and at least 5 years of work experience that must include prior project management experience. Duties will include the preparation of grant proposals, internal and external progress reports, individual and collaborative publication. The project lead will develop, interpret and implement standards, procedures, and protocols for the LysoSENS research program and may collaborate on determining strategic directions in the research program. Candidates must have a proven ability to lead other professionals.

Seems like the community has come a long way from the turn of the century, doesn't it? Raising enough money for formal hires is always a big organizational milestone, and congratulations are due to the SENS Foundation staff and volunteers who have worked hard to get to this point.

A translated interview with SENS Foundation co-founder Aubrey de Grey: "I have identified seven types of damage [that cause aging]. In five cases we can repair the damage in my opinion, by replacing irreversibly damaged cells by stem cells, or when garbage accumulates, we will remove [it]. In two cases, we need to engage in gene therapy, for example, through new DNA counteract mutations in the mitochondria. ... We should intervene as little as possible in the metabolic pathways themselves. This is too complicated, we do not know enough yet about it. I prefer the regenerative approach, the repair and maintenance. It is [sufficient] to repair the damage after it occurred. In this way, we do not [need to] understand all the molecular details and how they come about. But we have to intervene before the problems get out of control. ... A simple example is the stiffening of the extracellular matrix - this is the fibrous scaffold between cells. The stiffening occurs because certain molecules network with each other. There is a principal [agent], a molecule called [glucosepane], which has the largest share of the networking and reinforcement. We must find a way to break up about two-thirds of them again. If we break these reinforcements, it would eliminate about half of the damage. ... I think the probability is about 50 percent, that all of these therapies in 25 years actually show the desired results. The average life span might then be [increased by] about 30 years."

Link: http://translate.google.com/translate?u=http://www.heise.de/tr/artikel/Muell-entfernen-und-Zellen-erneuern-1230091.html

News from the field of stem cell research: "researchers [report] a game-changing advance in stem cell science: the creation of long-term, self-renewing, primitive neural precursor cells from human embryonic stem cells (hESCs) that can be directed to become many types of neuron without increased risk of tumor formation. ... It means we can generate stable, renewable neural stem cells or downstream products quickly, in great quantities and in a clinical grade - millions in less than a week - that can be used for clinical trials and, eventually, for clinical treatments. Until now, that has not been possible. ... Human embryonic stem cells hold great promise in regenerative medicine due to their ability to become any kind of cell needed to repair and restore damaged tissues. But the potential of hESCs has been constrained by a number of practical problems, not least among them the difficulty of growing sufficient quantities of stable, usable cells and the risk that some of these cells might form tumors. ... [Researchers] added small molecules in a chemically defined culture condition that induces hESCs to become primitive neural precursor cells, but then halts the further differentiation process. ... And because it doesn't use any gene transfer technologies or exogenous cell products, there's minimal risk of introducing mutations or outside contamination."

Link: http://www.sciencedaily.com/releases/2011/04/110425153554.htm

The jellyfish Turritopsis nutricula is one of the few species whose members might be considered immortal, based on what is presently known of its biology. The life course of this jellyfish is very far removed from that of humans; even more so than that of the lobster, another marine species that might be immortal - though there researchers know far too little to make the call one way or another.

Immortality in the sea lasts right up until something larger eats you, of course. The form of agelessness enjoyed by Turritopsis nutricula appears to be an adaptation to periods of starvation: it can retreat to earlier stages of its life cycle, and in the process its cells alter their character in an usual way:

It starts out as a larva that eventually sinks to the bottom of the ocean and attaches to a sturdy substrate and continues development into a polyp that resembles a sea plant. The polyp then matures to become a free-floating medusa, what we commonly recognize as jellyfish resembling an upside down saucer with tentacles. ... However, during times of stress like a shortage of food, Turritopsis responds by beginning to reverse the process before eventually becoming a polyp again. From this point then, it can again develop into a sexually mature medusa when conditions become more favorable. Theoretically, it can repeat this process indefinitely as its cells undergo a process called transdifferentiation, a rare biological process whereby any non-stem cell can become a different cell entirely. It is still unclear whether only specific cells can only become other specific cells or if any cell in Turritopsis has the potential to become any other cell.

Unlike other long-lived or apparently ageless animals, the principle biological process of interest here is transdifferentiation - being able to produce any type of cell from any other type of cell without having to go through intermediary stages such as the generation and differentiation of stem cells. Modern stem cell medicine depends on techniques for controlling and changing the state of cells - to be able to engineer pluripotent cells from ordinary cells, for example, or produce unlimited numbers of a particular type of cell for research, transplantation, and tissue engineering.

When it comes to transdifferentiation, the hope is that we will eventually be able to learn how creatures like Turritopsis skip the stem cell step and go directly from one cell type to another.

Reliable control over that process for human cells would greatly improve the state of the art in the field of regenerative medicine - and in fact research groups in the space are headed in that direction already.

One of the predictions of the reliability theory of aging and longevity is that we are all born damaged. Reliability theory evolved from the theories used to predict failure in mechanical systems; as such, it is a less an attempt to explain the roots of aging and more an attempt to frame an understanding of the way in which accumulating damage at the most fundamental levels of our biochemistry produces the observed patterns of aging.

The models of reliability theory only match up with reality if we assume that life starts with a certain level of preexisting biological damage, and that damage goes some way to determining later health and life expectancy. What happens in early life matters a great deal, it seems. This is why we are interested in such topics as the potential effects of solar radiation on the unborn, and the degree to which historical increases in longevity can be explained by a lower childhood burden of chronic disease.

I noticed another interesting data point today in an open access paper: a possible marker for the biological cost of being born to an older mother - something that we know bears an increased risk of health issues.

Parental ages and levels of DNA methylation in the newborn are correlated:

Changes in DNA methylation patterns with age frequently have been observed and implicated in the normal aging process and its associated increasing risk of disease, particularly cancer. Additionally, the offspring of older parents are at significantly increased risk of cancer, diabetes, and neurodevelopmental disorders. Only a proportion of these increased risks among the children of older parents can be attributed to nondisjunction and chromosomal rearrangements.

We found that methylation levels [associated with] 142 genes were significantly correlated with maternal age. A weaker correlation was observed with paternal age. ... Genes associated with [cancer] are significantly over-represented among the genes correlated with maternal age, and this suggests a link to known increased risks of cancer among the children of older parents. Similarly, gene functions related to neurodevelopment and neuroregulation are over-represented among the strongly correlated genes, and this may have relevance to the increasing risk of neurodevelopmental and psychiatric disorders in offspring as parental ages increase.

Biotechnology will be a great leveler of opportunity, a grand remover of adversity, offering the chance to repair deleterious consequences of ancestry, birth, and other biological circumstances beyond our control. Systematic altereration of DNA methylation will likely be a commonplace medical technology of the late 2020s, for example. This and many other potentially beneficial manipulations of DNA are almost within reach of the most advanced research groups today - and the biotechnologies of ten or fifteen years from today will far cheaper and more capable than the best machinery now available.

A look at current research on the definite health and potential longevity benefits of calorie restriction in humans: "Animals who consume fewer calories live longer and healthier lives. Now, a seminal study at the University of California, San Francisco (UCSF) is testing whether the same is true for extreme dieters. The calorie restriction study centers on two primary questions: What allows people to live in a manner many consider food deprived? And does it slow down aging? Called CRONA (Caloric Restriction with Optimal Nutrition and Aging Study), the investigation is probing the biological processes affected by extremely low caloric intake, including the impact on telomeres - tiny pieces of DNA that protect cell chromosomes. Short telomeres have been linked to a host of health problems including diabetes, heart disease and premature death. The UCSF study is the first to broadly examine the psychological profile of successful extreme dieters, gauging how their cognitive sharpness, impulse control, stress and personality differ from normal eaters and overeaters. ... Testing and data collection will continue through summer. The scientists are still recruiting control subjects who are either obese or 'free eaters' - not restricting food intake but not overweight. Interested parties can email cronastudy@gmail.com. ... We need information about what it takes to change your eating pattern for a long time. There are so many diets out there - people lose weight for six months, then regain it. We need to study what it is about the calorie restrictors that makes them able to do this for years and years." The new information on the biological response to calorie restriction is, I think, much more valuable than yet another study on willpower in humans.

Link: http://www.ucsf.edu/news/2011/04/9740/extreme-dieting-does-it-lead-longer-lives

Small scale efforts by a widespread people outside the academic and industry communities, and open and largely free access to plans and data are the future of biotechnology. It is a data-driven field, and will ultimately look just like the open source software community does today: "Following in the footsteps of revolutionaries like Steve Jobs and Steve Wozniak, who built the first Apple computer in Jobs's garage, and Sergey Brin and Larry Page, who invented Google in a friend's garage, biohackers are attempting bold feats of genetic engineering, drug development, and biotech research in makeshift home laboratories. ... For a few hundred dollars, anyone can send some spit to a sequencing company and receive a complete DNA scan, and then use free software to analyze the results. Custom-made DNA can be mail-ordered off websites, and affordable biotech gear is available on Craigslist and eBay. ... biohackers, like the open-source programmers and software hackers who came before, are united by a profound idealism. They believe in the power of individuals as opposed to corporate interests, in the wisdom of crowds as opposed to the single-mindedness of experts, and in the incentive to do good for the world as opposed to the need to turn a profit. Suspicious of scientific elitism and inspired by the success of open-source computing, the bio DIYers believe that individuals have a fundamental right to biological information, that spreading the tools of biotech to the masses will accelerate the pace of progress, and that the fruits of the biosciences should be delivered into the hands of the people who need them the most."

Link: http://www.technologyreview.com/biomedicine/37444/