Autophagy consists of a collection of cellular housecleaning processes responsible for recycling damaged cellular components. It is known to relate to longevity, as demonstrated in numerous animals studies in which aging is slowed via genetic or metabolic manipulation, and in which autophagy is seen to take place more energetically. This all seems logical, as aging is nothing more than an accumulation of unrepaired damage and the reactions to that damage, while autophagy seeks to minimize present damage before it causes more harm.

Since we've already touched on of autophagy and its relationship to longevity today, as well as the prospects for developing therapies based on increased levels of autophagy, I thought I'd point out this popular science article on the topic:

To keep themselves neat, tidy and above all healthy, cells rely on a variety of recycling and trash removal systems. If it weren't for these systems, cells could look like microscopic junkyards - and worse, they might not function properly.

One of the cell's trash processors is called the proteasome. It breaks down proteins, the building blocks and mini-machines that make up many cell parts. The barrel-shaped proteasome disassembles damaged or unwanted proteins, breaking them into bits that the cell can re-use to make new proteins. In this way, the proteasome is just as much a recycling plant as it is a garbage disposal.

Proteins aren't the only type of cellular waste. Cells also have to recycle compartments called organelles when they become old and worn out. For this task, they rely on an organelle called the lysosome, which works like a cellular stomach. Containing acid and several types of digestive enzymes, lysosomes digest unwanted organelles in a process termed autophagy.

While cells mainly use proteasomes and lysosomes, they have a couple of other options for trash disposal. Sometimes they simply hang onto their trash, performing the cellular equivalent of sweeping it under the rug. Scientists propose that the cell may pile all the unwanted proteins together in a glob called an aggregate to keep them from gumming up normal cellular machinery. If the garbage can't be digested by lysosomes, the cell can sometimes spit it out in a process called exocytosis. Once outside the cell, the trash may encounter enzymes that can take it apart, or it may simply form a garbage heap called a plaque. Unfortunately, these plaques outside the cell may be harmful, too.

Further study of the many ways cells take out the trash could lead to new approaches for keeping them healthy and preventing or treating disease.

Link: http://www.newswise.com/articles/how-cells-take-out-the-trash

Autophagy is the name given to a collection of processes that recycle damaged cellular components and unwanted or harmful molecules. Materials flagged for recycling are engulfed by one of the cell's lysosomes and then dismantled inside it. Greater levels of autophagy are observed in a majority of the means of extending life in laboratory animals through genetic or metabolic manipulation to slow aging, including calorie restriction, in which the body reacts to low levels of nutrients, raw materials for protein manufacture in cells, by stepping up its efforts to reclaim the needed raw materials from existing structures that are past their prime.

The association of enhanced longevity and enhanced autophagy shouldn't be a surprise: aging is the accumulation of unrepaired damage, and autophagy is a process that attempts to minimize the present level of cellular damage before it can cause more harm. At some point the research community will make inroads towards creating therapies based on boosted autophagy - though this doesn't appear to be happening anywhere near as rapidly as I expected it to. Here is an example of research into the regulation of autophagy, similar to many other papers published in past years, but the expected use of this sort of knowledge to build a treatment has yet to happen:

The discovery of a gene network regulating lysosomal biogenesis and its transcriptional regulator transcription factor EB (TFEB) revealed that cells monitor lysosomal function and respond to degradation requirements and environmental cues. We report the identification of transcription factor E3 (TFE3) as another regulator of lysosomal homeostasis that induced expression of genes encoding proteins involved in autophagy and lysosomal biogenesis [in] response to starvation and lysosomal stress.

We found that in nutrient-replete cells, TFE3 was recruited to lysosomes through interaction with active Rag guanosine triphosphatases (GTPases) and exhibited mammalian (or mechanistic) target of rapamycin complex 1 (mTORC1)-dependent phosphorylation. Phosphorylated TFE3 was retained in the cytosol through its interaction with the cytosolic chaperone 14-3-3. After starvation, TFE3 rapidly translocated to the nucleus and bound to the CLEAR (Coordinated Lysosomal Expression and Regulation) elements present in the promoter region of many lysosomal genes, thereby inducing lysosomal biogenesis.

Depletion of endogenous TFE3 entirely abolished the response [of] cells to starvation, suggesting that TFE3 plays a critical role in nutrient sensing and regulation of energy metabolism. Furthermore, overexpression of TFE3 triggered lysosomal exocytosis and resulted in efficient cellular clearance in a cellular model of a lysosomal storage disorder, Pompe disease, thus identifying TFE3 as a potential therapeutic target for the treatment of lysosomal disorders.

Link: http://dx.doi.org/10.1126/scisignal.2004754

With advancing age ever more cells in your body enter a state of senescence. They stop dividing and emit signals that both degrade surrounding tissue structures and raise the odds of nearby cells also becoming senescent. This is an adaptation of a mechanism involved in embryonic development that lowers the odds of suffering cancer: senescent cells appear in response to cellular damage in a range of circumstances, and the types of damage that provoke cellular senescence either raise the risk of cancerous cells emerging or accompany a rising risk of cancer in normal aging. So cellular senescence is a part of the balance that evolution has come to in humans between declining ability to function on the one hand and fatal cancer on the other.

The research community, however, is going to become very good at dealing with cancer in the decades ahead. Cellular senescence isn't a great partner for a technologically sophisticated humanity, as the downside in aging very much outweighs whatever good is being done. For my money I think that the first generation of effective treatments that reverse the contribution of cellular senescence to degenerative aging will be blunt efforts that involve the targeted destruction of near-all senescent cells. This targeted destruction in fact goes on all the time in younger years, as one of the jobs of the immune system is to seek out and remove problem cells. Unfortunately like all biological systems it becomes damaged and disarrayed in later life, and alongside the damage that provokes a greater incidence of cellular senescence this is one of the reasons why the body accumulates ever more senescent cells as the years pass. We don't need these senescent cells, they can be removed, and we will benefit from their removal. The technologies used will be very similar to those already in trials for the targeted destruction of cancer cells: immune therapies, nanoparticles, engineered viruses, and so forth.

Later forms of treatment may be more sophisticated, however. Why destroy senescent cells if they can be reprogrammed into a non-senescent state? The field of cellular programming is still in its infancy at this point, and even the most impressive results are half happenstance and incompletely understood in the context of the bigger picture. Researchers throw compounds at cells to see what happens, and out of this assemble theories that inform the next set of efforts to throw compounds at cells to see what happens. Cells are enormously complex mechanisms, but from these efforts will eventually emerge a field in which any cell can be instructed to act as we want it to - even while within the body.

Stem cell treatments are leading to a greater knowledge of the mechanisms by which senescent cells might be coerced back into a more useful and functional state. Just as the delivery of stem cells causes regeneration by changing the local tissue environment and releasing signals that convince native cells to get back to work, it seems that this may also beneficially influence the balance of signals that leads to greater or lesser levels of cellular senescence. This possibility is illustrated in the following research using cell cultures. When researchers cultured and stressed their cell lines in the presence of signals emitted by stem cells, there was measurably less cellular senescence than was the case without those signals:

Rat Induced Pluripotent Stem Cells Protect H9C2 Cells from Cellular Senescence via a Paracrine Mechanism

Cellular senescence may play an important role in the pathology of heart aging. We aimed to explore whether induced pluripotent stem cells (iPSCs) could inhibit cardiac cellular senescence via a paracrine mechanism.

We collected iPSC culture supernatant as conditioned medium (CM) for the rat cardiomyocyte-derived cell line H9C2. Then we treated H9C2 cells, cultured with or without CM, with hypoxia/reoxygenation to induce cellular senescence and measured senescence-associated β-galactosidase (SA-β-gal) activity, G1 cell proportion and expressionM of the cell cycle regulators p16INK4a, p21Waf1/Cip1 and p53 at mRNA and protein levels in H9C2 cells. In addition, we [measured] concentrations of trophic factors in iPSC-derived CM.

We found that iPSC-derived CM reduced SA-β-gal activity, attenuated G1 cell cycle arrest and reduced the expression of p16INK4a, p21Waf1/Cip1 and p53 in H9C2 cells. Furthermore, the CM contained more trophic factors, e.g. tissue inhibitor of metalloproteinase-1 and vascular endothelial growth factor, than H9C2-derived CM.

[We conclude that] paracrine factors released from iPSCs prevent stress-induced senescence of H9C2 cells by inhibiting p53-p21 and p16-pRb pathways. This is the first report demonstrating that antisenescence effects of stem cell therapy may be a novel therapeutic strategy for age-related cardiovascular disease.

Here is a Russian-language interview with Mikhail Batin of the Science for Life Extension Foundation, following on from the recent 3rd International Conference on the Genetics of Aging and Longevity in Sochi, Russia. The state of automated translation for Russian is still very rough around the edges, so the quoted material below is tidied up somewhat from the original:

Q: But with diseases such as cancer, cardiovascular disease, and diabetes, they occur not only in the old, but also in young people. What are your arguments that old age is a disease?

A: Well, the frequency of cancer in a person of age 70 is 200 times higher than at 20 years. All age-dependent disease incidence increases with age, and grows exponentially. Aging underlies these diseases. We just tend to think that it is normal when a person goes bad, developing poor vision, poor hearing, poor thinking - and this is not normal. Aging is an illness and people die because of it.

Q: Actually, people do not want to grow old, especially women. And those who have enough willpower to lead a healthy lifestyle, eat right, play sports. And experience shows that it is, in general, it helps them to get sick less and live longer. So, maybe that's enough? Need there any special measures to combat aging?

A: It helps, but not so much. Even the person leading a healthy lifestyle does not rule out the use of antibiotics, early diagnosis of diseases, etc. Yes, you need to eat less and move more, but that does not mean you cannot also do something significant, for example, to develop the means of reversing some processes of aging not affected by exercise and diet. The idea of ​​sufficiency is bad, let's instead go ahead and set big goals.

Q: And if people don't want to live long? There was a survey of Americans in which they were asked how much they want to live. Most chose a limit of 80-90 years. And to live to 120 years old is only desired by a few. So what to do - "an iron fist pounding mankind to happiness" or work to educate the public in order to change this position?

A: You know, people often want what other people want. This is common. They do not want to stand out from the masses. So people protect the present state of their world, it's such a conquering conservatism. Yet as soon as the radical possibilities to extend life emerge and become common, people will immediately want to use them. People do not refuse technology, they just do not want to think about making it.

Link: http://translate.google.com/translate?sl=ru&u=http://www.gazeta.ru/science/2014/04/03_a_5970617.shtml

One branch of investigation into the mechanisms and progression of aging uses comparisons between species of differing longevity as a way to identify where to work. The ultimate aim is to narrow down the exact biological differences between short-lived and long-lived species, a process that can probably be simplified by focusing first on the exceptional cases.

Surveys and theorizing of the sort quoted below are a part of the process of deciding which of the thousands of readily available species to study are most likely to yield useful information:

Maximum lifespan in birds and mammals varies strongly with body mass such that large species tend to live longer than smaller species. However, many species live far longer than expected given their body mass. This may reflect interspecific variation in extrinsic mortality, as life-history theory predicts investment in long-term survival is under positive selection when extrinsic mortality is reduced. Here, we investigate how multiple ecological and mode-of-life traits that should reduce extrinsic mortality (including volancy (flight capability), activity period, foraging environment and fossoriality), simultaneously influence lifespan across endotherms.

Using novel phylogenetic comparative analyses and to our knowledge, the most species analysed to date (n = 1368), we show that, over and above the effect of body mass, the most important factor enabling longer lifespan is the ability to fly. Within volant species, lifespan depended upon when (day, night, dusk or dawn), but not where (in the air, in trees or on the ground), species are active. However, the opposite was true for non-volant species, where lifespan correlated positively with both arboreality and fossoriality. Our results highlight that when studying the molecular basis behind cellular processes such as those underlying lifespan, it is important to consider the ecological selection pressures that shaped them over evolutionary time.

Those of you following along over the past decade or so as researchers picked out exceptional species in order to investigate the details of their biochemistry will not be too surprised to see flight linked with longevity. Bats and birds feature prominently in the lists of species with unusual longevity for their size, and there are a range of theories as to how the metabolic demands of flight might lead to the evolution of a longer-lived species.

Link: http://dx.doi.org/10.1098/rspb.2014.0298

Every cell in your body is a busy factory, constantly engaged in turning raw materials into complex proteins via the processes of gene expression, following the blueprints in your DNA. The source of much of the necessary supply of raw materials is the cell itself: a great deal of recycling takes place as damaged proteins and larger structures such as organelles are broken down into constituent molecules that are promptly fed back into the factory process.

This recycling isn't just a matter of obtaining parts: it is quality control for cellular machinery vital to life. Autophagy is the name given to the collection of processes by which unwanted and damaged cellular components are identified and then fed into the furnaces known as lysosomes. A lysosome is a specialized organelle packed with enzymes capable of dismantling near everything it is likely to receive in the course of its duties. It engulfs the refuse and destroys it, producing useful raw materials in the process.

With time, however, our lysosomes do in fact ingest a range of items that they cannot deal with. In our long-lived cells, many of which must last a lifetime, lysosomes become bloated and malfunctioning, packed to the gills with harmful materials collectively known as lipofusin. The ability of cells to keep themselves damage-free and functional deteriorates as a consequence, and this is one of the contributing causes of degenerative aging as a whole. It is particularly important in conditions such as macular degeneration, but a long laundry list of other age-related conditions - many of them ultimately fatal - have lysosomal dysfunction and lipofuscin accumulation noted as contributed causes.

We know that this happens, and we know that it causes great harm, but what can be done to prevent it and reverse it? To answer that question, here is the latest in a series of posts on rejuvenation research by philanthropist Jason Hope.

SENS Research Foundation Targets Lysosomal Aggregates

Cells create waste products and, left unaddressed, these byproducts disable body cells to cause serious illnesses. Scientists at SENS Research Foundation Research Center are currently developing ways to remove these waste products, known as lysosomal aggregates, from cells, in order to restore the cells to health and thereby treat these illnesses or prevent their onset. To understand the nature of the scientists' work, it helpful to create a working analogy that makes understanding lysosomal aggregates easier.

Lysosomal aggregates are like non-biodegradable plastic bags and other garbage rising over the tops of landfills to pollute nearby land. Left unaddressed, unhealthy substances from the garbage disrupt the lives of plants and animals surrounding the landfill to the point of causing disease and death to those organisms. The nature of the illness and disease depends largely on the type of waste polluting the landscape. Plastic bags might entangle a bird, for example, or antifreeze may poison a passing coyote. Each toxin causes a specific effect on a particular organism.

Each particular lysosomal aggregate tends to form in a specific type of body cell. When the amount of aggregate is large enough to interfere with normal cell function, the cell can no longer carry out its function, and as more and more cells of a given type become dysfunctional it leads to illness. Age-related macular degeneration, or AMD, is an excellent example of this action. Special cells in the retina of the eye, known as retinal pigment epithelium or RPE cells, produce the waste material A2E. Many scientists think the accumulation of A2E disables RPE cells to cause the vision loss associated with AMD.

The Lysosomal Aggregates team at SENS Research Foundation Research Center is working to identify optimal A2E-degrading enzymes, and to deliver them directly into the lysosomes in the eye. In their previous work, the team had been able to identify many enzymes capable of stopping A2E in a petri dish but was unable to deliver these enzymes into an actual lysosome in an eye. They are working to develop methods to deliver these enzymes to the lysosomes. One procedure in particular, known as SENS20, works both in vitro and in actual RPE cells, but others may work even better.

Lysosomal aggregates [are also] associated with atherosclerosis, commonly known as hardening of the arteries. Oxidation can cause breakdown of the "bad cholesterol" LDL in the bloodstream. This breakdown increases the levels of 7-ketocholesterol, or 7KC, known to cause the narrowed arteries and poor cardiac function associated with atherosclerosis. Researchers from Rice University are working to develop enzymes that reduce 7KC in hopes of reversing the processes that cause atherosclerosis.

SENS Research Foundation is making great strides in reducing the devastating health effects caused by lysosomal aggregates. With continued research, the scientists hope to someday treat or prevent widespread debilitating illnesses like age-related macular degeneration and atherosclerosis.

A web of correlations links health, longevity, wealth, education, and intelligence. More intelligent and educated people tend to be wealthier. They also tend to live longer. All sorts of sensible causes can be proposed, such as those involving better access to medical services and a better ability to make use of that access, or the education, willpower, and peer pressure to make improved lifestyle choices. Don't get fat, keep exercising, and so forth: over the long term calorie restriction and regular exercise produce benefits to health and life expectancy in the average individual that are large in comparison to that provided by any presently available medical technology. There are less usual suggestions as well, such as the possibility of a biological connection between better health and greater intelligence.

Biology and health is very complex, and there is plenty of room to argue cause versus effect and relative impact even in deceptively simple associations such as these. The data showing these associations is robust, however, and here is another example:

[Economists] crunched the numbers and found that the richer you are, the longer you'll live. [They] parsed this data from the University of Michigan's Health and Retirement Study, a survey that tracks the health and work-life of 26,000 Americans as they age and retire. The data is especially valuable as it tracks the same individuals every two years in what's known as a longitudinal study, to see how their lives unfold.

The good news is that men of all incomes are living longer. Yet the data shows that the life expectancy of the wealthy is growing much faster than the life expectancy of the poor. Here's the sort of detail this remarkable data set can show. You can look at a man born in 1940 and see that during the 1980s, the mid-point of his career, his income was in the top 10% for his age group. If that man lives to age 55 he can expect to live an additional 34.9 years, or to the age of 89.9. That's six years longer than a man whose career followed the same arc, but who was born in 1920. For men who were in the poorest 10%, they can expect to live another 24 years, only a year and a half longer than his 1920s counterpart.

The story is rather different for women. At every income level, for both those born in 1920 and 1940, women live longer than men. But for women, the longevity and income trends are even more striking. While the wealthiest women from the 1940s are living longer, the poorest 40% are seeing life expectancy decline from the previous generation. "At the bottom of the distribution, life is not improving rapidly for women anymore. Smoking stands out as a possibility. It's much more common among women at lower income levels."

Link: http://blogs.wsj.com/economics/2014/04/18/the-richer-you-are-the-older-youll-get/

Researchers have developed an improvement upon sutures that has a range of potential applications beyond merely sealing injuries:

The principle is simple: nanoparticles contained in a solution spread out on surfaces to be glued bind to the gel's (or tissue's) molecular network. This phenomenon is called adsorption. At the same time the gel (or tissue) binds the particles together. Accordingly, myriad connections form between the two surfaces. This adhesion process, which involves no chemical reaction, only takes a few seconds. In their latest, newly published study, the researchers used experiments performed on rats to show that this method, applied in vivo, has the potential to revolutionize clinical practice.

In a first experiment, the researchers compared two methods for skin closure in a deep wound: traditional sutures, and the application of the aqueous nanoparticle solution with a brush. The latter is easy to use and closes skin rapidly until it heals completely, without inflammation or necrosis. The resulting scar is almost invisible.

In a second experiment, still on rats, the researchers applied this solution to soft-tissue organs such as the liver, lungs or spleen that are difficult to suture because they tear when the needle passes through them. At present, no glue is sufficiently strong as well as harmless for the organism. Confronted with a deep gash in the liver with severe bleeding, the researchers closed the wound by spreading the aqueous nanoparticle solution and pressing the two edges of the wound together. The bleeding stopped. To repair a sectioned liver lobe, the researchers also used nanoparticles: they glued a film coated with nanoparticles onto the wound, and stopped the bleeding. In both situations, organ function was unaffected and the animals survived.

"Gluing a film to stop leakage" is only one example of the possibilities opened up by adhesion brought by nanoparticles. In an entirely different field, the researchers have succeeded in using nanoparticles to attach a biodegradable membrane used for cardiac cell therapy, and to achieve this despite the substantial mechanical constraints due to its beating. They thus showed that it would be possible to attach various medical devices to organs and tissues for therapeutic, repair or mechanical strengthening purposes.

Link: http://presse-inserm.fr/en/innovative-strategy-to-facilitate-organ-repair/12253/

The future of cell therapies includes regenerative treatments and tissue engineering, as well as many other possibilities, but it all depends on the development of highly efficient, low-cost ways to generate a ready supply of cells of any given type from a patient's own cells, such as a skin sample. The lower the cost the faster that research progresses today, and the establishment of low-cost methods of generating patient-specific cells is very much required to enable widespread use of affordable therapies tomorrow.

A little more than a decade ago it looked like the best way to create these cell supplies was to work on a technique called somatic cell nuclear transfer (SCNT), in which the nucleus from a patient's cell is introduced into an egg cell that has had its nucleus removed. The result recapitulates some of the early development of a blastocyst from which pluripotent cells can be harvested and developed into any type of human cell. Unfortunately this turned out to be more challenging than expected from a technical point of view, and as you may recall there was in addition a great deal of foolish political intervention that made it even harder to move forward. Then not so long afterwards the techniques for generating induced pluripotent stem (IPs) cells by direct reprogramming were discovered and the majority of the research community jumped ship for that much easier methodology.

Some researchers kept working on the roadblocks preventing implementation of SCNT in human cells, however, and have now finally achieved an initial success with adult human cells. This is the sort of result that can lead to the infrastructure necessary to generate patient-specific cells, but in this case it has more of the feel of the closing of a chapter. The leading edge of the research community now works with induced pluripotency and related forms of direct cell reprogramming, and is making rapid progress with those techniques. Success with SCNT is to be praised, but I think unlikely that it will gather much support in the present environment.

First Embryonic Stem Cells Cloned From A Man's Skin

Last year, scientists in Oregon said they'd finally done it, using DNA taken from infants. Robert Lanza, chief scientific officer at Advanced Cell Technology, says that was an important step, but not ideal for medical purposes. "There are many diseases, whether it's diabetes, Alzheimer's or Parkinson's disease, that usually increase with age," Lanza says. So ideally scientists would like to be able to extract DNA from the cells of older people - not just cells from infants - to create therapies for adult diseases.

"What we show for the first time is that you can actually take skin cells, from a middle-aged 35-year-old male, but also from an elderly, 75-year-old male" and use the DNA from those cells in this cloning process, Lanza says. They injected it into 77 human egg cells, and from all those attempts, managed to create two viable cells that contained DNA from one or the other man. Each of those two cells is able to divide indefinitely, "so from a small vial of those cells we could grow up as many cells as we would ever want."

Scientists use cloning to make stem cells matched to two adults

Lanza and his colleagues said their experiments revealed that some eggs were better at it than others. Researchers used 49 eggs from three women, though eggs from only two of them produced results. "The magic is in the egg," Lanza said.

Lanza said that most stem cell scientists have "jumped on the iPS bandwagon," but he argued that stem cells created by SCNT could still play a vital role in regenerative medicine. He envisions a day when multiple lines of stem cells are kept in banks and made available to patients based on their biological similarity, much the way blood and donor organs are now handled. "If we had these banks, we would have the raw material to do tissue engineering and grow up organs, or to grow up vessels, tendons or whatever you want."

Human Somatic Cell Nuclear Transfer Using Adult Cells

Derivation of patient-specific human pluripotent stem cells via somatic cell nuclear transfer (SCNT) has the potential for applications in a range of therapeutic contexts. However, successful SCNT with human cells has proved challenging to achieve, and thus far has only been reported with fetal or infant somatic cells. In this study, we describe the application of a recently developed methodology for the generation of human embryonic stem cells via SCNT using dermal fibroblasts from 35- and 75-year-old males. Our study therefore demonstrates the applicability of SCNT for adult human cells and supports further investigation of SCNT as a strategy for regenerative medicine.

This is an interesting view on the later stages Parkinson's disease that seems fairly orthogonal to the present mainstream focus on α-synuclein and its removal:

The cause of neuronal death in Parkinson's disease is still unknown, but a new study proposes that neurons may be mistaken for foreign invaders and killed by the person's own immune system. "This is a new, and likely controversial, idea in Parkinson's disease; but if true, it could lead to new ways to prevent neuronal death in Parkinson's that resemble treatments for autoimmune diseases."

For decades, neurobiologists have thought that neurons are protected from attacks from the immune system, in part, because they do not display antigens on their cell surfaces. "That idea made sense because, except in rare circumstances, our brains cannot make new neurons to replenish ones killed by the immune system. But, unexpectedly, we found that some types of neurons can display antigens."

Cells display antigens with special proteins called MHCs. Using postmortem brain tissue donated to the Columbia Brain Bank by healthy donors [researchers] first noticed - to their surprise - that MHC-1 proteins were present in two types of neurons. These two types of neurons - one of which is dopamine neurons in a brain region called the substantia nigra - degenerate during Parkinson's disease.

[The researchers] conducted in vitro experiments with mouse neurons and human neurons created from embryonic stem cells. The studies showed that under certain circumstances - including conditions known to occur in Parkinson's - the neurons use MHC-1 to display antigens. Among the different types of neurons tested, the two types affected in Parkinson's were far more responsive than other neurons to signals that triggered antigen display. The researchers then confirmed that T cells recognized and attacked neurons displaying specific antigens.

"Right now, we've showed that certain neurons display antigens and that T cells can recognize these antigens and kill neurons, but we still need to determine whether this is actually happening in people. We need to show that there are certain T cells in Parkinson's patients that can attack their neurons. This idea may explain the final step. We don't know if preventing the death of neurons at this point will leave people with sick cells and no change in their symptoms, or not."

Link: http://newsroom.cumc.columbia.edu/blog/2014/04/17/parkinsons-autoimmune-disease/

Targeted delivery of drugs and proteins to modify metabolism and cell behavior may in the future be accomplished by engineered cells. Cells already do a great many useful things, so why reinvent the wheel when there is existing machinery that can be adapted to new purposes? This is a line of research with the potential to radically change the face of medicine and our own biology, leading to a future in which most of us have large numbers of enhanced and altered cells in every organ, monitoring and reacting to local conditions in order to help maintain the body against the processes of aging and disease far more effectively than our present evolved mechanisms can manage.

A synthetic biology team has created a new technology for modifying human cells to create programmable therapeutics that could travel the body and selectively target cancer and other sites of disease. "The project addressed a key gap in the synthetic biology toolbox. There was no way to engineer cells in a manner that allowed them to sense key pieces of information about their environment, which could indicate whether the engineered cell is in healthy tissue or sitting next to a tumor."

The end result is a protein biosensor that sits on the surface of a cell and can be programmed to sense specific external factors. For example, the engineered cell could detect big, soluble protein molecules that indicate that it's next to a tumor. When the biosensor detects such a factor, it sends a signal into the engineered cell's nucleus to activate a gene expression program, such as the production of tumor-killing proteins or chemicals. Since this toxic program would be activated only near tumor cells, such an approach could minimize side effects as well as improve therapeutic benefits.

Called a Modular Extracellular Sensor Architecture (MESA), the biosensor platform is completely self-contained so that several different biosensors can be present in a single cell without interfering with one another, allowing bioengineers to build increasingly sophisticated functional programs. The platform is also highly modular, enabling the biosensors to be customized to recognize factors of relevance to various patients' needs. "By linking the output of these biosensors to genetic programs, one can build in a certain logical command, such as 'turn the output gene on when you sense this factor but not that factor.' In that way, you could program a cell-based therapy to specify which cells it should kill."

Link: http://www.mccormick.northwestern.edu/news/articles/2014/04/building-smart-cell-based-therapies.html

In these years we stand at the crossroads for human longevity. A long, slow, and largely unintentional upward trend in health and life expectancy has been running for near two hundred years now, caused by increases in wealth and technological progress, each driving the other. Increased longevity in turn helps to increase wealth and speed progress: all of these benefits are individually but facets of the whole gem.

The medical science of the past has blossomed into full-bored biotechnology, and change and growth in this field has become exceptionally rapid over the past twenty years, mirroring progress in computing hardware and software development. Scientists can now individually carry out tasks in a few months that would have required an entire laboratory staff and years of labor in the early 1990s, if it even possible at all back then. Many researchers advocate that now is the time to approach aging as the medical condition it is, to stop treating it with religious awe, as though it were some mystical thing that stands outside of the rest of medicine, and use the tools we have to make it go away.

Some of these researchers are engaged in a form of networked disruptive innovation within aging research that they hope will eventually displace the present mainstream. This is how progress happens in human organizations: the heretics agitate and prove themselves correct via research and development until such time as the old mainstream gives in and agrees that they were right all along.

That is the high road ahead from the crossroads. Upon this road the research community abandons its reluctance to treat aging, the public comes to think of aging in the same way as they presently think of cancer, research funding flows, and great progress is made towards means of halting and reversing the underlying causes of aging. Age-related diseases start to become things of the past, like widespread cholera and tuberculosis, just a few decades past this turning point.

But there are other roads ahead. Disruptive movements don't always win in their first spin around the block. The old guard can last for decades past their time, poisoning the well and ensuring that progress remains slow. Regulation can also suppress new paradigms, and indeed entire fields of human endeavor, for decades at a time - and medical development certain does not lack for obstructive bureaucracy. The treatment of aging is actually forbidden in the US by regulatory fiat, and there is no effective path towards gaining approval for the commercial application of potential therapy to intervene in the causes of aging. This is well known and the chilling effect percolates all the way back up the chain of research and development to create difficulties in fundraising for such goals.

So there are low roads to either side away from the crossroads. These are largely the ruts of status quo and slow progress in which billions of dollars continue to go towards research that increases our knowledge of the details of the molecular dance that is aging, but which can offer no plausible hope or promise of significantly extending life soon enough to matter to us. Life spans continue to edge upward, but we all die just a little older than our parents, and suffer all of the same age-related conditions, just a little less painfully. It is the road on which the study of aging for the sake of knowledge rather than action continues to dominate, and in which the public continues to be largely disinterested in extended healthy life or avoidance of the diseases of aging: marching towards death in their tens of millions, but never raising a hand to do anything about it.

This possibility is why advocacy for the better options in longevity science and human rejuvenation must exist. Without disruptive change in the public perception of aging and medicine for aging, without disruptive change in the attitudes of the scientific community, then the status quo is what we will get - and it will let us die by failing to take full advantage of all that can be done in this age of biotechnology.

The paper quoted below is a joint effort by Jan Vijg and Aubrey de Grey, both scientists who see the potential for big changes to the field in the years ahead and would like to see those changes come about. It isn't open access, unfortunately, but the abstract is a good encapsulation of the crossroads we presently find ourselves at.

Innovating Aging: Promises and Pitfalls on the Road to Life Extension

One of the main benefits of the dramatic technological progress over the last two centuries is the enormous increase in human life expectancy, which has now reached record highs. After conquering most childhood diseases and a fair fraction of the diseases that plague adulthood, medical technology is now mainly preoccupied by age-related disorders. Further progress is dependent on circumventing the traditional medical focus on individual diseases and instead targeting aging as a whole as the ultimate cause of the health problems that affect humankind at old age.

In principle, a major effort to control the gradual accumulation of molecular and cellular damage - considered by many as the ultimate cause of intrinsic aging - may rapidly lead to interventions for regenerating aged and worn-out tissues and organs. While considered impossible by many, there really is no reason to reject this as scientifically implausible. However, as we posit, it is not only scientific progress that is currently a limiting factor, but societal factors that hinder and may ultimately prevent further progress in testing and adopting the many possible interventions to cure aging.

Here is an open access paper that covers some of the challenges that have faced the interpretation of just how and why it is that mitochondria have an important role in the aging process. The mitochondrial free radical theory of aging has been broadly considered, in several forms, but as for just about every theory of aging early models turned out to be too simple and straightforward. The reality on the ground is more complex, which is why you'll find a mass of data that supports this theory and another mass of data that contradicts it:

Since its inception more than four decades ago, the Mitochondrial Free Radical Theory of Aging (MFRTA) has served as a touchstone for research into the biology of aging. The MFRTA suggests that oxidative damage to cellular macromolecules caused by reactive oxygen species (ROS) originating from mitochondria accumulates in cells over an animal's lifespan and eventually leads to the dysfunction and failure that characterizes aging.

A central prediction of the theory is that the ability to ameliorate or slow this process should be associated with a slowed rate of aging and thus increased lifespan. A vast pool of data bearing on this idea has now been published. ROS production, ROS neutralization and macromolecule repair have all been extensively studied in the context of longevity. We review experimental evidence from comparisons between naturally long- or short-lived animal species, from calorie restricted animals, and from genetically modified animals and weigh the strength of results supporting the MFRTA.

Viewed as a whole, the data accumulated from these studies have too often failed to support the theory. Excellent, well controlled studies from the past decade in particular have isolated ROS as an experimental variable and have shown no relationship between its production or neutralization and aging or longevity. Instead, a role for mitochondrial ROS as intracellular messengers involved in the regulation of some basic cellular processes, such as proliferation, differentiation and death, has emerged. If mitochondrial ROS are involved in the aging process, it seems very likely it will be via highly specific and regulated cellular processes and not through indiscriminate oxidative damage to macromolecules.

Link: http://dx.doi.org/10.1186/2046-2395-3-4

A few things are of interest in this survey, with one being that a majority of people don't like specific instances of societal change resulting from technological advances if asked about them, which isn't much of a surprise given human nature. Another is that extended human longevity shows up as a desired goal for a larger minority than has been the case in the past - I would expect to see growth in this number when measured, given the events of the past few years. This being a survey there is little distinction made between the fantastical drawn from science fiction and the plausible drawn from science, which is unfortunate, but it is still worth a look.

The American public anticipates that the coming half-century will be a period of profound scientific change, as inventions that were once confined to the realm of science fiction come into common usage. This is among the main findings of a new national survey by The Pew Research Center, which asked Americans about a wide range of potential scientific developments - from near-term advances like robotics and bioengineering, to more "futuristic" possibilities like teleportation or space colonization.

Asked to describe in their own words the futuristic inventions they themselves would like to own, the public offered three common themes: 1) travel improvements like flying cars and bikes, or even personal space crafts; 2) time travel; and 3) health improvements that extend human longevity or cure major diseases. One in ten Americans (9%) list the ability to travel through time as the futuristic invention they would like to have, and an identical 9% would want something that improved their health, increased their lifespan, or cured major diseases.

At the same time, many Americans seem to feel happy with the technological inventions available to them in the here and now - 11% answered this question by saying that there are no futuristic inventions that they would like to own, or that they are "not interested in futuristic inventions." And 28% weren't sure what sort of futuristic invention they might like to own.

A substantial majority of Americans (81%) believe that within the next 50 years people needing an organ transplant will have new organs custom made for them in a lab. Belief that this development will occur is especially high among men, those under age 50, those who have attended college, and those with relatively high household incomes. But although expectations for this development are especially high within these groups, three-quarters or more of every major demographic group feels that custom organs are likely to become a reality in the next half-century.

Link: http://www.pewinternet.org/2014/04/17/us-views-of-technology-and-the-future/

The research community is very interested in a reliable method of measuring biological age: not how old you are in years, but how far along you are in the aging process, how much damage has accumulated in cells and macromolecules and how well or poorly your organs and other systems are reacting to that damage. Such a measurement of age is known as a biomarker of aging, and while there are all sorts of measures that correlate fairly well with biological age - good enough for large statistical studies to use in order to mine data for meaning - there is not yet a good, accurate, standardized way to run some numbers and use them as a measure of how aged you are.

Why is this important? Principally because it costs an enormous amount of money to assess the ability of any treatment to slow or reverse aspects of aging and thereby extend healthy life. The only way to know at present is to wait and see, and even in mice that means years and millions of dollars. But what if we could be fairly sure that by taking some measurements after a single treatment, researchers could predict with a high degree of accuracy whether or not aging is reversed or slowed and future life span thus extended? If achieved, that would mean ten times as much work on assessment of possible therapies in mice could take place for a given amount of funding. That's a big deal, even without considering that the only practical way to determine whether a putative life-extending treatment actually works or not in humans is to establish an accurate biomarker of aging based on short term, immediate measures. It simply isn't practical to take the wait and see approach for decades.

Personally I rather hope that the arrival of an accepted biomarker of aging will do much to damp down the level of fraud and misinformation that spills forth from the "anti-aging" marketplace. There's always someone trying to sell a lie to the masses, and it is unfortunate that their voices are so very much louder than those of the scientific community. Given that pretty much nothing sold on the market today will move the needle at all on human life span, and nothing is yet shown to even match the benefits of calorie restriction or exercise, I look forward to a way to demonstrate this unequivocally.

In any case, in recent years the measurement of patterns of DNA methylation has shown promise as a potential biomarker of aging. DNA methylation is a part of the process of epigenetic changes that take place in response to circumstances, altering levels of proteins produced by cells. Our biology is essentially an assembly of fluid machines in which the controlling switches and levers are the levels of various proteins in circulation. Everything reacts to everything else, in a complex never resting dance of overlapping feedback loops at every level. From this, however, patterns emerge. Aging takes a broadly similar path for all of us, and thus there are some broadly similar reactions to its damage in our cells. The trick is having enough computational power and the right tools of biotechnology to be able to pull out those patterns from the thousands of unrelated variations in DNA methylation that exist in all our tissues.

This is a popular science piece, but still has some interesting information on how things are going with the DNA methylation approach to generating a biomarker of aging that might prove useful as a measure of the effectiveness of future treatments for aging:

Biomarkers and ageing: The clock-watcher

Horvath's clock emerges from epigenetics, the study of chemical and structural modifications made to the genome that do not alter the DNA sequence but that are passed along as cells divide and can influence how genes are expressed. As cells age, the pattern of epigenetic alterations shifts, and some of the changes seem to mark time. To determine a person's age, Horvath explores data for hundreds of far-flung positions on DNA from a sample of cells and notes how often those positions are methylated - that is, have a methyl group attached.

He has discovered an algorithm, based on the methylation status of a set of these genomic positions, that provides a remarkably accurate age estimate - not of the cells, but of the person the cells inhabit. White blood cells, for example, which may be just a few days or weeks old, will carry the signature of the 50-year-old donor they came from, plus or minus a few years. The same is true for DNA extracted from a cheek swab, the brain, the colon and numerous other organs. This sets the method apart from tests that rely on biomarkers of age that work in only one or two tissues, including the gold-standard dating procedure, aspartic acid racemization, which analyses proteins that are locked away for a lifetime in tooth or bone.

Others began downloading the epigenetic-clock program from Horvath's website to test it on their own data. Marco Boks at the University Medical Centre Utrecht in the Netherlands applied it to blood samples collected from 96 Dutch veterans of the war in Afghanistan aged between 18 and 53. The correlation between predicted and actual ages was 99.7%, with a median error measured in months. At Zymo Research, a biotechnology company in Irvine, California, Wei Guo and Kevin Bryant wondered whether the program would work on a set of urine samples Zymo had collected from 11 men and women aged between 28 and 72. The correlation was 98%, with a standard error of just 2.7 years.

[Researchers] expect that the most interesting use of the clock will be to detect 'age acceleration': discrepancies between a person's epigenetic and chronological ages, either overall or in one particular part of their body. Horvath says that recent work has found that people with HIV who have detectable viral loads appear older, epigenetically, than healthy people or those with HIV who have suppressed the virus. Another study, not yet published, observes that some tissues show significant age acceleration in morbidly obese people.