Antisenescence Effects of Stem Cell Therapies
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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.

Working to Remove the Heaps of Unburnable Cellular Trash that Contribute to Degenerative Aging
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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.

Somatic Cell Nuclear Transfer Achieved in Adult Human Cells
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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.
The Crossroads for Human Longevity
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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.

An Update on DNA Methylation Patterns as a Biomarker of Aging
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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.