FIGHT AGING! NEWSLETTER
April 20th 2015
Fight Aging! provides a weekly digest of news and commentary for thousands of subscribers interested in the latest longevity science: progress towards the medical control of aging in order to prevent age-related frailty, suffering, and disease, as well as improvements in the present understanding of what works and what doesn't work when it comes to extending healthy life. Expect to see summaries of recent advances in medical research, news from the scientific community, advocacy and fundraising initiatives to help speed work on the repair and reversal of aging, links to online resources, and much more.
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- An Introduction to the Redox Theory of Aging
- Protein Modification as a Biomarker of Aging
- Metchnikoff Day, an Opportunity to Promote the Study of Aging and Longevity
- A Brief Introduction to Model Organisms in Aging Research
- A Little mTOR Triumphalism
- Latest Headlines from Fight Aging!
- On Telomere Length and Cancer Risk
- Increased Production of Hsp22 Extends Life Span in Flies
- Evidence for Long Term Memory to Survive Vitrification in Nematode Worms
- Lifespan of Mice and Primates Correlates with Immunoproteasome Expression
- Stem Cell Therapy Slows the Onset of Macular Degeneration
- Tomorrow Will Be Different From Today
- Efforts to Quantify the Benefits of Different Levels of Exercise
- The Old are Slowly Becoming Younger
- The Low-Hanging Fruit of Cell Therapy Development
- Autologous Fat Cell Transplant Reduces Osteoarthritis Symptoms
AN INTRODUCTION TO THE REDOX THEORY OF AGING
There are a lot of theories of aging. Simply outlining the numerous categories of theory and offering a few comments as to which of the better known theories are currently well supported, dead, or disputed is a fairly detailed undertaking. It is hard to avoid delving into the history of the field when explaining how the research community ended up where it is today in terms of the various camps. There are evolutionary theories that seek to explain how aging came about, there are damage accumulation theories of aging, programmed aging theories that see aging as an evolved program of individual self-destruction, and any number of single-mechanism theories based on one or more researchers generalizing their narrow area of familiarity out to the whole body. Usually overgeneralizing, to be truthful: aging is a complex mix of at least initially independent causes, not one single mechanism.
The diversity of theories is really a reflection of just how much yet remains uncertain in the study of human biochemistry. In the sciences you will find theories proliferating wildly wherever there are few definitive answers due to the sheer complexity of the systems under examination. Inventive exploration and theorizing continues until some faction can prove themselves correct and everyone else wrong beyond any reasonable doubt. My expectation is that damage accumulation theories are mostly correct, that the SENS proposals contain a fair digest of which damage is fundamental and important rather than secondary or unimportant, and proof beyond any reasonable doubt will be provided in animal studies that test various SENS or SENS-like implementations of rejuvenation treatments. Large degrees of healthy life extension in the laboratory will prove the point faster and more cost-effectively than any research programs aiming to find and catalog all of the relevant mechanisms involved. This process is well underway for relevant areas in stem cell research, and has of late just begun for the clearance of senescent cells. Repair of other important forms of damage is yet to be earnestly tested: removal of various forms of metabolic waste, for example, such as amyloids and lipofuscin.
It has long been noted in parts of the aging research community that the activity of most of the researchers involved bears some resemblance to the tale of the blind men and the elephant. Each feels but a part of the whole, and that is their conception of the beast. Modern medical life science, even just a small field within the whole, is so complex and vast that researchers specialize in tiny slices of it, having only a superficial familiarity at best with everything else. It is often the case that when these researchers apply their knowledge to aging in isolation, without networking extensively, they propose theories that only cover a fraction of the biochemistry that the broader aging research community has identified as being relevant and involved in aging.
Redox theory of aging
Hundreds of philosophers and scientists have addressed the topics of longevity and aging, and many theories have been advanced. These have been recently reviewed, and I make no attempt to further summarize these important contributions. Rather, the present article provides a conceptual review based upon the emerging concept that redox systems function as a critical interface between the genome and the exposome. Relying extensively upon emerging understanding of redox systems biology, acquired epigenetic memory systems, and deductive reasoning, a simple theory is derived that aging is the decline of the adaptive interface of the functional genome and exposome that occurs due to cell and tissue differentiation and cumulative exposures and responses of an organism. This theory is not limited to redox processes but has a redox-dependent character due to the over-riding importance of electron transfer in energy supply, defense, reproduction and molecular dynamics of protein and cell signaling.
Several years ago, I presented a redox hypothesis of oxidative stress in which I concluded that oxidative stress is predominantly a process involving 2-electron, non-radical reactions rather than commonly considered 1-electron, free radical reactions. The central arguments were that (1) experimental measures showed that non-radical flux substantially exceeds free radical flux under most oxidative stress conditions, (2) radical scavenger trials in humans failed to show health benefits, and (3) normal cell functions involving sulfur switches are readily disrupted by non-radical oxidants. The redox hypothesis is thus founded upon the concept that oxidative stress includes disruption of redox circuitry in addition to the macromolecular damage resulting from an imbalance of prooxidants and antioxidants.
The redox hypothesis of oxidative stress contained four postulates:
1. All biologic systems contain redox elements [e.g., redox-sensitive cysteines], which function in cell signaling, macromolecular trafficking and physiologic regulation.
2. Organization and coordination of the redox activity of these elements occurs through redox circuits dependent upon common control nodes (e.g., thioredoxin, GSH).
3. The redox-sensitive elements are spatially and kinetically insulated so that "gated" redox circuits can be activated by translocation/aggregation and/or catalytic mechanisms.
4. Oxidative stress is a disruption of the function of these redox circuits caused by specific reaction with the redox-sensitive thiol elements, altered pathways of electron transfer, or interruption of the gating mechanisms controlling the flux through these pathways.
The current article represents an extension and development of these concepts into a redox theory of aging. This redox theory is not exclusively limited to redox reactions but rather emphasizes the key role of electron transfer in supporting central energy currencies (ATP, phosphorylation, acetylation, acylation, methylation and ionic gradients across membranes) and providing the free energy to support metabolism, cell structure, biologic defense mechanisms and reproduction. Importantly, improved understanding of the integrated nature of redox control and signaling in complex, multicellular organisms provide a foundation for this generalized theory.
PROTEIN MODIFICATION AS A BIOMARKER OF AGING
The development of fairly consistent, accurate means to measure biological age - as opposed to chronological age - from a tissue sample is an important thread in aging research. Aging is a process of damage accumulation, and rejuvenation would be achieved through damage repair. Research and development aimed at significant extension of healthy life span can only become cost-effective given good ways to measure damage, however. There must be some reliable means to quickly assess the results of a treatment that claims a degree of rejuvenation through the partial repair of a specific form of cellular or molecular damage. In some cases this might seem easy. Take senescent cell clearance, for example: you run the therapy in mice, and compare a range of measures known to scale by senescent cell count in tissue samples before and after the treatment regimen. However, all that really tells you is how well the therapy clears senescent cells. All aspects of biology interact with one another, and age is a global phenomenon. To determine how aged an individual is and how effective a treatment might be when it comes to the practical outcome of additional healthy life span added there is presently little to be done other than wait and see.
The biggest challenge in the development of life-extending therapies is funding and cost. On the one hand there is far too little funding directed towards finding ways to treat aging. On the other hand effectively evaluating an alleged means of treating aging currently requires life span studies, and even in mice that takes far too long and costs far too much to be done casually. If there were standardized, quick and easy markers of physiological age that could be assessed before and after a treatment, then this research and development might be able to proceed ten times as rapidly, and evaluation of possible therapies would be open to far more research groups. There are many, many more laboratories with the capacity and funding to carry out a speculative cheap study versus a speculative expensive study.
All of this is to explain why there is considerable interest in developing a cheap biomarker of aging that can reliably assess physiological age from a tissue sample. No-one wants to run a five year mouse study if there is a ten minute alternative that produces an answer of about the same accuracy. That ten minute alternative doesn't yet exist, but some lines of research seem promising, such as work on DNA methylation patterns that appear to be fairly consistent between individuals over the course of aging. There is also the suggestion that the approach should be to measure the fundamental forms of damage thought to cause aging - but all of them, not just the one being treated by the therapy under consideration. At the present time that might be more onerous than finding a good set of secondary consequences that are reactions to damage, such as epigenetic changes.
The open access paper linked below covers a fairly wide range of topics. The structures of our cells and tissues are built of proteins, and these proteins are constantly damaged and replaced. Many varied mechanisms toil constantly to remove proteins and cellular components as soon as they show damage or dysfunction. Nonetheless the difference between young tissue and old tissue is that old tissues have far more damage: misfolded proteins, malfunctioning structures inside cells, metabolic waste products such as advanced glycation endproducts (AGEs) gumming together structures in between cells, and on and so forth. The damage leaks through, and even damage repair mechanisms are not invulnerable; they falter with age due to much the same set of issues as causes dysfunction elsewhere. In the future repair technologies, such as those outlined in the SENS proposals, will bring about rejuvenation by reversing these forms of damage. Since these issues are a part of full set of causes of aging they are also potential markers of aging.
Protein modification and maintenance systems as biomarkers of ageing
Changes in the abundance and post-translational modification of proteins and accumulation of some modified proteins have been proposed to represent hallmarks of biological ageing. Non-enzymatic protein glycation is a common post-translational modification of proteins in vivo, resulting from reactions between glucose or its metabolites and amino groups on proteins, this process is termed "Maillard reaction" and leads to the formation of advanced glycation endproducts (AGEs). During normal ageing, there is accumulation of AGEs of long-lived proteins such as collagens and several cartilage proteins. AGEs, either directly or through interactions with their receptors, are involved in the pathophysiology of numerous age-related diseases, such as cardiovascular and renal diseases and neurodegeneration.
Beside protein glycation, it is also well known that levels of oxidised proteins increase with age, due to increased protein damage induced by reactive oxygen species (ROS), decreased elimination of oxidized protein (i.e. repair and degradation), or a combination of both. Since the proteasome is in charge of both general protein turnover and removal of oxidized protein, its fate during ageing has received considerable attention, and evidence has been provided for impairment of the proteasome function with age in different cellular systems. Thus, these protein maintenance systems may also be viewed as potential biomarkers of ageing.
It is expected that a combination of several biomarkers will provide a much better tool to measure biological age than any single biomarker in isolation. For the most part, the markers based on proteins and their modifications that have been chosen are directly related with mechanistic aspects of the ageing process. Indeed, they are relevant to such important physiological features such as protein homeostasis and glycoprotein secretion that have been previously documented as being altered with age. Therefore, it is expected that they may be less influenced by other factors not necessarily related with ageing.
METCHNIKOFF DAY, AN OPPORTUNITY TO PROMOTE THE STUDY OF AGING AND LONGEVITY
Élie Metchnikoff was a noted figure in the first days of modern immunology, with much of his most important work carried out in the closing decades of the 19th century. He is credited with coining the term gerontology for the study of aging, and was the author of The Prolongation of Life: Optimistic Studies - which through the miracles of modern technology one can now read online for free. I strongly recommend perusing the section entitled "Should We Try to Prolong Human Life?" as it shows how little arguments over the use of medicine to enhance human longevity have changed in the past century:
Although the duration of the life of man is one of the longest amongst mammals, men find it too short. From the remotest times the shortness of life has been complained of, and there have been many attempts to prolong it. Ought we to listen to the cry of humanity that life is too short and that it would be well to prolong it? Would it really be for the good of the human race to extend the duration of the life of man beyond its present limits? Already it is complained that the burden of supporting old people is too heavy, and statesmen are perturbed by the enormous expense which will be entailed by State support of the aged.
If the question were merely one of prolonging the life of old people without modifying old age itself, such considerations would be justified. It must be understood, however, that the prolongation of life would be associated with the preservation of intelligence and of the power to work. In the earlier parts of this book I have given many examples which show the possibility of useful work being done by persons of advanced years. When we have reduced or abolished such causes of precocious senility as intemperance and disease, it will no longer be necessary to give pensions at the age of sixty or seventy years. The cost of supporting the old, instead of increasing, will diminish progressively.
If attainment of the normal duration of life, which is much greater than the average life to-day, were to over-populate the earth, a very remote possibility, this could be remedied by lowering the birth-rate. Even at the present time, while the earth is far from being too quickly peopled, artificial limitation of the birth-rate takes place perhaps to an unnecessary extent.
Members of the energetic European grassroots community of longevity advocates propose to celebrate Metchnikoff's anniversary each year, and given his views and his work in medicine rightfully so, I say. That date is May 15th, and this year marks the 170th anniversary of Metchnikoff's birth. This initiative joins many others from past years, such as working to make celebrate the UN International Day of Older Persons as Longevity Day, all of which aim to raise awareness and build support for serious scientific efforts to treat and control degenerative aging.
Good advocacy is made up of many varied initiatives, year after year, for who knows which approach will go on to become a great success. Good advocacy is a matter of continually and inventively striving to deliver our message to ever more listeners, to persuade that next supporter, to raise that next dollar to fund the research that matters. The more that is done the easier it becomes: success attracts success, and every small gain matters.
May 15, 2015 - 170th anniversary of Élie Metchnikoff - the founder of gerontology
There is a tradition to celebrate the anniversaries of great persons (scientists, artists, writers, politicians, generals) to promote the area of their activity and popularize their ideology. It may be hoped that, in this year, the anniversary of Metchnikoff will serve to promote and popularize the science and ideology of healthy life extension, including the state level. The "Metchnikoff Day" can provide an impulse for organizing topical meetings and conferences, a stimulus for research, and publications in the media, dedicated to Metchnikoff's legacy and continuation of his life work - the study of aging and longevity. This may play a positive role not only for the advancement and popularization of research of aging and healthy longevity, but also for the promotion of optimism, peace and cooperation.
In view of the immense significance of degenerative aging processes for the emergence of virtually all diseases, both communicable and non-communicable, and in view of the accelerating development of potential means to intervene into and ameliorate these processes for the sake of achieving healthy longevity, Metchnikoff's pioneering contribution to this field assumes an ever greater global significance. The world is rapidly aging, threatening grave consequences for the global society and economy, while the rapidly developing biomedical science and technology stand in the first line of defense against the potential threat. These two ever increasing forces bring gerontology, describing the challenges of aging while at the same time seeking means to address those challenges, to the central stage of the global scientific, technological and political discourse. At this time, it is necessary to honor Metchnikoff, who stood at the origin of gerontological discourse, not just as a scientific field, but as a social and intellectual movement.
Currently events in honor of the Metchnikoff Day are being planned in Kiev, Ukraine, on behalf of the Kiev Institute of Gerontology of the Ukrainian Academy of Medical Sciences; St. Petersburg, Russia, on behalf of the Gerontological Society of the Russian Academy of Sciences and I.I. Mechnikov North-Western State Medical University; in Moscow on behalf of the National Research Center for Preventive Medicine of the Ministry of Healthcare of the Russian Federation and the Russian Longevity Alliance; Larnaca, Cyprus, on behalf of the ELPIs Foundation and the Cyprus Neuroscience and Technology Institute; Oxford, UK, on behalf of the Oxford University Scientific Society and Biogerontology Research Foundation; in Ramat Gan, Israel, on behalf of the Israeli Longevity Alliance and the International Society on Aging and Disease (Israel). It may be hoped that, following these examples, more events and publications will be held around the world in honor of this day.
A BRIEF INTRODUCTION TO MODEL ORGANISMS IN AGING RESEARCH
The varied approaches to research developed over past decades by the aging research community are driven by two things: firstly that we live for a long time, and secondly the absence of a way to accurately determine an individual's biological age. The only way to measure the effects of potential treatments is to carry out life span studies, and in humans that is impractical to say the least. Thus research into aging and longevity starts with short-lived animals such as nematode worms and flies: exploration and experimentation takes place using these species because life span studies can be carried out in a suitably short period of time to make progress. Promising work moves to mice, where life span studies can last for five years and cost millions. Only later do potential treatments make it to human clinical trials, if at all. This is all much the same as most modern medical research; the process of discovery and development moves incrementally from a state of being far from human biology and cheap to work on to a state of being close to human biology and very expensive to work on.
To a surprising degree the fundamental biology of cells, regulation of metabolism, and mechanisms of aging are similar in even very widely separated species. Aging and many of its interesting epicycles such as the calorie restriction response appeared very early in evolutionary history, a long way down in the tree of life. Thus research in lower animals can still be relevant to human cellular biochemistry, and provide insight into human aging. Nonetheless, worms are not mice and mice are not people. The cost of investigative research that starts with other species is that there is a fair degree of failure when translating promising work over to mammals, and yet more failure when moving from short-lived mammals such as mice to long-lived mammals such as humans. That is acceptable given that the alternative is no research at all, as all studies would be prohibitively expensive to carry out.
Another aspect of research into aging and its associated medical conditions is that genetically altered lineages of laboratory animals are frequently employed. The reasons for this are again economic at root. If you want to study a specific condition, such as old age for example, it is more cost-effective to work with mice that suffer from a DNA repair deficiency that mimics some aspects of accelerated aging than it is to work with normal mice. More research can be carried out more rapidly with accelerated aging mice, even when accounting for the fact that a significantly greater fraction of the results will be irrelevant to normal aging. The same applies to the many different animal models of specific age-related diseases: these are all loose replicas intended to share some characteristics of the disease as it occurs in humans, but under the hood they are not the same thing at all. Animal models are a way to make progress in a cost-effective manner, not an accurate rendition. These things are always worth bearing in mind when reading research results based on animal studies.
Do Model Animals Tell Us Anything about Human Aging?
Using model animals in gerontological studies has yielded an enormous wealth of useful information about the mechanisms of human aging and longevity. Animal models were crucial in identifying the conserved pathways that regulate human aging. Model organisms are fundamental for aging research, because there are serious limitations of using human subjects, such as the length of lifespan, genetic heterogeneity and vast differences in environmental influences. The shape of survival curves represents the health of the organism over time. Model organisms display significantly different lifespans, however the survival curves resemble those of humans quite remarkably.
Yeasts have been instrumental in identifying the major conserved aging pathways shared among a large variety of species. Despite the fact that yeast is a unicellular organism that has significant differences in its genetic pathways with humans, the advantages of using yeast as an aging model include their fast growth, low cost and easy storage and maintenances of organism strains. Over the years researchers have developed a broad variety of genetic manipulations that make yeast a powerful tool in the hands of an aging biologist.
The roundworm Caenorhabditis elegans is a powerful model for studying aging due to its short lifespan. It is easy to culture and maintain strains because nematodes can be kept frozen and suffer no apparent damage upon thawing. The animals are optically transparent and can be used in high-throughput automated experiments, which makes them a perfect tool for answering the most pressing questions in biology of aging. However, there are obvious drawbacks of using C. elegans as a model for human aging. They are evolutionary distant from humans, lack tissues like brain, blood, they don't have internal organs and are post-mitotic, meaning that nematodes lack the ability to regenerate their tissues and are limited in serving as a model of aging of highly proliferative tissues.
Fruit fly D.melanogaster
Fruit flies have many advantages as a model system for aging studies. They have a relatively short lifespan of 60-80 days, which is more than that of a nematode, but compared to them drosophila have more distinct tissues and organs including the brain, eyes, kidney, liver and heart. Fruit flies have proliferating stem cell populations in their guts. Flies share about 60% of disease-related genes with humans, which makes them a desirable model also given their low cost and easy handling. However, maintaining a transgenic strain is more costly and labor-heavy, since whole flies cannot be frozen and thawed without damage.
Hydra is definitely not the most popular model organism, but it might be overlooked quite groundlessly. Hydras are notorious for their negligible senescence. This very fact makes them a very desirable system to study. In fact, there is no apparent senescence in asexually reproducing hydras, yet the signs of aging can be seen after the organism reproduces sexually. Another overlooked fact is that hydras share 6071 genes with humans, whereas fruit flies have 5696 genes in common with humans, and nematodes - only 4751. Among the known human aging-related genes at least 80% are shared with hydra.
The most widely used fish model is the zebrafish D.rerio. It lives for about 2-3 years, which is not particularly beneficial, because its lifespan is similar of rodents, but it is more evolutionary distant from humans. Nonetheless, zebrafish has a remarkable ability to regenerate its tissues, which is an advantage for elucidating the mechanisms of tissue regeneration and longevity. Another fish may be a more promising laboratory model for aging - turquoise killifish Nothobranchius furzeri. Killifish is one of the shortest-lived vertebrate with a lifespan of only 13 weeks. Its small size and high fecundity offer a considerable advantage in terms of reducing laboratory costs on housing and maintenance.
Mice are invaluable in aging research. There are approximately 99% of human orthologs in mice, which is a significant advantage compared to invertebrate models. Mouse lifespan is approximately 2-3 years depending on the strain, which makes them a more expensive tool in the arsenal of an aging biologist. Inbred mice have been studied very extensively and a large body of knowledge about aging mechanisms, age-related diseases and existing and potential therapies was created using this model. Using inbred lines is a double-edged sword: on one hand, genetic differences between animals are virtually non-existent, however this is not representative of human population and it is not clear to what extent the results can be transferred to humans.
Naked mole rats
Heterocephalus glaber, the naked mole rat, is the most long-lived rodent with a maximum life span of approximately 30 years. Naked mole rat exhibits negligible senescence, virtually no age-related increase in mortality and high reproduction levels until death. They have several signs of age-related pathology similar to humans, such as osteoarthritis and degeneration of the retina. Naked mole rats can provide clues to mechanisms of longevity and potential therapies in humans, and hence are an extremely valuable model animal. There are several disadvantages of using them as laboratory animals, however, including specific housing conditions like low light levels, high temperature and humidity. Very long lifespan poses an obvious limitation on the variety of experiments suitable for this model.
Rhesus macaques have been used in various types of research, however there are not too many studies of age-related mechanisms in primates. The main reasons for that are their long lifespan, which is more than 30 years, their size and weight, which complicate housing and maintenance and make this model an expensive and hard to handle. However, there are several distinct advantages of using non-human primates for studying age-related pathologies, such as Alzheimer's disease and other neurodegenerative diseases that can't be recapitulated in mouse models.
A LITTLE MTOR TRIUMPHALISM
It's always good to listen to viewpoints that you happen to disagree with. This is why I pay attention to research strategies and researchers informed by programmed aging theories such as the hyperfunction hypothesis that builds on antagonistic pleiotropy. In this view aging is the consequence of various developmental processes running off the rails, colliding, and fighting one another along the way, producing dysregulation and damage. This is programmed in the sense that it is an inevitable consequence of the way in which the many biological systems evolved to perform in early life. Thus evolved programs cause accumulations of cellular and molecular damage, which goes on to create further harm.
This is exactly backwards from the more mainstream view in the research community, and how I myself see the balance of evidence, which is that cellular and molecular damage accumulates through the normal operation of metabolism. That damage causes increasingly large reactions in evolved biological systems, few of them good, as their operating parameters and local environment become ever more dysfunctional. Damage causes more damage, and the process accelerates rapidly in later life, just as in any complicated machine. One of the most fascinating things about aging research at the present time is that biology is so fantastically complex that there is room enough yet to argue over whether damage causes change or change causes damage. There is so much left unknown and fuzzy still at this stage, despite the mountains of knowledge accumulated, that researchers still have great latitude to theorize and rearrange the chunks of what is known.
The end result is a lot of theorizing, as is always the case in any territory where much is left to be mapped. This will continue until enough proof arrives to settle the debate. In the case of the most important debate in aging research, which is between programmed aging and aging as damage, the most rapid and cost-effective way to settle this would be to implement initial prototypes of the SENS proposals for rejuvenation treatments. These are based entirely on the view of aging as damage accumulation, and involve the repair of specific forms of cellular and molecular damage thought to be fundamental, caused by the ordinary operation of metabolism rather than by some other form of damage. If aging is programmed then SENS will not work well at all, producing only fleeting benefits before the programs assert themselves to create more damage. If aging is damage, then SENS prototypes will greatly extend healthy life spans in laboratory animals such as mice. The cost of producing these prototypes is probably in the vicinity of a billion or two dollars and 10-20 years, which is less than the cost for a Big Pharma entity to develop a single drug these days.
One of the originators of the hyperfunction theory of aging is very much in favor of manipulating mTOR, mechanistic target of rapamycin as a way to treat aging. He is a prolific author on this topic, and feels that work on rapamycin - and related drug candidates such as everolimus - in recent years goes a long way towards bolstering his case for mTOR as a master regulator of the aging process. If you are an adherent of the programmed aging viewpoint then altering metabolic operation, such as by dialing up or dialing down circulating levels of specific proteins, is exactly the approach that should be taken to treat aging. Restore something that looks more like youthful metabolism and damage will be repaired to at least some degree, depending on how far things have gone. If you follow the aging as damage viewpoint, on the other hand, then altering metabolic operation is a matter of rearranging deckchairs on the Titanic: it fails to address the underlying cause of frailty, degeneration, and disease, and therefore can only produce poor or fleeting benefits.
I think you'll find this an interesting piece, being almost exactly reversed in many of its viewpoints from much of the research I point out. All groups have their triumphalism, and one can appreciate a well conducted expression of that urge even when fairly certain that the author is wrong in his or her big picture view of the science:
Rejuvenating immunity: "anti-aging drug today" eight years later
Until recently, aging was believed to be a functional decline caused by accumulation of random molecular damage, which cannot be prevented. Breaking this dogma, hyperfunction theory described aging as a continuation of growth, driven by signaling pathways such as TOR (Target of Rapamycin). TOR-centric model predicts that rapamycin (and other rapalogs) can be used in humans to treat aging and prevent diseases. In proper doses and schedules, rapamycin and other rapalogs not only can but also must extend healthy life-span in humans. This theory was ridiculed by opponents and anonymous peer-reviewers. Yet, it was predicted in 2008 that "five years from now, current opponents will take the TOR-centric model for granted". And this prediction has been fulfilled.
Currently, humans and animals (in protected environment) die from age-related diseases, which are manifestation of aging. By slowing aging, rapamycin and calorie restriction can delay age-related diseases including cancer. They extend life span. Yet, the causes of death seem to be the same. Or not? Why is this important? Consider an analogy. 300 years ago in London, 75% of people died from external causes (infections, trauma, starvation) before they reached the age of 26. So only a few died from mTOR-driven aging. Only when most external causes have been eliminated, people now die from mTOR-driven age-related diseases. Similarly, if TOR-driven aging would be eliminated by a rational combination of anti-aging drugs, even then we still would not be immortal. There will be new, currently unknown causes of death. I call this post-aging syndrome. We do not know what it is. But we know that accumulation of molecular damage or telomere shortening (as examples) eventually would cause post-aging syndrome.
Even in the ancient world, when most people died from "external causes", symptoms of mTOR-driven aging were well known. In contrast, we do not know symptoms of post-aging syndrome. Aging is quasi-programmed and is not accidental. Although its rate varies among individuals, the chances to outlive aging and to die from post-aging syndrome are very low. Still, we may identify these symptoms in humans over 110 years old and especially in animals treated with rapamycin (and other anti-aging modalities). Inhibition of mTOR may extend life span, thus revealing post-aging syndrome. How will we know that we observe post-aging syndrome? There are potential criteria: Animals and humans die from either unknown diseases, unusual variants of known-disease and rare diseases. Or at least, the range of age-related diseases is dramatically changed. As discussed in 2006, causes of post-aging syndrome may include accumulation of random molecular damage, telomere shortening, selfish mitochondria and so on.
While gerontologists were studying free radicals and anti-oxidants, the TOR-centric (hyperfunction) theory revealed anti-aging drugs such as rapamycin and metformin. There are several potential anti-aging drugs in clinical use. Combining drugs and modalities, selecting doses and schedules in clinical trial will ensure the maximal lifespan extension. Simultaneously, medical progress improves aging-tolerance. Aging tolerance is the ability to survive despite aging. For example, bypass surgery allows patients with coronary disease to live, despite aging-associated atherosclerosis. Gerontologists do not need to catch the train that has already departed. No need to study rapamycin, which already entered the clinic. This is now a merely medical task. Gerontologists may continue to study free radicals and accumulation of random molecular damage as a potential cause of post-aging syndrome (not aging). It is important to study post-aging syndrome, to be ready to fight it, when medical progress with rapamycin will allow us to reach post-aging age: perhaps 50 years from now.
LATEST HEADLINES FROM FIGHT AGING!
ON TELOMERE LENGTH AND CANCER RISK
Monday, April 13, 2015
Here is an interesting study on the association of average telomere length with cancer risk, a relationship that is apparently quite hard to pull from raw epidemiological data:
Telomere shortening is an inevitable, age-related process, but it can also be exacerbated by lifestyle factors such as obesity and smoking. Thus, some previous studies have found an association between short telomeres and high mortality, including cancer mortality, while others have not. A possible explanation for the conflicting evidence may be that the association found between short telomeres and increased cancer mortality was correlational but other factors (age and lifestyle), not adjusted for in previous studies, were the real causes. Genetic variation in several genes associated with telomere length (TERC, TERT, OBFC1) is independent of age and lifestyle. Thus, a genetic analysis called a Mendelian randomization could eliminate some of the confounding and allow the presumably causal association of telomere length and cancer mortality to be studied.
Researchers used data from two prospective cohort studies, the Copenhagen City Heart Study and the Copenhagen General Population Study, including 64,637 individuals followed from 1991-2011. Participants completed a questionnaire and had a physical examination and blood drawn for biochemistry, genotyping, and telomere length assays. For each subject, the authors had information on physical characteristics such as body mass index, blood pressure, and cholesterol measurements, as well as smoking status, alcohol consumption, physical activity, and socioeconomic variables. In addition to the measure of telomere length for each subject, three single nucleotide polymorphisms of TERC, TERT, and OBFC1 were used to construct a score for the presence of telomere shortening alleles.
A total of 7607 individuals died during the study, 2420 of cancer. Overall, as expected, decreasing telomere length as measured in leukocytes was associated with age and other variables such as BMI and smoking and with death from all causes, including cancer. Surprisingly, and in contrast, a higher genetic score for telomere shortening was associated specifically with decreased cancer mortality, but not with any other causes of death, suggesting that the slightly shorter telomeres in the cancer patients with the higher genetic score for telomere shortening might be beneficial because the uncontrolled cancer cell replication that leads to tumor progression and death is reduced.
INCREASED PRODUCTION OF HSP22 EXTENDS LIFE SPAN IN FLIES
Monday, April 13, 2015
Hsp22 is a heat shock protein in the fly genome. Like other heat shock proteins it is involved in hormesis, wherein cells repair themselves more aggressively in response to heat, toxins, and other forms of stress. If the stress is mild or short-lived then the result is a net reduction in cellular damage. If this persists for long enough then the individual experiences improved health and longevity: increased cellular repair efforts and altered levels of heat shock proteins are observed in many of the approaches shown to slow aging in laboratory species. There is consequently some interest in the development of therapies based on triggering increased cellular housekeeping without the need for the initial stress, and manipulating levels of heat shock proteins seems like a good starting point:
Mitochondria are involved in many key cellular processes and therefore need to rely on good protein quality control (PQC). Three types of mechanisms are in place to insure mitochondrial protein integrity: reactive oxygen species scavenging by anti-oxidant enzymes, protein folding/degradation by molecular chaperones and proteases and clearance of defective mitochondria by mitophagy.
Drosophila melanogaster Hsp22 is part of the molecular chaperone axis of the PQC and is characterized by its intra-mitochondrial localization and preferential expression during aging. As a stress biomarker, the level of its expression during aging has been shown to partially predict the remaining lifespan of flies. Since over-expression of this small heat shock protein increases lifespan and resistance to stress, Hsp22 most likely has a positive effect on mitochondrial integrity. Accordingly, Hsp22 has recently been implicated in the mitochondrial unfolded protein response of flies. This review will summarize the key findings on D. melanogaster Hsp22 and emphasis on its links with the aging process.
EVIDENCE FOR LONG TERM MEMORY TO SURVIVE VITRIFICATION IN NEMATODE WORMS
Tuesday, April 14, 2015
Cryonics is the low-temperature preservation of the deceased in order to grant them a chance at a renewed life when technologies for restoration are developed. One of the big outstanding questions is the degree to which cryopreservation successfully preserves the fine structure of the brain and thus the data of the mind. The fact that cold water drowning victims can live again after an hour or more of brain death tells us that memory is encoded in physical structures, with the current consensus suggesting it is located in synaptic connections between neurons. Scanning technologies have been used to show that cryopreservation via vitrification of cryoprotectant-infused tissue does indeed preserve the fine structure of brain cell connections, but there is always the need for more and better proof. At the present time studies involving restoration of vitrified individuals must be carried out in lower animals, as researchers are still far from the point at which they can safely restore vitrified mammals:
Can memory be retained after cryopreservation? Our research has attempted to answer this long-standing question by using the nematode worm Caenorhabditis elegans (C. elegans), a well-known model organism for biological research that has generated revolutionary findings but has not been tested for memory retention after cryopreservation. Our study's goal was to test C. elegans' memory recall after vitrification and reviving.
Using a method of sensory imprinting in the young C. elegans we established that learning acquired through olfactory cues shapes the animal's behavior and the learning is retained at the adult stage after vitrification. Our research method included olfactory imprinting with the chemical benzaldehyde (C6H5CHO) for phase-sense olfactory imprinting at larval stage 1, the fast cooling SafeSpeed method for vitrification at larval stage 2, reviving, and a chemotaxis assay for testing memory retention of learning at the adult stage. Our results in testing memory retention after cryopreservation show that the mechanisms that regulate the odorant imprinting (a form of long-term memory) in C. elegans have not been modified by the process of vitrification or by slow freezing.
LIFESPAN OF MICE AND PRIMATES CORRELATES WITH IMMUNOPROTEASOME EXPRESSION
Tuesday, April 14, 2015
It is known that cellular repair processes are important in the determination of life span. Many of the methods of modestly slowing aging in laboratory species are accompanied by increased rates of cellular housekeeping, the recycling of damaged proteins and cell components. One set of these processes is centered around the proteasome, responsible for breaking down unneeded or damaged proteins, and here researchers demonstrate a correlation between proteasomal activity and species longevity in mammals:
Within the animal kingdom there is extraordinary variation in lifespan. Members of some species only live a few days or weeks, while others live tens, if not hundreds, of years. This large variation in species lifespan found in nature provides a powerful tool for the identification of factors that regulate the rate of aging. There is now a body of evidence to suggest that primary skin-derived fibroblasts can be used to evaluate aspects of cell biology that may differ between long-lived and short-lived species. This approach is not based on any assumption that changes in fibroblast properties would significantly affect organismal lifespan, but rather on the notion that evolutionary changes that produce slow aging might affect multiple cell types, including some that contribute to long-lasting resistance to disease and disability, as well as others, like fibroblasts, that are easy to cultivate and expand under standardized conditions for scores of species in parallel.
Here, we evaluated skin-derived fibroblasts and demonstrate that among primate species, longevity correlated with an elevation in proteasomal activity as well as immunoproteasome expression at both the mRNA and protein levels. Immunoproteasome enhancement occurred with a concurrent increase in other elements involved in MHC class I antigen presentation. Fibroblasts from long-lived primates also appeared more responsive to IFN-γ than cells from short-lived primate species, and this increase in IFN-γ responsiveness correlated with elevated expression of the IFN-γ receptor protein IFNGR2. Elevation of immunoproteasome and proteasome activity was also observed in the livers of long-lived Snell dwarf mice and in mice exposed to drugs that have been shown to extend lifespan, including rapamycin, 17-α-estradiol, and nordihydroguaiaretic acid. This work suggests that augmented immunoproteasome function may contribute to lifespan differences in mice and among primate species.
STEM CELL THERAPY SLOWS THE ONSET OF MACULAR DEGENERATION
Wednesday, April 15, 2015
Age-related macular degeneration has a fairly direct relationship to the accumulation of a mix of metabolic wastes called lipofuscin in long-lived retinal cells. There are other contributing causes, but that is an important one. Cell repair mechanisms are impacted, cells falter and die as a result and are not replaced, and progressive blindness follows the consequent retinal damage. Here researchers show that the overall process of degeneration can be significantly slowed via a stem cell therapy, though it is unclear as to how it affects lipofuscin accumulation versus other mechanisms:
Age-related macular degeneration occurs when the small central portion of the retina, known as the macula, deteriorates. The retina is the light-sensing nerve tissue at the back of the eye. Macular degeneration may also be caused by environmental factors, aging and a genetic predisposition. When animal models with macular degeneration were injected with induced neural progenitor stem cells, which derive from the more commonly known induced pluripotent stem cells, healthy cells began to migrate around the retina and formed a protective layer. This protective layer prevented ongoing degeneration of the vital retinal cells responsible for vision. "This is the first study to show preservation of vision after a single injection of adult-derived human cells into a rat model with age-related macular degeneration." The stem cell injection resulted in 130 days of preserved vision in laboratory rats, which roughly equates to 16 years in humans.
Researchers first converted adult human skin cells into powerful induced pluripotent stem cells (iPSC), which can be expanded indefinitely and then made into any cell of the human body. In this study, these induced pluripotent stem cells were then directed toward a neural progenitor cell fate, known as induced neural progenitor stem cells, or iNPCs. "These induced neural progenitor stem cells are a novel source of adult-derived cells which should have powerful effects on slowing down vision loss associated with macular degeneration. Though additional pre-clinical data is needed, our institute is close to a time when we can offer adult stem cells as a promising source for personalized therapies for this and other human diseases." Next steps include testing the efficacy and safety of the stem cell injection in preclinical animal studies to provide information for applying for an investigational new drug. From there, clinical trials will be designed to test potential benefit in patients with later-stage age-related macular degeneration.
TOMORROW WILL BE DIFFERENT FROM TODAY
Wednesday, April 15, 2015
We live in an era of very rapid change driven by technological progress. Today's world is enormously different from that of three or four decades past: consider the pervasive effects of the revolution in communications and computing technologies that has taken place over that time. Yet, human nature being what it is, most of the people who lived through this profound shift in capabilities and culture are nonetheless very skeptical of claims that the future will look radically different from today in any important aspect. It is strange.
In particular the concept of actuarial escape velocity leading to thousand year life spans is a very hard sell. People look at the large number that is very different from today's maximum life span and immediately reject it out of hand, no matter the reasonable argument behind it. Any medical technology that produces some rejuvenation in old patients buys extra time to develop better means of rejuvenation. At some point the first pass at rejuvenation treatments will improve such that remaining healthy life expectancy grows at more than a year with each passing year. At that point life spans will become indefinite, limited only by accident or rare medical conditions not yet solved.
It doesn't help that most of the public has very little knowledge of the present state of medical research in any field, never mind the specific details of how aging might be treated and brought under medical control. The only solution to that issue is to keep on talking: educate, advocate, and spread the word.
It is likely the first person who will live to be 1,000 years old is already alive today. This is according to a growing regiment of researchers who believe a biological revolution enabling humans to experience everlasting youthfulness is just around the corner. At the epicentre of the research is Aubrey de Grey, co-founder or the California-based Strategies for Engineered Negligible Senescence (SENS) Research Foundation.
"The first thing I want to do is get rid of the use of this word immortality, because it's enormously damaging, it is not just wrong, it is damaging. It means zero risk of death from any cause - whereas I just work on one particular cause of death, namely ageing." de Grey said his research aims to undo the damage done by the wear and tear of life, as opposed to stopping the ageing process altogether. "If we ask the question: 'Has the person been born who will be able to escape the ill health of old age indefinitely?' Then I would say the chances of that are very high. Probably about 80 per cent."
"The therapies that we are working on at the moment are not going to be perfect. These therapies are going to be good enough to take middle age people, say people aged 60, and rejuvenate them thoroughly enough so they won't be biologically 60 again until they are chronologically 90. That means we have essentially bought 30 years of time to figure out how to re-rejuvenate them when they are chronologically 90 so they won't be biologically 60 for a third time until they are 120 or 150. I believe that 30 years is going to be very easily enough time to do that."
EFFORTS TO QUANTIFY THE BENEFITS OF DIFFERENT LEVELS OF EXERCISE
Thursday, April 16, 2015
The available evidence from animal studies shows that lack of exercise causes poor health and a shorter life expectancy, while moderate regular exercise causes better health and a longer life expectancy. In humans the data can largely only show correlations rather than cause and effect, but the same pattern emerges. So it is reasonable to expect that regular moderate exercise provides improved odds of a healthier, modestly longer life, and that a sedentary lifestyle is harmful in comparison. The next question is whether more exercise is better, and that one is hard to answer based on work to date, but researchers are making inroads:
Exercise has had a Goldilocks problem, with experts debating just how much exercise is too little, too much or just the right amount to improve health and longevity. Two new, impressively large-scale studies provide some clarity, suggesting that the ideal dose of exercise for a long life is a bit more than many of us currently believe we should get, but less than many of us might expect. The studies also found that prolonged or intense exercise is unlikely to be harmful and could add years to people's lives. No one doubts, of course, that any amount of exercise is better than none. Like medicine, exercise is known to reduce risks for many diseases and premature death. But unlike medicine, exercise does not come with dosing instructions. The current broad guidelines from governmental and health organizations call for 150 minutes of moderate exercise per week to build and maintain health and fitness. But whether that amount of exercise represents the least amount that someone should do - the minimum recommended dose - or the ideal amount has not been certain.
In the broader of the two studies, researchers gathered and pooled data about people's exercise habits from six large, ongoing health surveys, winding up with information about more than 661,000 adults, most of them middle-aged. Using this data, the researchers stratified the adults by their weekly exercise time, from those who did not exercise at all to those who worked out for 10 times the current recommendations or more (meaning that the exercised moderately for 25 hours per week or more). Then they compared 14 years' worth of death records for the group. They found that, unsurprisingly, the people who did not exercise at all were at the highest risk of early death. But those who exercised a little, not meeting the recommendations but doing something, lowered their risk of premature death by 20 percent. Those who met the guidelines precisely, completing 150 minutes per week of moderate exercise, enjoyed greater longevity benefits and 31 percent less risk of dying during the 14-year period compared with those who never exercised. The sweet spot for exercise benefits, however, came among those who tripled the recommended level of exercise, working out moderately, mostly by walking, for 450 minutes per week, or a little more than an hour per day. Those people were 39 percent less likely to die prematurely than people who never exercised.
The other new study of exercise and mortality reached a somewhat similar conclusion about intensity. While a few recent studies have intimated that frequent, strenuous exercise might contribute to early mortality, the new study found the reverse. For this study, Australian researchers closely examined health survey data for more than 200,000 Australian adults, determining how much time each person spent exercising and how much of that exercise qualified as vigorous, such as running instead of walking, or playing competitive singles tennis versus a sociable doubles game. Then, as with the other study, they checked death statistics. And as in the other study, they found that meeting the exercise guidelines substantially reduced the risk of early death, even if someone's exercise was moderate, such as walking. But if someone engaged in even occasional vigorous exercise, he or she gained a small but not unimportant additional reduction in mortality. Those who spent up to 30 percent of their weekly exercise time in vigorous activities were 9 percent less likely to die prematurely than people who exercised for the same amount of time but always moderately, while those who spent more than 30 percent of their exercise time in strenuous activities gained an extra 13 percent reduction in early mortality, compared with people who never broke much of a sweat.
THE OLD ARE SLOWLY BECOMING YOUNGER
Thursday, April 16, 2015
Aging is accumulated cell and tissue damage, and the slow growth of healthy human life expectancy that has taken place over the past two centuries thus reflects a lesser load of a damage present in individuals of a given age. The old in their 60s and 70s today are on average less damaged and less frail than people of the same chronological age were in the past. This trend is incidental, however, an unintended side-effect of broad improvements in medicine and related technologies that have other immediate goals: control of infectious disease, treatment of specific age-related conditions, and so forth. Things will change in the near future as the focus slowly turns to deliberate efforts to treat aging as a medical condition, as this should produce much faster gains in healthy human life span.
Faster increases in life expectancy do not necessarily produce faster population aging, according to new research. This counterintuitive finding was the result of applying new measures of aging to future population projections for Europe up to the year 2050. "Age can be measured as the time already lived or it can be adjusted taking into account the time left to live. If you don't consider people old just because they reached age 65 but instead take into account how long they have left to live, then the faster the increase in life expectancy, the less aging is actually going on."
Traditional measures of age simply categorize people as "old" at a specific age, often 65. But previous research has shown that the traditional definition puts many people in the category of "old" who have characteristics of much younger people. "What we think of as old has changed over time, and it will need to continue changing in the future as people live longer, healthier lives. Someone who is 60 years old today, I would argue is middle aged. 200 years ago, a 60-year-old would be a very old person. The onset of old age is important because it is often used as an indicator of increased disability and dependence, and decreased labor force participation. Adjusting what we consider to be the onset of old age when we study different countries and time periods is crucial both for the scientific understanding of population aging for the formulation of policies consistent with our current demographic situation."
In the new study the researchers compared the proportion of the population that was categorized as "old" using the conventional measure that assumes that people become "old" at age 65 and the proportion based on their new measure of age, which incorporates changes in life expectancy. The study looked at three scenarios for future population aging in Europe, using three different rates of increase for life expectancy, from no increase to an increase of about 1.4 years per decade. The results show that, as expected, faster increase in life expectancy lead to faster population aging when people are categorized as "old" at age 65 regardless of time or place, but, surprisingly, that they lead to slower population aging when the new measures of age are used.
THE LOW-HANGING FRUIT OF CELL THERAPY DEVELOPMENT
Friday, April 17, 2015
It is always going to be easier to develop treatments for non-vital organs, and in some cases work on cell therapies for those organs can be simpler and less costly for other, unrelated reasons. Thus progress is faster in these areas, and we should expect to see widespread availability of first generation, comparatively simple therapies well in advance of more ambitious goals, such as the regeneration of complex internal organs:
The regenerative medicine company RepliCel Life Sciences is developing potential cures for chronic tendinosis, damaged or aging skin, and pattern baldness by reseeding affected areas with specific cell populations isolated from patients' own healthy hair follicles. RepliCel is picking the low-hanging fruit of regenerative medicine - low technological risk, underserved markets, clear clinical indications. Furthermore, commercial success is not dependent on successful reimbursement negotiations. "On the technical level, we're not asking these cells to do anything other than what they naturally do, or be anything more than they are. These are adult, somatic cells derived from the patient which we simply isolate and grow. We're not differentiating, genetically modifying, or manipulating these cells in any way."
From the scientific and manufacturing perspective, RepliCel is using the hair follicle as the cell source because the cells are simple to collect, grow well in culture, and are both relatively naive and highly functional. On a clinical level, the company is simply addressing a deficit of active cells in the patient by local delivery of cells shown to function in ways needed to solve a human condition such as tendinosis or pattern baldness. "The cells are injected in ways and places that largely eliminate any concerns around in vivo cell migration. [This approach ensures] enough cells stay in situ and viable to affect a sustained effect."
For tendinosis - a disrupted healing cycle of the tendon - nonbulbar dermal sheath (NBDS) fibroblast cells are isolated from a biopsy of hair follicles taken from the back of the scalp. After these cells are replicated, creating populations of millions of cells, they are injected into the wound site to jump-start the disrupted wound repair. In early-stage trials researchers used a similar approach with tendinosis patients who had been failed by other therapies. The NBDS approach returned these patients to painless, near-normal function. In the next 18 months, RepliCel expects to conclude a Phase I/II study at the University of British Columbia involving 28 participants.
Phase II trials to treat baldness - specifically, androgenetic alopecia - will begin this year. For this therapy, dermal sheath cup (DSC) cells are isolated from the base of the hair follicle, replicated into the millions, and injected to the area of thinning hair. "DSC cells are responsible for maintaining the number of dermal papillae cells, which directly corresponds to the hair thickness. We are simply delivering a volume of androgen-insensitive DSC cells into an area where androgen-sensitive DSC cells have disappeared ... to restore the normal hair follicle cycle." In animal studies, this approach grew hair on the feet of mice (which have no hair follicles there). When these cells were injected into their ears, the healthy cells migrated into resident hair follicles, making that hair thicker.
AUTOLOGOUS FAT CELL TRANSPLANT REDUCES OSTEOARTHRITIS SYMPTOMS
Friday, April 17, 2015
This is a good example of first generation cell therapies that have been available via medical tourism for quite some time, with enough information available for patients to make an informed decision about use, but are only now working their way through the regulatory system in the US:
Osteoarthritis (OA), a debilitating and painful degenerative disease, strikes an estimated 14 percent of adults 25 years of age and older, a third of adults age 65 and older in the U.S. alone. Those who suffer from OA may one day have a new and effective cell therapy, thanks to a team of Czech researchers who studied the effectiveness of using an OA patient's own adipose (fat) cells in a unique transplant therapy aimed at reducing the symptoms of this prevalent and difficult to treat condition as well as healing some of the damage caused by OA. The study, carried out with 1,114 OA volunteer patients who received autologous (self-donated) fat cell transplants saw their symptoms improved by the therapy.
"Adipose-derived cells have potential application in a wide range of clinical disorders, including myocardial infarction, stroke, Crohn's disease, multiple sclerosis (MS), rheumatoid arthritis, and breast augmentation and reconstruction. In this study we evaluated the safety and efficacy of freshly isolated autologous stromal vascular fraction cells (SVF cells). We hypothesized that the SVF cell treatment might contribute to cartilage healing." The study followed and evaluated 1,114 patients (median age 62, range 19-94 years; 52.8% male) treated with a single dose of SVF cells isolated from lipoaspirate. Patients were followed for between 12 and 54 months with a median of 17.2 months of follow-up. Their evaluations were based on pain, non-steroid analgesic usage, limping, extent of joint movement and stiffness before treatment and at three, six, and 12 months. Hip and knee joints were the most common joints treated and some patients had more than one joint treated.
"No serious side effects, systemic infection or cancer was associated with SVF cell therapy," reported the researchers. "Most patients improved gradually three to 12 months after treatment." The evaluations demonstrated that at least a 75 percent score improvement was noticed in 63 percent of the patients and at least a 50 percent score improvement was documented in 91 percent of the patients after 12 months. Typically patients in the study consumed large amounts of painkillers for their symptoms. Researchers found that painkiller usage declined dramatically after treatment.