FIGHT AGING! NEWSLETTER
November 16th 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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- Why Does Cancer Risk Result from Excess Fat Tissue?
- UK Cryonics and Cryobiology Research Group Launched
- Lower Protein Replacement Rates Observed in Various Methods Producing Enhanced Longevity in Mice
- Recent Research on Blood Pressure and Aging
- Slowing Aging in Accelerated Aging Mice Should Always Be Taken with a Grain of Salt
- Latest Headlines from Fight Aging!
- A Measure of Reduced Mortality through Increased Exercise
- Towards a Blood Test for Alzheimer's Disease
- Exercise Slows Aspects of Cardiac Aging in Rats
- Inhibiting Wnt Signaling to Treat Osteoarthritis
- The Prospects for Pig to Human Xenotransplantation
- Towards an Implanted Artificial Kidney
- Progress Towards Engineered Extracellular Matrix
- Researchers Aim for Limb Regeneration by 2030
- Investigating Mitochondrial Rejuvenation During Cellular Reprogramming and Embryonic Development
- An Example of Engineering Immune Cells to Target Cancer
WHY DOES CANCER RISK RESULT FROM EXCESS FAT TISSUE?
Here I'll point out a recent popular science article on the mechanisms underlying the correlation between cancer and obesity. It is well known and well proven by the scientific community that being overweight is bad for you, even if large sections of the public appear to be solidly in a state of denial on this topic. If you choose to carry excess visceral fat tissue for any great length of time as an adult, even decades later, even having lost that weight, the demographic data strongly suggests that you have a significantly increased risk of suffering all of the common age-related conditions: cancer, heart disease, dementia, and so forth. If you maintain that fat - or keep adding to it over the years, as an increasingly large fraction of the population does - then your odds become even worse. The more fat tissue you have, and the longer you have it for, the shorter your life expectancy, the more you will spend on medical expenses, and the less healthy you will be over the long term.
When trying to explain why this is the case, what it is under the hood that connects fat tissue to ill health, the first candidate mechanism on the list is chronic inflammation. In fact, whether or not you put on weight with age, the growing dysfunction of your immune system will cause rising levels of chronic inflammation, and this inflammation contributes to the pathology of near all of the common and fatal age-related conditions. Fat tissue makes this progression faster and a lot worse, however. Visceral fat is metabolically active; it does a lot to shift the alteration of human biochemistry, and the more of it there is the more it distorts the normal operation of metabolism. The inflammation is most likely caused by some combination of signals from visceral fat tissue that aggravates the immune system, producing results such as a feedback loop of abnormal behavior in macrophage cells.
Nothing in biology has only a single cause, however. Everything is complicated, everything interacts with other mechanisms. The relationship between fat tissue and age-related disease is going to be a story that spreads far beyond inflammation, for all that inflammation is the obvious starting point given what is known of its importance in aging. Take a look at this article, for example, which focuses only on the interactions of cancer and fat tissue:
Breaking the Cancer-Obesity Link
The most recent data from the National Center for Health Statistics indicate that 69 percent of US adults are overweight and half of those are obese. Worldwide, an estimated 2.2 billion adults are overweight or obese, and many of these individuals exhibit the hallmarks of metabolic syndrome: elevated blood pressure and high levels of blood sugar and cholesterol. Increased circulating levels of insulin, inflammatory cytokines, and other factors are also common in obese individuals. And while these metabolic and immune changes are problems in and of themselves, they are not the only health issues faced by the obese population. Through these and other possible mediators, obesity increases the risk and/or worsens the outcome of several chronic diseases, including many types of cancer. This year, obesity overtook smoking as the top preventable cause of cancer death in the U.S., with some 20 percent of the 600,000 cancer deaths per year attributed to obesity.
A major challenge in understanding the complex relationship between obesity and cancer has been distinguishing which host factors are causally linked and which are simply bystanders. Obesity can induce a complex state of systemic metabolic dysregulation characterized by insulin resistance and high levels of circulating insulin and glucose. Over the last two decades, however, researchers have used genetic or pharmacologic approaches to make progress in deciphering which of the many changes mediates the obesity-cancer link. Intercellular signaling is undoubtedly one contributing factor. Proteins, lipid intermediates, and other molecules secreted or shed from cells - collectively referred to as the secretome - carry messages between distant organ systems and tumor cells, as well as among tumor and host cells in their microenvironment. These signaling pathways involve an increasingly large roster of obesity-related hormones, growth factors, nutrient metabolites, chemokines, and cytokines that promote tumor development and/or progression. For example, insulin resistance in obese individuals drives insulin production in the pancreas and results in excess insulin in circulation. High levels of insulin can promote cancer growth through interaction with tumor cells' insulin receptors and/or IGF-1 receptors. Expression of the IGF-1 receptor is also necessary for the transformation of normal epithelial cells into cancer cells by numerous oncogenes, suggesting that greater IGF-1 signaling can also enhance the early stages of cancer development. In addition to the secretome, the tumor microenvironment encompasses extracellular matrix components and multiple cell types, including adipocytes and macrophages, which in obese people are highly active and capable of secreting a large number of cancer-promoting hormones and cytokines.
Another factor that appears to be involved in the obesity-inflammation connection, but has not yet been strongly linked to cancer risk and progression, is the gut microbiome. Obesity is associated with an overall reduction in gut bacterial diversity, and decreased bacterial richness has been linked to elevated systemic inflammation. These studies suggest that obesity-related perturbations of the gut microbiome and barrier function associated with a high-calorie diet can induce chronic systemic and adipose tissue inflammation, which is known to play a role in the progression of several cancer types.
In addition to putting people at an increased risk for developing cancer, obesity also worsens a cancer patient's prognosis. Research from our group and others has shown that a variety of cancers grow at faster rates in obese patients than in lean individuals. Furthermore, obesity appears to increase the chances that a patient's cancer will metastasize. A variety of factors may underlie the obesity-metastasis link, including circulating factors such as leptin, adiponectin, and IGF-1; adipose tissue remodeling, including alterations in adipose-derived stem cells; and other changes to the tumor microenvironment.
UK CRYONICS AND CRYOBIOLOGY RESEARCH GROUP LAUNCHED
A group of UK researchers have recently banded together to coordinate research into cryonics and cryobiology, the low-temperature preservation of tissues. Only small collections of cells can presently be reversibly cryopreserved, but there is a strong incentive to build the means to reversibly preserve whole organs and other large tissue structures. This is probably a matter of firstly developing a better form of cryoprotectant, one that is minimally toxic and easily cleared, and secondly putting more effort into producing robust, minimally damaging cooling and warming protocols. When developed, the ability to store whole organs indefinitely will prove useful in the very near future to expand the pool of donor organs, and remain useful in the decades ahead to reduce the cost of producing and delivering organs as needed. Never underestimate how much money can be saved by the ability to warehouse products as needed.
The lack of any present ability to reverse the state of cryopreservation in complex tissues is not an impediment to the use of indefinite low-temperature storage as a form of emergency medical care, as has been the case in the cryonics industry for decades now. A good cryopreservation as rapidly as possible after clinical death means that the fine structure of the brain is likely preserved, based on present evidence, the data of the mind is thus retained, and the patient can wait for as long as it takes for medical technology to advance to the point at which restoration and repair is feasible. A future in which a cryopreserved brain can be restored to life is also a future in which the cell and tissue damage that causes aging can be repaired, or indeed a new body built to order. Both of those goals in advanced medicine are well understood and near term in comparison to the sort of molecular nanotechnology industry needed to clear out toxic cryoprotectant and go cell by cell to repair the other harms caused by present means of preservation.
In any case, this new research effort is coordinated by João de Magalhães, whom regular readers will recognize as one of the members of the transhumanist community of past decades who followed his inclinations into aging research, and now leads a laboratory in that field, doing his part to push forward the state of the art. A whole range of figures and initiatives relating to human longevity, including the Aubrey de Grey and the SENS Research Foundation, can be traced back to that small community of futurists with a strong interest in radical life extension. If you can clearly see the future you want, you should reach for it, help to make it real.
It is interesting that de Magalhães chooses to now make some inroads into supporting progress in cryonics alongside his work on aging. It is perhaps in the nature of a calculation that everyone should make: at what point do you think that the intersection of progress towards rejuvenation therapies and your own personal decline into old age makes it smart to put more effort towards advancing the state of the cryonics industry? Cryonics and cryopreservation is the only viable backup plan for those of us who will age to death before the advent of working rejuvenation treatments. If I were a decade older or SENS-style rejuvenation research was not making at least slow progress then I'd certainly be putting more of my efforts into supporting the cryonics industry. I should probably be doing more than I am on that front regardless. People in the middle of the present span of life shouldn't be complacent; research in the life sciences takes a long time, and the backup plan of cryonics is there for a reason. I encourage you to think over your own balance of choices.
In the meanwhile, congratulations are due de Magalhães for setting up this initiative and in doing so helping to improve the state of cryonics. One of the best things that can happen for the small cryonics industry is for organ cryopreservation to prosper and be adopted by the medical mainstream; it will mean more funding and legitimacy for lines of research and improvement in methodologies that can also be applied to cryonics, meaning cryopreservation as emergency medical care for people who cannot be saved in any other way.
New UK cryobiology research network launched
A new network has been established by UK scientists to advance and promote research into cryobiology - the effects of extremely low temperature on living organisms and cells. The UK Cryonics and Cryopreservation Research Network is being coordinated by Dr Joao Pedro de Magalhaes, a Senior Lecturer at the University of Liverpool's Institute of Integrative Biology, who studies the molecular basis of ageing.
At present, cryopreservation technology is only successful for cell lines and very small tissues. More research is required before whole organs can successfully be cryopreserved while retaining their biological integrity. Dr de Magalhaes said: "Cryobiology is a crucial area of research for modern biotechnology due to the importance of biobanking; from developing reliable stem cell storage systems, organ banking for transplants as well as storage for engineered tissues."
Cryonics has been a topic of much debate over the years, with many scientists doubting whether current cryogenically frozen individuals can ever be brought to life. Dr de Magalhaes said: "Although cryonics is not feasible at present, technological breakthroughs in cryobiology may, in the future, decrease the amount of damage to levels that permit reversible cryopreservation. One of the goals of our research network is to discuss the ethical, medical, social and economic implications of these potential breakthroughs that would radically change our perceptions of life and death."
UK Cryonics and Cryopreservation Research Network
We are the UK Cryonics and Cryopreservation Research Network The UK Cryonics and Cryopreservation Research Network is a group of UK researchers who, together with international advisors, aim to advance research in cryopreservation and its applications.
Although we are a small group, we hope to promote academic and industrial activity on cryopreservation, and discuss its potential applications, including the idea of cryopreserving whole humans, commonly known as cryonics. We acknowledge that cryonics is a controversial topic, but like any unprovable approach we think its scientific discussion is necessary to permit its understanding by the public and by the wider scientific community, and it allows us to address many of the misunderstandings surrounding cryonics. We also think that cryopreservation, cryogenics and cryonics are fields with a huge potential impact on human medicine whose societal implications should be considered and debated.
We hope to attract and excite students and other researchers about cryobiology, contribute to knowledge exchange and help attract interest and funding to the field.
LOWER PROTEIN REPLACEMENT RATES OBSERVED IN VARIOUS METHODS PRODUCING ENHANCED LONGEVITY IN MICE
Today I'll point out an interesting open access paper in which the authors discuss what is probably an aspect of the observation that greater proteostasis correlates with greater longevity. Proteostasis is just a fancy way of saying the types, behaviors, and amounts of proteins produced by cells and present in tissues remain essentially the same over time, taking into account cyclic short term variations in response to repeated circumstances such as sleep, eating, and so on. As an individual ages, however, all these things change as the operation of cellular metabolism reacts to growing levels of damage. Since protein levels are the signals and controlling dials and switches of cells, ongoing age-related change in cellular behavior implies a lack of proteostasis and vice versa.
Given this, discussing proteostasis in connection with longevity and aging has always seemed a little tautological to me. It is a measure of consequences, another way of saying that aging has occurred. Aging is caused by damage, so of course there is a correlation between reactions to damage and longevity. However, it is probably the case that some measures of proteostasis will be useful as biomarkers of aging, in much the same way that some measures of epigenetic changes seem promising. A robust biomarker of aging would be a very useful tool indeed, as it could be used to rapidly test putative rejuvenation treatments, scoring their outcome on the whole of an individual's biology, rather than only their targets. For example, when senescent cell clearance therapies are deployed, determining their effects on senescent cell counts will be a part of the process, but at the moment is still necessary to wait around to see what the effects on long term health and life span will be. Even in rodents that takes years and millions. Replacing that cost with a simple test a month after treatment will greatly speed up the field.
In this paper the researchers look at the replacement rates of proteins, which is probably a function of at least the level of ongoing damage to proteins that would require them to be replaced, and rates of cellular replication, which have been observed to be lower in some forms of enhanced longevity in laboratory animals. They find that the former but not the latter correlates with life span:
Reduced in vivo hepatic proteome replacement rates but not cell proliferation rates predict maximum lifespan extension in mice
Over the last 50 years, several dietary, genetic, and pharmacological interventions have been identified that extend maximum life span in laboratory animals, including mice. Understanding the molecular underpinnings of the aging process and the biochemical pathways affected by interventions that attenuate the development of age-related diseases is a high priority. In particular, identifying metrics of biological processes, or biomarkers (BMs), that are involved in the slowing of aging in laboratory mammals will be essential for guiding the future development of interventions to extend human healthspan.
To identify such processes that play an etiologic role in age-related disease, our approach has been to test potential flux-based BMs of maximum life span extension. The concept underlying this strategy is that the activity of a metabolic process is best characterized by the molecular flux rate traversing the pathway and that changes in the flux rates of metabolic processes that play a causal role in the functional alterations of the condition may manifest earlier and more sensitively than static pathologic changes or complex clinical outcomes. Optimally, the functional role and measurement technique for these molecular processes will be translatable into human studies.
This rate-based BM approach may be particularly promising in combination with what is currently the most robust program for testing proposed interventions for extension of maximum life span in mammals: the National Institute on Aging's (NIA) Interventions Testing Program. These studies are the current gold standard for evaluating changes in lifespan in genetically heterogeneous mice but are time- and resource-intensive, limiting the number of interventions that can be tested each year. An initial screening strategy based on a panel of early BMs of maximum life span extension could be used to further refine which candidate interventions should be prioritized for inclusion into life span studies in mice. This represents an attractive approach for identifying interventions with the potential to extend human healthspan.
Here, we used stable-isotope mass spectrometric measurement tools to screen for BMs based on the activity of targeted physiologic pathways believed to be involved in the aging process. These measurements were performed in three different yet well-established mouse models of maximum life span extension, each on a different genetic background and each at relatively early time points in the life span of the model. The three models evaluated were Snell Dwarf mice, which are homozygous for a loss-of-function mutation in the Pit1 gene involved in anterior pituitary development; calorie-restricted (CR) mice, in which calories are reduced without malnutrition; and mice treated with rapamycin (Rapa).
A reduction in cell proliferation rates has been hypothesized to contribute to maximum life span extension by inhibiting the promotional phase of carcinogenesis and delaying cellular replicative senescence. A reduction in protein synthesis rates or slowing of protein replacement rates (RRs) (turnover) might in principle reflect preserved proteome homeostasis (proteostasis), which normally declines with age. A reduction in protein synthetic burden may preserve proteostasis by limiting the accumulation of misfolded and/or damaged proteins, possibly by increasing translational fidelity, chaperone capacity, and/or proteolytic capacity. Accordingly, the goal of the work presented here was to test the hypothesis that reduced cell proliferation rates, reduced protein synthesis rates, reduced protein RRs (prolonged half-lives), or other proteome alterations are early BMs of maximum life span extension in mice.
The major findings of this work are as follows: (i) A reduction in hepatic proteome RRs (longer half-lives) is a common feature of all three models evaluated (Snell Dwarf, CR, and Rapa-treated mice); (ii) a strong correlation exists between the degree to which hepatic proteome RRs are reduced and the degree of maximum life span extension in these models; and (iii) in vivo cell proliferation rates are not consistently reduced at early time points in all these models.
The first observation could have more than one underlying cause. We do not believe that our data suggest that a reduction in hepatic proteome RRs is an initiating factor that directly promotes maximum life span extension in the three models evaluated here. Rather, our hypothesis is that reduced hepatic proteome RRs reflect a reduced demand for protein renewal, and thus improved proteostasis in these models, likely due to reduced levels of misfolded and/or damaged proteins. The data presented here differentiate between several potential mechanisms of improved hepatic proteostasis in these models. In principle, a variety of cellular adaptations could reduce the levels of misfolded and/or damaged proteins, including an increase in proteolytic editing capacity, an increase in chaperone capacity, a reduction in the levels of damaging metabolites, or an increase in translational fidelity. The data presented here are not consistent with increased proteolytic editing as a major contributing factor to improved proteostasis, as reduced rather than increased proteome RRs (proteolytic rates) were consistently observed in all three models. We also found that the levels of the chaperones that we assessed were either unchanged or reduced in all three models, suggesting that an increase in chaperone capacity is an unlikely contributing factor to improved proteostasis. Consistent with improved proteostasis, as well as an absence of accumulated unfolded proteins in the ER in these three models, our proteomic analyses revealed that the synthesis of proteins involved in protein processing in the endoplasmic reticulum was reduced relative to the synthesis of all other proteins in the three models.
RECENT RESEARCH ON BLOOD PRESSURE AND AGING
Here I'll point out a couple of recent research publications on the topic of blood pressure in aging. Blood pressure is a useful metric in the progression of aging, not least because it can be cheaply and reliably measured. It is also a good example of the split between primary and secondary aging, as processes from both categories lead to higher blood pressure.
Primary aging is made up of the processes we cannot avoid, and only modestly slow via lifestyle choices. It is damage that accumulates as a consequence of the normal operation of metabolism. The accumulation of cross-links in the extracellular matrix and calcification of tissues leads to a progressive stiffening of blood vessel walls, and this loss of elasticity in blood vessels appears to be enough to explain the age-related rise in blood pressure that in some people is large enough to lead to clinical hypertension. Even lesser levels of high blood pressure slowly deform and weaken important structures in the cardiovascular system, exacerbate the processes causing atherosclerosis to develop in blood vessel walls, and increase the harm done to the brain by breakages in tiny blood vessels.
Secondary aging is caused by poor lifestyle choices. Most of the truly bad choices known to negatively impact life expectancy - including lack of exercise and being overweight - raise blood pressure in addition to their other effects, and this increase in blood pressure has all of the same detrimental effects as the increase caused by the processes of primary aging. Becoming fit in the general sense, through exercise and maintaining a sane weight, tends to lower blood pressure. One of the mediating mechanisms here is the influence of visceral fat on metabolism, but there are numerous other possibilities, all with varying degrees of supporting evidence.
What is known of the role of high blood pressure in the chain of cause and consequence that leads to age-related disease and death provides many good reasons to work on reducing your own personal pace of secondary aging. In fact the medical community is starting to think that past guidelines on blood pressure goals have been, if anything, too lax. If you spend too long with high blood pressure, and even the best of presently available treatments, drugs to reduce blood pressure, while capable of reducing risk of death cannot undo the restructuring and weakening of the cardiovascular system that has already taken place.
How Low to Go for Blood Pressure?
A new study finds that at least 16.8 million Americans could potentially benefit from lowering their systolic blood pressure (SBP) to 120 mmHg, much lower than current guidelines of 140 or 150 mmHg. The scientists calculated the potential impact of preliminary results from the Systolic Blood Pressure Intervention Trial (SPRINT). The initial analysis of SPRINT showed that using antihypertensive medications to reach a lower SBP target of 120 mmHg could greatly reduce risk for heart failure, heart attack, and death, compared to a target of 140 mmHg (SBP is the top number in a blood pressure reading). It's estimated that one in three U.S. adults have high blood pressure, or hypertension, a significant health concern. "SPRINT could have broad implications. Millions of Americans whose blood pressure is under control according to current guidelines may be considered uncontrolled if new guidelines adopt the intensive target of less than 120 mmHg studied in SPRINT."
A Randomized Trial of Intensive versus Standard Blood-Pressure Control
The most appropriate targets for systolic blood pressure to reduce cardiovascular morbidity and mortality among persons without diabetes remain uncertain. We randomly assigned 9361 persons with a systolic blood pressure of 130 mm Hg or higher and an increased cardiovascular risk, but without diabetes, to a systolic blood-pressure target of less than 120 mm Hg (intensive treatment) or a target of less than 140 mm Hg (standard treatment). At 1 year, the mean systolic blood pressure was 121.4 mm Hg in the intensive-treatment group and 136.2 mm Hg in the standard-treatment group. The intervention was stopped early after a median follow-up of 3.26 years owing to a significantly lower rate of myocardial infarction, other acute coronary syndromes, stroke, heart failure, or death from cardiovascular causes in the intensive-treatment group than in the standard-treatment group (1.65% per year vs. 2.19% per year).
Blood Pressure Medication Can't Undo All Damage
Treating out-of-control blood pressure with antihypertensive medication can greatly reduce your risk for heart attack, stroke and heart failure, but the current approach to treatment can't undo all of the previous damage or restore cardiovascular disease risk to ideal levels, a new study suggests. "The best outcomes were seen in those who always had ideal levels of blood pressure and never required medications. Those who were treated with medication and achieved ideal levels were still at roughly twice the risk of those with untreated ideal levels. And, of course, people with untreated or uncontrolled high blood pressure were at even greater risk." The new findings strongly suggest that there should be an even greater effort to maintain lower blood pressure levels in younger adults to avoid increases in blood pressure over time that may eventually require medication.
Those of us following SENS rejuvenation research should be thinking at this point that all of the data above only reinforces how important it is to make inroads in repairing the damage of primary aging. In this case that means finding a way to break down the most common cross-links that contribute to loss of elasticity in human tissues, those based on glucosepane. The SENS Research Foundation is one of the few organizations funding gluosepane research with the aim of a treatment to clear these cross-links. An effective therapy here would likely provide a greater and more reliable impact on cardiovascular aging and blood pressure than any presently available treatment, since it would be removing one of the root causes of blood vessel stiffening, which is in turn a root cause of high blood pressure.
SLOWING AGING IN ACCELERATED AGING MICE SHOULD ALWAYS BE TAKEN WITH A GRAIN OF SALT
A publicity release has been doing the rounds and a number of people have pointed it out to me in the past day, something that usually only tends to happen for items much more interesting than this one. The release covers research into J147, a drug candidate for Alzheimer's disease that has been under investigation in animal studies for the past few years. It has now been tested in the SAMP8 lineage of engineered mice that suffer from accelerated aging, and the researchers are touting a slowing of that acceleration of aging as measured by cognitive decline and changes in gene expression. As is often the case, omissions and oversimplification of necessary details occurred somewhere between the lab and the publicity office, and as a consequence people are paying more attention to this research than it merits. The most important of these omissions is the fact that J147 was tested on an accelerated aging mouse lineage; without that detail, the publicity release makes the research sound much more useful than it is.
Researchers frequently start work in animal models that have been altered to allow for shorter studies. The cost of these studies is large in comparison to working with cells, so being able to cut that cost in half, for example, by using an accelerated aging lineage is often worth it. Mouse studies can cost millions and take years, and a million in funding goes a long way in early stage research; there are always other projects that need funding. Unfortunately when it comes to research potentially relevant to aging this use of accelerated aging lineages usually means that the results are very technical in nature and largely meaningless for anyone trying to judge whether not the outcome is useful. The literature is littered with examples of researchers slowing the progression of - or partly reversing - accelerated aging by somewhat fixing the issue that caused that accelerated aging, and then later finding that their work had little to no effect on the progression of normal aging. Part of the problem here is that there really is no such thing as "accelerated aging." Aging is an accumulation of cell and tissue damage, yes, and what looks like accelerated aging can be created by piling on damage, such as by interfering with DNA repair mechanisms. But the end result bears only a tenuous relationship to the progression of normal aging, and once you're down to the detail level of building therapies based on manipulating specific cellular mechanisms it is unlikely that benefits to an accelerated aging lineage also accrue in the same way for a normal aging lineage.
There are always exceptions. Senescent cell clearance was first demonstrated in accelerated aging mice, and then later showed the same sort of benefits in normal mice. In that case there were good technical reasons and a weight of evidence to lead researchers to expect that the results would carry over. That isn't something that a layperson can be expected to wade through for every line of research, however. The exceptions to the general rule are infrequent enough that, personally, I'd advise people to just ignore published research results in accelerated aging mouse lineages. The press invariably makes much more of it than it is worth, and most of this work loses any possible relevance to normal aging as it progresses. It never hurts to wait and see rather than get excited over this sort of result.
Below find excerpts from the publicity materials and open access paper for the latest research into the effects of J147, and judge for yourself the poor quality of the release materials when it comes to representing the nature of the research. It is an undeniably interesting set of results, but this is something that I'd want to see repeated in normal mice before paying any great attention to it. In fact I'd be inclined to see this more in the way of a trial balloon to gather support for the longer and more expensive lifespan study in normal mice that might be carried out next:
Experimental drug targeting Alzheimer's disease shows anti-aging effects
Research expanded upon their previous development of a drug candidate, called J147, which takes a different tack by targeting Alzheimer's major risk factor - old age. In the new work, the team showed that the drug candidate worked well in a mouse model of aging not typically used in Alzheimer's research. When these mice were treated with J147, they had better memory and cognition, healthier blood vessels in the brain and other improved physiological features. "Initially, the impetus was to test this drug in a novel animal model that was more similar to 99 percent of Alzheimer's cases. We did not predict we'd see this sort of anti-aging effect, but J147 made old mice look like they were young, based upon a number of physiological parameters."
The old mice that received J147 performed better on memory and other tests for cognition and also displayed more robust motor movements. The mice treated with J147 also had fewer pathological signs of Alzheimer's in their brains. Importantly, because of the large amount of data collected on the three groups of mice, it was possible to demonstrate that many aspects of gene expression and metabolism in the old mice fed J147 were very similar to those of young animals. These included markers for increased energy metabolism, reduced brain inflammation and reduced levels of oxidized fatty acids in the brain. Another notable effect was that J147 prevented the leakage of blood from the microvessels in the brains of old mice.
A comprehensive multiomics approach toward understanding the relationship between aging and dementia
One model of aging is the senescence-accelerated prone 8 (SAMP8) mouse, that has a progressive, age-associated decline in brain function similar to human AD patients. As they age, SAMP8 mice develop an early deterioration in learning and memory as well as a number of pathophysiological alterations in the brain including increased oxidative stress, inflammation, vascular impairment, gliosis, Aβ accumulation and tau hyperphosphorylation.
Because age is the greatest risk factor for sporadic Alzheimer's disease (AD), phenotypic screens based upon old age-associated brain toxicities were used to develop the potent neurotrophic drug J147. Since certain aspects of aging may be primary cause of AD, we hypothesized that J147 would be effective against AD-associated pathology in rapidly aging SAMP8 mice and could be used to identify some of the molecular contributions of aging to AD.
An inclusive and integrative multiomics approach was used to investigate protein and gene expression, metabolite levels, and cognition in old and young SAMP8 mice. J147 reduced cognitive deficits in old SAMP8 mice, while restoring multiple molecular markers associated with human AD, vascular pathology, impaired synaptic function, and inflammation to those approaching the young phenotype. The extensive assays used in this study identified a subset of molecular changes associated with aging that may be necessary for the development of AD.
LATEST HEADLINES FROM FIGHT AGING!
A MEASURE OF REDUCED MORTALITY THROUGH INCREASED EXERCISE
Monday, November 9, 2015
Researchers find an association between reduced mortality and increased daily walking distance in a long-term study that used pedometers to measure participant activity. The 10,000 steps mentioned as a reference point sums to about five miles of walking, taking an hour to an hour and a half depending on pace, which might be considered in the context of recent work on the dose-response curve for exercise. It has been suggested that the present health body recommendations of half an hour a day are too low, and doubling that level is worth it from the point of view of additional gains.
A study finds that an increase in the number of steps walked each day has a direct correlation with long term mortality. This was the first time research had been able to make the link between exercise, measured directly through pedometers, and reduced mortality over time in people who appeared healthy at the outset. "Inactivity is a major public health problem, with conditions like obesity costing the economy tens of billions every year. This shows more clearly than before that the total amount of activity also affects life expectancy. Previous research measured physical activity by questionnaire only, but these results are more robust and give us greater confidence that we can prevent death from major diseases by being more active. This study should greatly encourage individuals to ensure they do regular exercise and prompt governments to create more opportunities for physical activity in communities."
The study monitored 3,000 Australians over 15 years. "The participants were given pedometers and data was collected at the beginning and again approximately five years later during the trial to measure the number of steps they took each day. Participants were an average age of 58.8 years old at commencement and the major end point was death due to any cause." A sedentary person who increased his or her steps from 1,000 to 10,000 per day had a 46% lower mortality risk. A sedentary person who increased his or her steps to 3,000 per day, five days a week had a 12% reduction in death. The association between daily steps and mortality was largely independent of factors such as Body Mass Index (BMI) and smoking.
TOWARDS A BLOOD TEST FOR ALZHEIMER'S DISEASE
Monday, November 9, 2015
Researchers are working on the assessment of patterns of autoantibodies in the blood as a way to determine progression towards Alzheimer's disease and other age-related conditions. The levels of these autoantibodies appear to reflect the presence of specific forms of damage to tissues and systems in the body and brain, and that in turn can be linked to the early-stage pathology of a number of age-related diseases.
Researchers are nearing development of a blood test that can accurately detect the presence of Alzheimer's disease, which would give physicians an opportunity to intervene at the earliest, most treatable stage. The work focuses on utilizing autoantibodies as blood-based biomarkers to accurately detect the presence of myriad diseases and pinpoint the stage to which a disease has progressed.
By detecting Alzheimer's disease long before symptoms emerge, the researchers hope those with disease-related autoantibody biomarkers will be encouraged to make beneficial lifestyle changes that may help to slow development of the disease. While the cause of Alzheimer's remains elusive, it is clear that maintaining a healthy blood-brain barrier is a critical preventative measure. Diabetes, high cholesterol, high blood pressure, stroke and being overweight jeopardize vascular health. As blood vessels in the brain weaken or become brittle with age, they begin to leak, which allows plasma components including brain-reactive autoantibodies into the brain. There, the autoantibodies can bind to neurons and accelerate the accumulation of beta amyloid deposits, a hallmark of Alzheimer's pathology.
The blood test developed by the researchers has also shown promise in detecting other diseases, including Parkinson's, multiple sclerosis and breast cancer. All humans possess thousands of autoantibodies in their blood, and these autoantibodies specifically bind to blood-borne cellular debris generated by organs and tissues all over the body. An individual's autoantibody profile is strongly influenced by age, gender and the presence of specific diseases or injuries. Diseases cause characteristic changes in autoantibody profiles that, when detected, can serve as biomarkers that reveal the presence of the disease.
EXERCISE SLOWS ASPECTS OF CARDIAC AGING IN RATS
Tuesday, November 10, 2015
Exercise is known to improve health and modestly slow the progression of age-related degeneration. Here is one example of numerous ongoing research programs that seek to define the effects of exercise on specific aspects of the aging process:
Aging is an inevitable trend of the world's population, and it is accompanied with serious age-related health issues in modern society that must be investigated. Aging is the most important risk factor in cardiovascular disease (CVD), which is the leading cause of death worldwide. The major factor in heart failure during aging is heart remodeling, including long-term stress-induced cardiac hypertrophy and fibrosis. Exercise is good for aging heart health, but the impact of exercise training on aging is not defined.
This study used 3-, 12- and 18-month-old rats and randomly divided each age group into no exercise training control groups (C3, A12 and A18) and moderate gentle swimming exercise training groups (E3, AE12 and AE18). The protocol of exercise training was swimming five times weekly with gradual increases from the first week from 20 to 60 min for 12 weeks.
Analyses of protein from rat heart tissues and sections revealed cardiac inflammation, hypertrophy and fibrosis pathway increases in aged rat groups (A12 and A18), which were improved in exercise training groups (AE12 and AE18). There were no heart injuries in young rat hearts in exercise group E3. These data suggest that moderate swimming exercise training attenuated aging-induced cardiac inflammation, hypertrophy and fibrosis injuries of rat hearts.
INHIBITING WNT SIGNALING TO TREAT OSTEOARTHRITIS
Tuesday, November 10, 2015
Wnt signaling has long been investigated in connection with the processes of adult regeneration and embryonic development. This latest news notes progress towards a class of therapies that inhibit the Wnt pathway, potentially producing regeneration in adult tissues where it would not normally occur, or slowing damage caused by inappropriate growth in tissues where the Wnt pathway is overactive in aging.
Researchers have unveiled pre-clinical and clinical research that demonstrated successful modulation of the Wnt pathway for potential applications in regenerative medicine. They have developed an injectable investigational drug that inhibits the Wnt pathway, causing endogenous stem cells to regenerate knee cartilage in animals.
Osteoarthritic joints are characterized by degradation of the articular cartilage, which provides the cushioning between bones, and by bony protrusions called osteophytes, which interfere with function and exacerbate the pain associated with osteoarthritis. An overactive Wnt pathway in the affected joint causes the formation of more (spurious) bone instead of (healthy) cartilage, leading to pain, loss of function, stiffness, and deformity.
Clinical data indicate that the small molecule inhibitor of the Wnt pathway SM04690 may slow joint space narrowing and possibly increase joint space in the knee. Clinicians generally perceive an increase in joint space as evidence of preservation or regrowth of cartilage. The researchers recently concluded a 24 week placebo-controlled, double-blind, randomized Phase I clinical trial, studying the safety and preliminary efficacy of SM04690 in patients with moderate to severe osteoarthritis of the knee. The results also suggested that a single injection with SM04690 appeared to be safe and potentially effective in improving function and reducing pain for patients with osteoarthritis of the knee. Subsequently, researchers began enrollment in an approximately 400-patient Phase II clinical trial.
THE PROSPECTS FOR PIG TO HUMAN XENOTRANSPLANTATION
Wednesday, November 11, 2015
The use of pigs to expand the supply of donor organs for human patients is coming closer to reality. A number of new technologies are enabling researchers to remove the various blocking issues in cross-species transplantation: cheap and efficient gene therapy, decellularization, and so forth. It is still proving to be challenging. Ultimately this will be, I suspect, a comparatively brief transitional technology, eclipsed in the decades ahead by the ability to grow organs from a patient's own cells. Here is an update on the state of the xenotransplantation field:
A US lab has performed about 50 pig-to-primate transplants to test different combinations of genetic modifications in the pig and immune-suppressing drugs in the primate. Even so, the team has not had a primate survive for longer than a few days. The complexities of the immune system and the possibility of infection by pig viruses are formidable and drove large companies out of the field in the early 2000s. That trend may now be reversing, thanks to improved immunosuppressant drugs and advances in genome-editing technologies such as CRISPR/Cas9. These techniques allow scientists to edit pig genes, which could cause rejection or infection, much more quickly and accurately than has been possible in the past.
Some researchers now expect to see human trials with solid organs such as kidneys from genetically modified pigs within the next few years. United Therapeutics has spent 100 million in the past year to speed up the process of making transgenic pigs for lung transplants - the first major industry investment in more than a decade. It says that it wants pig lungs in clinical trials by 2020. But others think that the timeline is unrealistic, not least because regulators are uneasy about safety and the risk of pig organs transmitting diseases to immunosuppressed humans. "I think we're getting closer, in terms of science. But I'm not yet convinced we've surpassed all the critical issues that are ahead of us. Xenotransplantation has had a long enduring reality that every time we knock down a barrier, there's another one just a few steps on."
Over a decade of little progress towards whole organ transplants, a few research teams and start-up companies began pursuing pig tissue transplants: a much simpler goal than using solid organs because the immune response is not as severe. In April, Chinese regulators approved the use of pig corneas from which all the cells have been removed. Also on the near horizon are pig insulin-producing islet cells that might be transplanted into people with diabetes. The first commercially available islets are likely to come from technology designed by Living Cell Technologies, that has developed a process to encapsulate pig islet cells in a gelatinous 'dewdrop' that protects them from the human immune system. The product is currently in late-stage clinical trials in several countries. Patients implanted with the cells have survived more than nine years without evidence of immune rejection or infection. "I think people are coming around to look at xenotransplantation in a more-favourable light knowing that we have strong safety data."
Solid organs still pose a challenge. The handful of researchers who have continued to work with them have solved some of the problems, such as identifying other key pig antigens and the correct combinations of immunosuppressant drugs. But different organs have different problems: kidneys may be safer than hearts, for instance. Lungs are extremely difficult to transplant, because they have extensive networks of blood vessels, which provides more opportunities for primate blood to meet pig proteins and to coagulate.
TOWARDS AN IMPLANTED ARTIFICIAL KIDNEY
Wednesday, November 11, 2015
Filtration in biology is a tractable problem to solve, to build devices that can carry out at least part of the function of organs like the kidneys by removing unwanted substances from the blood. There are already numerous fairly effective means of carrying out dialysis outside the body, for example. These technologies will improve and minimize in the years ahead until the state of the art is a durable, implanted artificial organ intended to augment or largely replace the kidneys. One group of researchers here provide an update on their current progress towards this goal:
A surgically implantable, artificial kidney based on advances in nanofilter technology could be a promising alternative to kidney transplantation or dialysis for people with end stage renal disease (ESRD). Currently, more than 20 million Americans have kidney diseases, and more than 600,000 patients are receiving treatment for ESRD. "We aim to conduct clinical trials on an implantable, engineered organ in this decade, and we are coordinating our efforts with both the NIH and the U.S. Food and Drug Administration."
One component of the new artificial kidney is a silicon nanofilter to remove toxins, salts, some small molecules, and water from the blood. Researchers designed it based on manufacturing methods used in the production of semiconductor electronics and microelectromechanical systems. The new silicon nanofilters offer several advantages - including more uniform pore size - over filters now used in dialysis machines. The silicon nanofilter is designed to function on blood pressure alone and without a pump or electrical power.
The project's goal is to create a permanent solution to the scarcity problem in organ transplantation. "We are increasing the options for people with chronic kidney disease who would otherwise be forced onto dialysis." The artificial kidney being developed is designed to be connected internally to the patient's blood supply and bladder and implanted near the patient's own kidneys, which are not removed. A national team of scientists and engineers at universities and small businesses are working toward making the implantable artificial kidney available to patients.
PROGRESS TOWARDS ENGINEERED EXTRACELLULAR MATRIX
Thursday, November 12, 2015
Tissue engineers cannot yet construct sufficiently complex extracellular matrix structures with the correct mechanical and other properties to support the growth of entire organs from scratch. This is why the use of decellularized organs is one line of development, providing a donor extracellular matrix scaffold that can be repopulated with the recipient's cells. This news release is an example of the present state of the art in progress towards building sections of extracellular matrix:
Imitation may be the sincerest form of flattery but the best way to make something is often to co-opt the original process and make it work for you. In a sense, that's how scientists accomplished a new advance in tissue engineering. The team reports culturing cells to make extracellular matrix (ECM) of two types and five different alignments with the strength found in natural tissue and without using any artificial chemicals that could make it incompatible to implant. ECM is the fibrous material between cells in tissues like skin, cartilage, or tendon that gives them their strength, stretchiness, squishiness, and other mechanical properties. To help patients heal wounds and injuries, engineers and physicians have strived to make ECM in the lab that's aligned as well as it is when cells make it in the body. So far, though, they've struggled to recreate ECM. Using artificial materials provides strength, but those don't interact well with the body. Attempts to extract and build upon natural ECM have yielded material that's too weak to reimplant.
The team tried a different approach to making both collagen, which is strong, and elastin, which is stretchy, with different alignments of their fibers. They cultured ECM-making cells in specially designed molds that promoted the cells to make their own natural but precisely guided ECM. The strategy built on the insight that when cells clump together and grow in culture, they pull on each other and communicate as they would in the body. The molds therefore were made from agarose so that cells wouldn't stick to the sides or bottom. Instead they huddled together.
To guide ECM growth in particular alignments, the researchers used molds with very specific shapes, often constrained by pegs the cells had to grow around. For instance, to make a rod with collagen fibers aligned along its length (like a tendon) they cultured chondrocyte cells in a dog bone-shaped mold with loops on either end. To make a skin-like "trampoline" of elastin, where the ECM fibers run in all directions, they cultured fibroblast cells to grow in an open area suspended at the center of a honeycomb shape. After the researchers grew various forms of ECM, they did some stress testing. They took the dog bone-shaped tissues made precise measurements of the tissue strength under the force of being pulled apart. The measurements confirmed the self-assembled tissue was about as strong as that found in some of the body's tissues, such as skin, cartilage or blood vessels.
RESEARCHERS AIM FOR LIMB REGENERATION BY 2030
Thursday, November 12, 2015
It is interesting to see more researchers willing to place timelines on the regeneration or tissue engineering of replacement limbs, as is the case here. It is a sign of confidence and progress in the foundations of the field. So far the closest approach to this goal has been the decellularization of donor rat limbs, followed by replacement of cells with those of a potential recipient to produce a leg ready for transplantation, but it seems to me just as likely that human limb regrowth will result from advances in the understanding of regeneration in species like salamanders, in which individuals are capable of regenerating lost limbs.
The University of Connecticut has announced the launch of its new grand research challenge: regeneration of a human knee within 7 years, and an entire limb within 15 years. This major international research undertaking, called The HEAL Project, stands for Hartford Engineering a Limb. This is a collaboration of top tissue engineering, regenerative medicine, and bioengineering experts dedicated to the mission of advancing the fields and developing future therapies for patients living with musculoskeletal defects or who have limb injury or loss. "The launch of the HEAL Project is a transformative moment for science and medicine. This is the first international effort ever for knee and limb engineering. The time is now to pursue this much needed grand challenge to benefit those patients suffering from debilitating knee injuries, osteoarthritis, or affected by the devastating effects of limb injury or loss."
Researchers project it will take 7 to 15 years for first knee and then limb regeneration breakthroughs based on the time it took to successfully regenerate bone and ligaments. To work toward its milestones, HEAL will be building upon the latest advances in regenerative engineering, tissue regeneration, stem cell research, nano-materials science, physics, developmental biology, and advanced manufacturing. In addition, researchers will conduct clinical trials to test any new promising therapies. "Our research group will harness the concepts of convergence, bringing together our talents, latest scientific knowledge, research advances, and cutting-edge tools to help make our grand challenge of knee and limb regeneration a reality."
INVESTIGATING MITOCHONDRIAL REJUVENATION DURING CELLULAR REPROGRAMMING AND EMBRYONIC DEVELOPMENT
Friday, November 13, 2015
The changes involved in producing induced pluripotent stem cells from ordinary somatic cells, such as those from a skin sample, are accompanied by mitochondrial rejuvenation, a clearance of mitochondrial damage associated with aging. This also occurs in the earliest stages of embryonic development, turning old parental cells into young child cells. It is not beyond the bounds of the possible to suggest that perhaps just this mitochondrial part of the transformation could be split off and used as the basis for a therapy - though other approaches to mitochondrial repair are far closer to realization. Also, it may well be that mitochondria are so vital to cellular function that it is impossible to safely induce such radical changes in adult tissues given the way in which cells are presently structured. As usual, the only way to find out is to dig deeper into what is going on under the hood, as researchers are doing here. The original research release is in PDF format only, unfortunately, but it provides a better explanation than any of the other available resources:
A new study suggests that old mitochondria - the oxygen-consuming metabolic engines in cells - are roadblocks to cellular rejuvenation. By tuning up a gene called Tcl1, which is highly abundant in eggs, researchers were able to suppress old mitochondria to enhance a process known as somatic reprogramming, which turn adult cells into embryonic-like stem cells. Researchers found that Tcl1 does its job by suppressing mitochondrial polynucleotide phosphorylase (PnPase), thereby inhibiting mitochondrial growth and metabolism.
Stem cell researchers had known that egg (or oocyte) cytoplasm contains some special unknown factors that can reprogramme adult cells into embryonic-like stem cells, either during egg-sperm fertilisation or during artificial cloning procedures. While researchers had invented a technology called induced pluripotent stem cell (iPSC) reprogramming to replace the ethically controversial oocyte-based reprogramming technique, oocyte-based reprogramming was still deemed superior in complete cellular reprogramming efficiency. To address this shortfall, researchers combined oocyte factors with the iPSC reprogramming system. Their bioinformatics-driven screening efforts1 led to two genes: Tcl1 and its cousin Tcl1b1. After a deeper investigation, the team found that the Tcl1 genes were acting via the mitochondrial enzyme, PnPase. "We were quite surprised, because nobody would have thought that the key to the oocyte's reprogramming powers would be a mitochondrial enzyme. The stem cell field's conventional wisdom suggests that it should have been some other signalling genes instead."
Tcl1 is a cytoplasmic protein that binds to the mitochondrial enzyme PnPase. By locking PnPase in the cytoplasm, Tcl1 prevents PnPase from entering mitochondria, thereby suppressing its ability to promote mitochondrial growth and metabolism. Thus, an increase in Tcl1 suppresses old mitochondria's growth and metabolism in adult cells, to enhance the somatic reprogramming of adult cells into embryonic-like stem cells. These new insights could boost efficacy of the alternative, non-oocyte based iPSC techniques for stem cell banking, organ and tissue regeneration, as well as further our understanding of how cellular metabolism rejuvenates after egg-sperm fertilisation.
AN EXAMPLE OF ENGINEERING IMMUNE CELLS TO TARGET CANCER
Friday, November 13, 2015
Here I'll point out a recent update on one line of targeted cancer therapies presently under development. These forms of treatment will ultimately replace the much less discriminating therapies of today, and will be used to control and clear cancers with few side-effects for the patient. Forms of immunotherapy that involve altering immune cells to target the distinctive chemistry of cancer cells are one of the most promising of present strategies, as they have been shown to be effective against metastatic cancer. If metastasis can be controlled, most cancers will become far less threatening as a result:
Biomedical engineers have developed specialized white blood cells - dubbed "super natural killer cells" - that seek out cancer cells in lymph nodes. For tumor cells, the lymph nodes are a staging area and play a key role in advancing metastasis throughout the body. In the study, the biomedical engineers killed the cancerous tumor cells within days, by injecting liposomes armed with TRAIL (Tumor necrosis factor Related Apoptosis-Inducing Ligand) that attach to "natural killer" cells - a type of white blood cell - residing in the lymph nodes. Tthese natural killer cells became the "super natural killer cells" that find the cancerous cells and induce apoptosis, where the cancer cells self-destruct and disintegrate, preventing the lymphatic spread of cancer any further. "In our research, we use nanoparticles - the liposomes we have created with TRAIL protein - and attach them to natural killer cells, to create what we call 'super natural killer cells' and then these completely eliminate lymph node metastases in mice."
In cancer progression, there are four stages. At stage I, the tumor is small and has yet to progress to the lymph nodes. In stages II and III, the tumors have grown and likely will have spread to the lymph nodes. At the stage IV, the cancer has advanced from the lymph nodes to organs and other parts of the body. Between 29 and 37 percent of patients with breast, colorectal and lung cancers are diagnosed with metastases in their tumor-draining lymph nodes - those lymph nodes that lie downstream from the tumor, and those patients are at a higher risk for distant-organ metastases and later-stage cancer diagnoses. In January 2014, the researchers published research that demonstrated by attaching the TRAIL protein to white blood cells, metastasizing cancer cells in the bloodstream were annihilated. "So, now we have technology to eliminate bloodstream metastasis - our previous work - and also lymph node metastases."