FIGHT AGING! NEWSLETTER
April 13th 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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- SENS Research Foundation Newsletter for April 2015
- Inching Closer to Neuregulin-1 as a Target for Regenerative Heart Therapies
- The Dark Matter of Senescent Cell Clearance Research: Other Approaches and Quiet Research Groups
- Stem Cell Transplantation Suppresses Cellular Senescence in Aging Rat Hearts
- Telomere Erosion is Complex, But Looks More Like a Measure of Damage than a Source of Damage
- Latest Headlines from Fight Aging!
- Media Attention Given to Philanthropic Funding of Early Stage Longevity Science
- A Survey of Recent Initiatives in Longevity Science
- Vigorous Activity Correlates with Lower Mortality Rate
- A Review of Promoting Health and Longevity Through Diet
- An Introduction to IGF-1 in Aging
- A Potential Approach to Clearing Cytomegalovirus
- Investigating the Mechanical Details of AGE Accumulation in Tissues
- Loss of TIMP1 and TIMP3 Maintains Youthful Stem Cell Activity in Aging Mice
- How Lipofuscin Disrupts Autophagy in the Retina
- Reviewing Immune Checkpoint Targeting in Cancer Research
SENS RESEARCH FOUNDATION NEWSLETTER FOR APRIL 2015
The SENS Research Foundation's April newsletter turned up in my inbox today, along with the news that registration is open for the Rejuvenation Biotechnology 2015 conference to be held later this year in San Francisco, California. This conference series aims to lay the groundwork for closer collaboration between academia and industry in the forthcoming development and commercialization of the first generation of effective treatments for aging. The first conference in the series was held last year and well-received by all accounts; there are a number of very interesting presentation videos to be found online.
Registration NOW OPEN for the 2015 Rejuvenation Biotechnology Conference
SENS Research Foundation is pleased to announce that registration is now open for the 2015 Rejuvenation Biotechnology Conference. For the second year in a row, the Rejuvenation Biotechnology Conference will convene the foremost leaders from academia, industry, investment, policy, and disease advocacy to share knowledge, strategize, and explore the potential for a truly effective approach to managing all age-related disease.
The Rejuvenation Biotechnology Conference Poster Session is now open for abstract submissions. Participants will present their work during two evening poster sessions at the conference. Abstracts are due June 1st. Primary authors of accepted abstracts will be notified on July 1, 2015.
SRF Education: 2015 Summer Scholars Class Selected
SENS Research Foundation is pleased to announce the completion of our evaluation process of an outstanding group of applicants for the 2015 SRF Summer Scholars Program. Sixteen students have been selected to conduct research at eight institutions. Prior host institutions (the Buck Institute for Research on Aging, the Harvard Stem Cell Institute, the University of Oxford, the Wake Forest Institute for Regenerative Medicine and the SRF Research Center) will be joined this year by new host partners Sanford-Burnham Medical Research Institute, the Scripps Research Institute, and Stanford University.
Thank You to our Amazon Smile Users
Everyone at SENS Research Foundation would like to thank our supporters who have made us the recipient of their AmazonSmile donations. We just received a check from the AmazonSmile Foundation based on your purchases from October 1 - December 31st. If you'd like to take this opportunity to help fund our fight against age-related disease, it's not too late to join in! Just sign up, and remember to go to AmazonSmile whenever you are shopping on Amazon.
The latest question of the month is a fairly general query on progress in diagnostic technologies, and the response is a long one. You should definitely head on over and read the whole thing at the SENS Research Foundation website rather than just the preamble quoted below:
Question of the Month #9: What is the role of novel diagnostics in rejuvenation biotechnologies?
Q: I'm a biotech graduate currently reading up to produce a PhD proposal. My main areas of interest are in diagnostics, and after reading about rejuvenation biotechnology I've become very interested in contributing to regenerative medicine against ageing. Is there a crossover between diagnostics and the work under SENS Research Foundation? If so I'd love to hear about it.
A: There is definitely a need for novel diagnostics, particularly in the course of the critical three decades ahead, as the first rejuvenation biotechnologies enter into human clinical use.
As you probably know, rejuvenation biotechnologies are therapies that prevent, arrest, and potentially reverse age-related disease and dysfunction using a "damage-repair" approach. Such therapies work by directly removing, repairing, replacing, or rendering harmless the cellular and molecular damage wrought in our tissues by the biological aging process. This contrasts rejuvenation biotechnology with today's medical approach, in which the target is the metabolic pathways that contribute to such damage instead of the damage itself. Current medicines are thus typically first tested for their effects on the metabolic "risk factors" that ultimately contribute to diseases of aging.
Rejuvenation biotechnologies, by contrast, will not directly perturb these metabolic processes (although in some cases they may maintain or restore metabolic processes in youthful condition, when aging normally leads to their dysfunction). Effects on these "risk factors" will therefore either be nonexistent, or manifest themselves many years later, when recipients continue to exhibit youthful metabolic function, in contrast to the age-related aberrations that emerge in untreated aging persons.
All this means that new ways of evaluating these novel medicines will be needed - first for their initial preclinical and clinical development, and later for their clinical use. Instead of reflecting dynamic, regulated physiological and metabolic processes, diagnostics that will facilitate the development and use of rejuvenation biotechnology will be noninvasive markers of the presence, removal, or repair of the cellular and molecular damage that accumulates in aging tissues.
INCHING CLOSER TO NEUREGULIN-1 AS A TARGET FOR REGENERATIVE HEART THERAPIES
Neuregulin-1 (NRG-1) is one of those proteins that shows up in a number of places in research relevant to aging and regeneration, and in a variety of quite different contexts. That suggests it is probably not central to the processes of interest, but rather sufficiently related that manipulating it can alter the operation of multiple systems influential in maintenance of tissues and healing. Biology is very complex indeed, and the fact that any given process of interest can be altered by changing circulating levels of any of a score of proteins makes it a real challenge to determine what is actually going on under the hood.
So we have NRG-1 as a possible suspect in naked mole-rat longevity, based on measured levels in the brains of old individuals versus those of old mice and humans. Levels of NRG-1 in the brain seem to correlate with species longevity, in rodents at least. All of that is quite different from the role of NRG-1 in heart regeneration, however: it was noted some years ago that is possible to spur greater than usual tissue maintenance in heart tissues by artificially raising levels of NRG-1. The heart is lacking in regenerative capacity in comparison to other tissue types, so there is some interest in the medical community in finding ways to safely and temporarily work around that limitation.
That heart tissue research took place back in 2009, which rather underscores the point that medical science is not something that moves at the pace of politics or sports. When we talk about the incredible pace of research today, we mean that sometimes you'll see follow-on papers and new advances two to three years after an initial breakthrough. More commonly, expect five to ten years to elapse between an initially promising result and some more practical implementation, and it may take numerous cycles of a few years of work each to make meaningful progress. This is fast in comparison to the past, but it doesn't fit well with the modern news cycle, or with the short-term memory of the public. Supporting science isn't an easy sell to a world that wants all the answers and all of the shiny things right now, or tomorrow at the very latest. Still, here you have the latest in the story of neuregulin-1 and heart regeneration, another incremental advance towards the goal of building a regenerative therapy based on the mechanisms explored in this paper. That end goal still seems about as far away as it was in 2009, frankly:
Research finds turbo-charging hormone can regrow the heart
Researchers have discovered a way to stimulate muscle regrowth in the heart of a mouse. The animal study found it was possible to regenerate muscle cell numbers in the heart by up to 45%, by 'turbo-charging' a hormone that helped coordinate cell growth. "Unlike blood, hair or skin cells, which can renew themselves throughout life, cell division in the heart virtually comes to a standstill shortly after birth, which means the heart can't fully regenerate if it is damaged later in life. Previous studies have demonstrated that it is possible to coax heart muscle cells to proliferate again, but only at very trivial levels. What the research team has been able to do is boost heart muscle cell numbers by as much as 45% after a heart attack."
The scientists focused on a signalling system in the heart driven by a hormone called 'neuregulin'. By switching the neuregulin pathway to 'turbo charge', the researchers found that heart muscle cells continued to divide in a spectacular way in both the adolescent and adult periods. Stimulating the neuregulin pathway during a heart attack led to replacement of lost muscle. "This big achievement will focus the attention of the field on heart muscle cell replacement as a therapeutic option for ischemic heart disease. The dream is that one day we will be able to regenerate damaged heart tissue, much like a salamander can regrow a new limb if it is bitten off by a predator. Just imagine if the heart could learn to regrow and heal itself. That would be the ultimate prize."
ERBB2 triggers mammalian heart regeneration by promoting cardiomyocyte dedifferentiation and proliferation
The murine neonatal heart can regenerate after injury through cardiomyocyte proliferation, although this capacity markedly diminishes after the first week of life. Neuregulin-1 (NRG1) administration has been proposed as a strategy to promote cardiac regeneration. Here, using loss- and gain-of-function genetic tools, we explore the role of the NRG1 co-receptor ERBB2 in cardiac regeneration.
NRG1-induced cardiomyocyte proliferation diminished one week after birth owing to a reduction in ERBB2 expression. Cardiomyocyte-specific Erbb2 knockout revealed that ERBB2 is required for CM proliferation at embryonic/neonatal stages. Induction of a constitutively active ERBB2 (caERBB2) in neonatal, juvenile and adult cardiomyocytes resulted in cardiomegaly, characterized by extensive cardiomyocyte hypertrophy, dedifferentiation and proliferation. Transient induction of caERBB2 following myocardial infarction triggered cardiomyocyte dedifferentiation and proliferation followed by redifferentiation and regeneration. Thus, ERBB2 is both necessary for CM proliferation and sufficient to reactivate postnatal cardiomyocyte proliferative and regenerative potentials.
THE DARK MATTER OF SENESCENT CELL CLEARANCE RESEARCH: OTHER APPROACHES AND QUIET RESEARCH GROUPS
There is no such thing as a scientific breakthrough. Advances in science and its application don't emerge from out of the blue, especially in very complex fields such as medical research, where any meaningful progress requires a team, and in very close-knit fields such as aging research, where everyone knows everyone else and at least a little about what they are working on. If the latest news looks like a breakthrough to you, that just means that you didn't know much about the people who spent years working on the foundations, the incremental advances, and the early prototypes. And why should you? You have your life to live, your own work to get on with. There is far too much going on in the world for any one individual to notice.
That is just as true of me as anyone else. I certainly don't have a view of every interesting corner of the research community, and even now there are no doubt numerous scientists working on projects relevant to the SENS model for human rejuvenation through repair of cellular and molecular damage whom I have never heard of. Even the highly networked folk at the SENS Research Foundation are surprised by what turns up some days, and they have far more insight than I. One of the consequences of rapid progress in biotechnology is that people outside the core aging research community have the ability to make useful and important contributions. Most of the technologies proposed as means of damage repair to treat aging did not originate in the aging research community, and I'd expect that state of affairs to continue as new options arise. So if you have a few fellows in a well-equipped lab in India or on the other side of a language barrier in China, tinkering on a possible approach and actually getting somewhere interesting when it comes to a proof of concept, it is quite plausible that we'd never hear anything of it until after the fact.
Frankly, it's hard enough just to keep abreast of what is going on in the US. Take senescent cell clearance for example; the demonstration in 2011 of improved health in accelerated aging mice via removal of senescent cells was clearly a wake up call for a number of researchers. In what is a comparatively short time for the research community, we have seen the recent publication on the use of existing drugs to clear senescent cells in ordinary mice, showing improved healthspan as a result, and a startup company was funded by the Methuselah Foundation earlier this year to have a go at commercializing a different approach to the removal of senescent cells. That is just the stuff that makes it to the point of press release and news in this community, however. It is not all that is going on, and the 2011 technology demonstration wasn't a sudden breakthrough from nowhere: work on cellular senescence with an eye to selectively destroying these unwanted cells was underway for years before that point.
For example, Cenexys has existed since 2009 and claims to "develops therapies to clear senescent cells from the body to treat age-related diseases." Perhaps it is a dead venture, judging by the lack of news, but perhaps not; the principal director certainly has an interesting and successful history. Then there is SIWA Regenerative Medicine, a company that has apparently also been working on senescent cell clearance for a while. Being first alas often means being bypassed at some speed by later ventures, but SIWA seems to be alive and kicking:
SIWA Regenerative Medicine
We have developed inventions that we believe can retard or reverse the aging process, reduce inflammation and enhance stem cell transplant success by promoting tissue and organ regeneration. We believe these inventions also can be applied as therapies in lessening the impact of diseases associated with aging. Specifically, we have developed processes for identifying and removing senescent cells that inhibit cellular regeneration to obtain the recognized benefits in health and function associated with the results of such cellular regeneration. We have filed multiple families of patent applications covering our inventions.
We were the first to publish a practical description of selectively removing senescent cells in order to retard or reverse aging. In a November 2011, paper that appeared in the journal Nature, other researchers reported creation of an artificial system that independently confirmed the soundness of the scientific principles behind the approach and other intellectual property that we published years before.
SIWA's Approach To Clearing Senescent Cells To Increase Healthspan
SIWA Regenerative Medicine Corporation announced today that Lewis Gruber, founder, CEO and inventor of SIWA's injectable drug-based approach to clearing senescent cells for increasing healthspan, will join scientists from Charles River Laboratories at 2:45 p.m. on March 23, 2015 in San Diego at the Society of Toxicology Annual Meeting to discuss and present SIWA's demonstration of successful use in naturally aged mice of a monoclonal version of SIWA's drug candidate. The results of the work performed by Charles River for SIWA include an increase in gastrocnemius muscle mass and reduction of a senescent cell mRNA marker to the level of young mouse controls.
The company has made some interesting patent filings over the past decade, such as Selective Removal of Cells Having Accumulated Agents:
The present invention makes use of the discovery that the differential resonant frequency of a cell caused by the accumulation of at least one agent that causes, or is associated with, a pathological or undesired condition, such as proteins, lipids, bacteria, viruses, parasites or particles, may be used to distinguish and eliminate cells in which the accumulated agent leads to a difference in the resonant frequency of the cell, by applying ultrasound treatment. The cells associated with the accumulated agent have a resonant frequency which is distinct from cells of the same type. By selecting the frequency of the ultrasound applied to the tissue to feed energy into the resonant frequency, the cells with the accumulated agent will be destroyed or induced to undergo apoptosis.
STEM CELL TRANSPLANTATION SUPPRESSES CELLULAR SENESCENCE IN AGING RAT HEARTS
The usual model for presently available stem cell therapies is for stem cells to be taken from the patient, often from bone marrow, greatly expanded in number, and reintroduced into target tissues. This has been shown over the past decade to produce a wide range of benefits, with an increasing degree of confidence and reliability as techniques have improved. Stem cell transplants have been demonstrated to suppress inflammation, encourage greater regeneration on the part of native cell populations, and improve various other measures of tissue health. Different approaches and different stem cell types tend to produce a different mix of benefits. At this point some types of cell therapy are definitely more robust than others: stem cell treatments for joint issues and heart disease have a much greater expectation of benefits than, say, trying to treat autoimmune disorders or nerve damage.
Stem cell therapies are still under continued development. It is far from the case that every mechanism involved in the beneficial effects of stem cell transplantation is fully understood. A broad range of work is ongoing in many laboratories with the aim of creating a catalog of the effects of stem cell treatments, all of which feeds back into efforts to build better versions of existing cell therapies and introduce new therapies where none exist. An example of this sort of research is linked below: the researchers show that transplantation of mesenchymal stem cells reduces a few common measures of cellular senescence in rat hearts, both in cell culture and living animals. This may be important from the point of view of aging and age-related decline in tissue function. Senescent cells can no longer divide. They accumulate in damaged and old tissues, a defensive reaction that probably evolved to reduce cancer incidence by disabling replication in cells more likely to become cancerous. Unfortunately senescent cells emit all sorts of harmful molecular signals, and in large numbers they cause significant inflammation, tissue remodeling, and degradation of function. The presence of senescent cells is one of the contributing causes of degenerative aging.
It isn't clear from this research whether the use of stem cells produces any reversal of cellular senescence versus prevention of senescence only. By its definition senescence is an irreversible state of growth arrest, but there is a modest amount of evidence to suggest that at least some tissue types can cross the that line in both directions given the right stimulus.
Study Showing How Stem Cells Slow Aging May Lead to New Heart Failure Treatments
Aging is a complex and multifaceted process, resulting in damage to molecules, cells and tissue that in turn leads to declining organs. Mesenchymal stem cells, found in bone marrow, can generate bone, cartilage and fat cells that support the formation of blood and fibrous connective tissue. These stem cells also can be coaxed in the laboratory into becoming a variety of cell types, from cardiomyocytes (heart muscle cells) and neurons, to osteoblasts, smooth muscle cells, and more.
Several studies have already shown that MSCs can reverse age-related degeneration of multiple organs, restore physical and cognitive functions of aged mice, and improve age-associated osteoporosis, Parkinson's disease and atherosclerosis. "We previously showed that MSCs offer an anti-senescence action on cardiomyocytes as they grow older. However, what we didn't know was whether these findings from a cellular model could be applied to more physiological conditions in whole animals. That's what we wanted to learn with this study." They decided to explore their question using rats. After injecting MSCs into rat cardiomyoctyes being cultured in lab dishes and receiving encouraging results, they repeated the procedure on a group of young (4 months old) rats and old (20 months) rats, too. The results in both instances demonstrated that MSCs have a significant anti-aging effect.
Bone Marrow Mesenchymal Stem Cell Transplantation Retards the Natural Senescence of Rat Hearts
Bone marrow mesenchymal stem cells (BMSCs) have been shown to offer a wide variety of cellular functions including the protective effects on damaged hearts. Here we investigated the antiaging properties of BMSCs and the underlying mechanism in a cellular model of cardiomyocyte senescence and a rat model of aging hearts. Neonatal rat ventricular cells (NRVCs) and BMSCs were cocultured in the same dish with a semipermeable membrane to separate the two populations. Monocultured NRVCs displayed the senescence-associated phenotypes, characterized by an increase in the number of β-galactosidase-positive cells and decreases in the degradation and disappearance of cellular organelles in a time-dependent manner. The levels of reactive oxygen species and malondialdehyde were elevated, whereas the activities of antioxidant enzymes superoxide dismutase and glutathione peroxidase were decreased, along with upregulation of p53, p21Cip1/Waf1, and p16INK4a in the aging cardiomyocytes.
These deleterious alterations were abrogated in aging NRVCs cocultured with BMSCs. Qualitatively, the same senescent phenotypes were consistently observed in aging rat hearts. Notably, BMSC transplantation significantly prevented these detrimental alterations and improved the impaired cardiac function in the aging rats. In summary, BMSCs possess strong antisenescence action on the aging NRVCs and hearts and can improve cardiac function after transplantation in aging rats. The present study, therefore, provides an alternative approach for the treatment of heart failure in the elderly population.
TELOMERE EROSION IS COMPLEX, BUT LOOKS MORE LIKE A MEASURE OF DAMAGE THAN A SOURCE OF DAMAGE
Telomeres are repeating DNA sequences of that cap the ends of chromosomes. A little of that length is lost when DNA is copied during cell division, and telomere length is thus a part of the system of linked mechanisms that limits the replicative life span of ordinary somatic cells. The vast majority of cells in the body are somatic cells, and they are subject to this Hayflick limit: they can only divide a few dozen times before self-destructing or lapsing into a senescent state. Tissues consisting of somatic cells are maintained by stem cell populations that deliver a supply of fresh somatic cells with long telomeres: when a stem cell divides one of the daughter cells remains a stem cell while the other differentiates to become a somatic cell of a specific type.
How do stem cells continue to deliver long-telomere descendants if they are consistently dividing? They lengthen their telomeres through the activity of telomerase, an enzyme whose chief identified function is to add more repeating DNA sequences to the ends of telomeres. In our species telomerase is only active in some circumstances, such as in stem cells and cancers, but many other species, including other mammals, have somewhat different telomere dynamics. That is a basic sketch of a very complex system: cells have a countdown mechanism, tissues are largely made of cells that cannot adjust that mechanism, and a small, select group of cells that continually reset their own countdown are responsible for building new cells as the old ones run down and die.
Average telomere length, proportion of very short telomeres, and other similar statistics are usually measured in immune cells present in a blood sample. Average telomere length decreases with advancing age, but also with illness. On a fairly short time frame this measure can move up and down: the erosion over a lifetime is a long slope made up of a lot of oscillation about a mean. A range of research and development over the past decade has focused on restoring telomere length as a potential life-extending treatment, based on the idea that loss of telomere length is a contributing cause of aging. A number of early attempts failed to get anywhere, but a few years ago researchers demonstrated improved health and life extension in mice via artifically increased telomerase activity. The root causes are not yet firmly pinned down, but probably have a lot to do with increased stem cell activity and consequently better tissue and organ maintenance over the course of degenerative aging. That, of course, is not the same thing as merely having longer telomeres on average in somatic cells.
The bulk of the rest of the evidence regarding telomere biology looks very much to me as though average telomere length is a very indirect reflection of the state of our biology as a whole. How damaged are we? How active are our stem cells? What is being measured by average telomere length in white blood cells is some amalgam of the pace of cell replacement by stem cells, state of immune system health, and the level of underlying damage that drives changes in those biological systems. There are counter-arguments to that view, such as the recent discovery that telomeres seem to influence gene expression profiles across the genome differently depending on their length.
Here is an open access paper that looks at some of the recent research into telomere length and its role in our biology, concluding that "recently obtained knowledge shifts the telomere paradigm from a simple clock counting cell divisions to a more complex process recording the history of stress exposure within a cell lineage."
Telomeric aging: mitotic clock or stress indicator?
Telomeres are located at chromosomal ends and allow cells to distinguish chromosome ends from double-strand breaks and protect chromosomes from end-to-end fusion, recombination, and degradation. Telomeres are not linear structures, telomeric DNA is maintained in a loop structure due to many key proteins. This structure serves to protect the ends of chromosomes. Telomeres are subjected to shortening at each cycle of cell division due to incomplete synthesis of the lagging strand during DNA replication owing to the inability of DNA polymerase to completely replicate the ends of chromosome DNA ("end-replication problem"). Therefore, they assume to limit the number of cell cycles and act as a "mitotic clock". Shortened telomeres cause decreased proliferative potential, thus triggering senescence.
Telomere length is highly heterogeneous in somatic cells, but generally decreases with age in proliferating tissues thereby constituting a barrier to tumorigenesis but also contributing to age-related loss of stem cells. Telomerase maintains telomere length by adding telomeric DNA repeats to chromosome ends in prenatal tissues, gametes, stem cells, and cancerous cells. In proliferative somatic cells, it is usually inactive or expressed at levels that are not high enough to maintain the stable telomere length. Repair of critically short ("uncapped") telomeres by telomerase enzyme is limited in somatic cells, and cellular senescence, apoptosis and/or a permanent cell cycle arrest are triggered by a critical accumulation of uncapped telomeres. Shortened telomeres have also been observed in a variety of chronic degenerative diseases, including type 2 diabetes, cardiovascular disease, osteoporosis, and cancer. The specific molecular mechanism by which short telomeres trigger the development of diseases is, however, not yet determined. It has been proposed that telomere shortening per-se might not be a direct signal for cell cycle arrest, but rather the consequence of telomere loss. It can promote a pro-inflammatory secretory phenotype, in turn contributing to a variety of age-related diseases.
Replicative attrition, however, is not the only explanation for age-dependent telomere shortening. Some studies demonstrate that this process can be non-replicative and significantly stress-dependent because of the deficiency of a telomere-specific damage repair. Oxidative stress is one of the most important stress factors causing telomere shortening. Telomeric DNA is known to be more susceptible to oxidative damage than non-telomeric DNA. In human cell lines, telomeres generally shorten by 30-200 base pairs at each round of DNA replication, but only approximately 10 base pairs of this reduction are a consequence of the end-replication problem; the remaining loss is likely owing to oxidative damage.
The complexity of processes underlying age-related telomere erosion came from several longitudinal studies of telomere dynamics in vivo. Traditionally, it was assumed that telomeres are stable structures, which may be changed only in unidirectional way - shortening over the lifetime. Today, however, it has become increasingly clear that telomeres shortening over time in an oscillatory rather than linear fashion and they may be either shortened or lengthened under certain conditions. Several pilot studies indicate that treatment procedures targeting to reduce stress, e.g. meditation, along with the enhanced physical activity and changes in dietary patterns, can slow or even reverse telomere shortening owing to the elevated telomerase activity. The elongation of telomeres may be caused by the telomerase-mediated extension or appear due to the "pseudo-telomeric lengthening." The latest is due to the fact that, since telomere lengths are commonly measured in a mixed leukocyte population, mean telomere length can increase because of a redistribution of cell subpopulations, i.e., change in the percentage of various cell types in the blood samples.
Given data from recent studies, a concept that replicative senescence is a "clocked" and stepwise process seems doubtful, and repeatedly reported reproducibility of both replicative lifespans and rates of telomere shortening could be the result of stochastic rather than programmed events. In other words, it seems that telomeres can be an indicator of stress-induced damage level rather than a mitosis "counter." Moreover, considering the fact that oxidative stress represents a common causative mechanism for both age-related telomere shortening and age-associated disease, there are reasons to believe that relationships between telomere length and morbidity or mortality are non-causal, and telomere length can be an indicator of previous exposure to oxidative stress that may, in turn, cause both greater telomere shortening and higher risk of chronic disease. Thereby, perceived stressful events, though correlated with telomere length, may likely have independent effects on health and longevity. By summarizing recent research findings, it is concluded that recently obtained knowledge "shifts the telomere paradigm from a simple clock counting cell divisions to a more complex process recording the history of stress exposure within a cell lineage." This point of view, based on the accumulated evidence, appears plausible, and requires further investigation.
LATEST HEADLINES FROM FIGHT AGING!
MEDIA ATTENTION GIVEN TO PHILANTHROPIC FUNDING OF EARLY STAGE LONGEVITY SCIENCE
Monday, April 6, 2015
Much of the most important research into aging, work that might produce the foundations of rejuvenation therapies, is still funded only by philanthropic donations at this stage. As the state of the science advances this support is receiving more attention from the press and public, part of a process that will see more funding institutions join in, arriving after initial technology demonstrations such as clearance of senescent cells. Institutional funding is very conservative and almost never provides support for the early stage, high risk research that advances the state of the art. Philanthropy is needed because little progress would happen without it.
Seated at the head of a table for 12 with a view of the city's soaring skyline, Peter Thiel was deep in conversation with his guests, eclectic scientists whose research was considered radical, even heretical. It was 2004 and Thiel had recently made a tidy fortune selling PayPal, which he co-founded, to eBay. He had spent what he wanted on himself and was now soliciting ideas to do good with his money.
Among the guests was Cynthia Kenyon, a molecular biologist and biogerontologist who had garnered attention for doubling the life span of a roundworm by disabling a single gene. Aubrey de Grey, a British computer scientist turned theoretician who prophesied that medical advances would stop aging. And Larry Page, co-founder of an Internet search darling called Google that had big ideas to improve health through the terabytes of data it was collecting. The chatter at the dinner party meandered from the value of chocolate in one's diet to the toll of disease on the U.S. economy to the merits of uploading people's memories to a computer versus cryofreezing their bodies. Yet the focus kept returning to one subject: Was death an inevitability - or a solvable problem?
A number of guests were skeptical about achieving immortality. But could science and technology help us live longer, to, say, 150 years? Now that, they agreed, was a worthy goal. Within a few months, Thiel had written checks to Kenyon and de Grey to accelerate their work. Since then he has doled out millions to other researchers with what he calls "breakout" ideas that defy conventional wisdom. "If you think you can only do very little and be very incremental, then you'll work only on very incremental things. It's self-fulfilling. It's those who have an optimism about what can be done that will shape the future."
He and the tech titans who founded Google, Facebook, eBay, Napster and Netscape are using their billions to rewrite the nation's science agenda and transform biomedical research. Their objective is to use the tools of technology to understand and upgrade what they consider to be the most complicated piece of machinery in existence: the human body. The entrepreneurs are driven by a certitude that rebuilding, regenerating and reprogramming patients' organs, limbs, cells and DNA will enable people to live longer and better. The work they are funding includes hunting for the secrets of living organisms with insanely long lives, engineering microscopic nanobots that can fix your body from the inside out, figuring out how to reprogram the DNA you were born with, and exploring ways to digitize your brain based on the theory that your mind could live long after your body expires.
A SURVEY OF RECENT INITIATIVES IN LONGEVITY SCIENCE
Monday, April 6, 2015
The article linked below is largely characteristic of the recent media attention given to the SENS research programs, Google Venture's Calico Labs initiative, the Palo Alto Longevity Prize, and so forth. One noteworthy difference is space given to researcher Richard Miller's continued opposition to SENS and its principal proponent Aubrey de Grey, presently chief science officer of the SENS Research Foundation. Miller and de Grey have sparred in public in the past, but I wasn't aware that he continued to hold such views. Other opponents of SENS from past years have either fallen silent or turned around to show their support for the initiative in one way or another. The scientific advisory board of the SENS Research Foundation is an impressive lineup of luminaries of medical and life science research.
At this point Miller begins to look out of touch; de Grey heads a research foundation that has for years funded diverse scientific programs, leading to papers published in collaboration with renowned organizations in the field. Areas of research that de Grey has been advocating and funding for more than a decade are of late beginning to show their worth, such as clearance of senescent cells. It seems out of sorts to be claiming that de Grey "does not do any research" or that you "have never seen him present any data or research findings". Wise up, I say. Get with the times.
Aubrey de Grey of the pioneering SENS Research Foundation, a non-profit partially funded by Peter Thiel is optimistic about longevity. "I've taken plenty of heat for suggesting that someone is alive on earth now who will live to 1,000 and it's extraordinary to me that it's such an incendiary claim. People have a bizarre attitude towards aging. They think that it's some kind of separate thing that isn't a medical problem and isn't open to medical intervention."
However, many scientists do not agree with de Grey and are quite vocal about it. Dr. Richard Miller, who has a PhD in Human Genetics from Yale, has been critical of de Grey's work for quite sometime. Miller, along with many colleagues, published a scathing review of de Grey. In it writing that "the idea that a research programme organized around the SENS agenda will not only retard ageing, but also reverse it - creating young people from old ones - and do so within our lifetime, is so far from plausible that it commands no respect at all within the informed scientific community."
When asked if there have been any breakthroughs from SENS in the last 10 years that might sway him or his colleagues, Miller had this to say: "De Grey does not do any research, so far as I know. He comes to meetings a lot, but I have never seen him present any data or research findings. He does not have a lab; he theorizes. What de Grey does is not science - it's advertising. Asking if the SENS theories have been 'proven' in the last 10 years is like asking if there's new proof for the Nike Theory of Athletic Excellence, 'Just Do It.'"
However, de Grey says he is already doing lab work that targets lifelong accumulating damage. This damage is initially harmless when you're young but grows until your body succumbs to it. For example, de Grey says that people will get heart disease unless work is done to fix it but there are better ways to beat heart disease than surgery. He believes the idea of surgery altogether is primitive. "The technology that needs to be implemented to defeat heart disease is an enzyme or enzymes that can be introduced into human cells and allow them to clean up the garbage of the arteries themselves." De Grey says he has already created a proof of concept of this technology at his lab, albeit only in cell culture so far.
Apart from the lab work that needs to go into fulfilling these goals, there is the problem of societal acceptance. "The major obstacle is public popular misunderstanding of the nature of the crusade and the importance of it," says de Grey. In this respect, de Grey faces an enormous uphill battle from the scientific community. "If you were to poll the authors of the most recent 100 papers on aging in Aging Cell, or Journals of Gerontology, or Science, and ask them whether it will, in the next 100 years, be possible to turn old people young again...I think you'd get nearly 100 percent consensus that de Grey's claims are not based on evidence," says Miller.
The other major problem is the same one that arises in any great endeavor - cash. "We could be going three times faster if we had the funding that we needed, and that means that an awful lot of lives are being lost," says de Grey. "The amount of money that is needed to solve these problems is absolutely trivial. The budget that SENS currently has is a few million per year and I reckon that we would very realistically be in a position where the money wasn't limiting if we had only one more zero on that."
VIGOROUS ACTIVITY CORRELATES WITH LOWER MORTALITY RATE
Tuesday, April 7, 2015
While the evidence for the benefits of regular moderate exercise is voluminous and unassailable, there is comparatively little to back any one approach to exercise over another, and little to show that undertaking any more than moderate exercise will produce meaningfully greater benefits to long-term health. Thus is it always interesting to see studies that show a fairly robust correlation between differences in exercise and mortality rates, but as ever bear in mind that correlation does not imply causation. It is plausible that data reflects the tendency for healthier people to exercise more vigorously rather than it being a case of more vigorous exercise producing healthier people:
The researchers followed 204,542 people for more than six years, and compared those who engaged in only moderate activity (such as gentle swimming, social tennis, or household chores) with those who included at least some vigorous activity (such as jogging, aerobics or competitive tennis). They found that the risk of mortality for those who included some vigorous activity was 9 to 13 per cent lower, compared with those who only undertook moderate activity. "The benefits of vigorous activity applied to men and women of all ages, and were independent of the total amount of time spent being active. The results indicate that whether or not you are obese, and whether or not you have heart disease or diabetes, if you can manage some vigorous activity it could offer significant benefits for longevity."
The current advice is for adults to accumulate at least 150 minutes of moderate activity or 75 minutes of vigorous activity per week. "The guidelines leave individuals to choose their level of exercise intensity, or a combination of levels, with two minutes of moderate exercise considered the equivalent of one minute of vigorous activity. It might not be the simple two-for-one swap that is the basis of the current guidelines. Our research indicates that encouraging vigorous activities may help to avoid preventable deaths at an earlier age. Previous studies indicate that interval training, with short bursts of vigorous effort, is often manageable for older people, including those who are overweight or obese."
A REVIEW OF PROMOTING HEALTH AND LONGEVITY THROUGH DIET
Tuesday, April 7, 2015
This open access review paper comes from scientists long involved in calorie restriction research, in search of mechanisms to explain why a lower calorie intake results in improved health and life span, and attempting to quantify the benefits in humans:
The discovery that aging can be ameliorated by dietary, genetic, and pharmacological interventions has opened up the prospect of a broad-spectrum, preventive medicine for aging-related diseases. Single-gene mutations that extend animal lifespan can ameliorate natural, age-dependent loss of function and the pathology of aging-related diseases, including neurodegeneration. Furthermore, laboratory animal models of slowed aging, naturally long-lived species such as the naked mole rat, and some humans that achieve the age of 100 have all demonstrated that a long life is not inevitably associated with late-life disability and disease. Recent work has shown that specific dietary interventions can also promote long life and healthy old age.
Reduced food intake, avoiding malnutrition, can ameliorate aging and aging-associated diseases in invertebrate model organisms, rodents, primates, and humans. Dietary restriction (DR), implemented as chronic and coordinate reduced intake of all dietary constituents except vitamins and minerals, was first shown 80 years ago to extend lifespan in rats. DR in both rats and mice improves most aspects of health during aging. Exceptions include resistance to infection and wound healing. However, these conditions rapidly improve with re-feeding, and DR animals can then outperform controls. DR can produce substantial benefits with, for instance, ∼30% of DR animals dying at old ages without gross pathological lesions, compared with only 6% of ad-libitum-fed controls. DR started in young, adult Rhesus monkeys greatly improves metabolic health; prevents obesity; delays the onset of sarcopenia, presbycusis, and brain atrophy; and reduces the risk of developing and dying of type 2 diabetes, cancer, and cardiovascular disease.
Recent findings indicate that meal timing is crucial, with both intermittent fasting and adjusted diurnal rhythm of feeding improving health and function, in the absence of changes in overall intake. Lowered intake of particular nutrients rather than of overall calories is also key, with protein and specific amino acids playing prominent roles. Nutritional modulation of the microbiome can also be important, and there are long-term, including inter-generational, effects of diet. The metabolic, molecular, and cellular mechanisms that mediate both improvement in health during aging to diet and genetic variation in the response to diet are being identified. These new findings are opening the way to specific dietary and pharmacological interventions to recapture the full potential benefits of dietary restriction, which humans can find difficult to maintain voluntarily.
AN INTRODUCTION TO IGF-1 IN AGING
Wednesday, April 8, 2015
Of the many proteins and signaling pathways shown to influence the pace of aging, insulin-like growth factor 1 (IGF-1) is perhaps the most studied:
The really fun thing about discussing signaling networks (the inputs that let cells make decisions based on their environment) in aging is the wide range of ways that these pathways exert their influence. They take inputs (nutrition, hormones, toxic molecules) and use their existing programming (epigenetic state) to make decisions. Components that control one process, such as regulating body size, can play roles in completely different processes. Today, I'll discuss an example involving insulin-like growth factor 1 or IGF1, a close relative of insulin (a hormone that regulates blood glucose levels). While IGF1 was initially discovered due to its effect on blood glucose, it has since turned out to exert profound effects on a wide variety of processes that also include body size, longevity and cancer.
People who have too little IGF1 signaling may develop dwarfism (such as Laron syndrome), while too much IGF1 can lead to various forms of gigantism and increased risk of age-related diseases. IGF1 is an important molecule in development, as demonstrated by its key role in size determination; however IGF1 does much more than just determine how large an animal or human will be. IGF1 signaling has cropped up as a central player in fundamental studies on the genetic basis of aging. Using the small roundworm, Caenorhabditis elegans, scientists discovered that IGF1 signaling has a profound effect on aging. When IGF signaling is lost (in this case by losing the receptor, called DAF2 in the worm), juvenile worms enter into a developmental state characterized by small size and a greatly extended lifespan (the dauer). When IGF1 signaling is lost later in development, these worms develop into adults, but still display a long lifespan (twice as long as worms that have normal IGF signaling). This discovery was one of the first to identify a gene linked to extending lifespan, and represents an important milestone the modern field of aging.
Does reducing IGF1 signaling during aging extend lifespan in humans? Unfortunately, the jury is still out on this. Studies lowering IGF1 in adult mice have shown mixed results, however, two other lines of research discussed further support the role of IGF1 as major factor in aging in mammals. The first arises from the differences in IGF1 levels in small dogs. As it turns out, this mutation affects both body size and longevity, that is, small dogs (that make less IGF1) tend to live longer than large dogs that make more IGF1. Second, people with Laron syndrome or Laron-type dwarfism have naturally reduced IGF1 levels. Laron syndrome results from a dysfunction of the growth hormone receptor, resulting in reduced levels of insulin and IGF1 levels. These individuals are typically short in stature (less than four feet) and have a reduced risk of cancer and diabetes; however there have not been comprehensive studies on whether these individuals have an extended life span.
A POTENTIAL APPROACH TO CLEARING CYTOMEGALOVIRUS
Wednesday, April 8, 2015
Cytomegalovirus (CMV) is a herpesvirus that causes few if any noticeable issues in most people when they are first exposed to it. By the time old age rolls around, near everyone tests positive for CMV. It is thought that the presence of this virus goes some way towards explaining the age-related decline of the adaptive immune system. The immune system has in effect a limited number of cells at any given time since the replacement rate is low in adults. Since CMV cannot be cleared from the body, and continually reemerges to challenge the immune system, ever more immune cells become devoted to battling CMV rather than defending the body from new threats.
It is worth keeping an eye on progress towards therapies capable of clearing CMV, but in old people even an excellent clearance treatment will likely be of little use. The damage has already been done at that point, the immune system already misconfigured and out of balance. What is needed is a way to selectively destroy the CMV-specialized cells to free up space and trigger their replacement with fresh immune cells.
Human cytomegalovirus (HCMV) is an extremely common virus, which as other members of the herpes virus family causes life-long infections in humans. Most individuals are exposed to HCMV during childhood, yet symptoms can be easily fought off by a healthy immune system. HCMV infects 60% of the population in industrialized countries, and almost everybody in less affluent places. This virus persists for life by hiding in blood-making ("hematopoietic") stem cells, where it lies dormant and goes completely unrecognized. It occasionally reactivates in the descendants of these hematopoietic stem cells, but these bouts are rapidly tamed by the immune system. However, in people whose immune system has been compromised, e.g. by AIDS, and organ transplant recipients who have to take immunosuppressive drugs, HCMV reactivation can cause devastating symptoms.
Researchers have discovered a protein that switches HCMV between dormancy and reactivation. They found this protein to be bound to the HCMV genome in latently infected hematopoietic stem cells and, upon a variety of external stimuli, to undergo a modification that allows for viral activation. Furthermore, the researchers were able to control this switch with a drug called chloroquine, usually used against malaria. When they treated hematopoietic stem cells containing dormant HCMV with chloroquine, the virus reactivated and became exposed, opening the door to maneuvers aimed at eliminating virus-infected cells.
The simplicity of the study's design underlies its enormous significance. On one hand, it sheds light on the molecular mechanism by which HCMV becomes dormant in hematopoietic stem cells, possibly offering insights into similar infections by other herpes viruses. On the other hand, the study provides a straightforward method for forcing HCMV out of dormancy in infected tissue. Coupled with a simultaneous dose of an antiviral, this could become a standard regimen for eradicating HCMV from high-risk patients and purging it from tissue before transplantation. Researchers are now testing the method's efficiency in purging HCMV from cells to be used for bone marrow transplantation. Following that step, the group will be developing the first trials in humans.
INVESTIGATING THE MECHANICAL DETAILS OF AGE ACCUMULATION IN TISSUES
Thursday, April 9, 2015
Advanced glycation end-products, AGEs, are a class of sugary metabolic waste produced in the normal operation of cellular biochemistry. Some types of AGE are short-lived and easily disposed of, while others are persistent and accumulate in tissues over time. These longer lived AGEs form cross-links in the extracellular matrix, the scaffolding of proteins that supports cells and determines the structural properties of tissue such as the strength of bone and cartilage or the elasticity of skin and blood vessels. Cross-linking has been shown to degrade tissue elasticity and strength, and is of particular interest as a contributing cause of blood vessel stiffening, one of the first steps leading to age-related cardiovascular disease.
In this paper researchers dig deeper into exactly how one particular type of AGE affects the mechanical properties of elastic tissue. They find, unexpectedly, that they cannot explain increasing tissue stiffness by examining the lowest level of extracellular matrix structure, where AGE cross-links form between collagen strands intended to slide alongside one another:
Collagen cross-linking by AGEs has been increasingly implicated as a central factor in the onset and progression of connective tissue disease. For the first time we report the physical effects of AGEs on collagen molecular and supramolecular deformations under load. We identify and describe altered damage mechanisms that could play a central role in connective tissue disease processes. Our data provide evidence that accumulation of AGEs dramatically affects collagen fibril failure behavior and stress relaxation. These functional parameters strongly reflect how collagen structures accommodate mechanical load and overload. Because the temporal and spatial dynamics of connective tissue damage and repair involve an intricate balance of mechanically driven catabolic and anabolic processes, even slight changes in collagen mechanics or patterns of damage accumulation may detrimentally affect tissue homeostasis. Such changes in extracellular matrix mechanics are likely to be exacerbated by resistance of AGE modified substrates to proteolytic enzymes that drive and regulate balanced matrix remodeling, or by chronic activation of inflammatory mediators that drive fibrosis.
We employed synchrotron small-angle X-ray scattering (SAXS) and carefully controlled mechanical testing after introducing AGEs in explants of rat-tail tendon using the metabolite methylglyoxal (MGO). Mass spectrometry and collagen fluorescence verified substantial formation of AGEs by the treatment. Associated mechanical changes of the tissue (increased stiffness and failure strength, decreased stress relaxation) were consistent with reports from the literature. SAXS analysis revealed clear changes in molecular deformation within MGO treated fibrils. Underlying the associated increase in tissue strength, we infer from the data that MGO modified collagen fibrils supported higher loads to failure by maintaining an intact quarter-staggered conformation to nearly twice the level of fibril strain in controls. This apparent increase in fibril failure resistance was characterized by reduced side-by-side sliding of collagen molecules within fibrils, reflecting lateral molecular interconnectivity by AGEs.
Surprisingly, no change in maximum fibril modulus accompanied the changes in fibril failure behavior, strongly contradicting the widespread assumption that tissue stiffening in ageing and diabetes is directly related to AGE increased fibril stiffness. We conclude that AGEs can alter physiologically relevant failure behavior of collagen fibrils, but that tissue level changes in stiffness likely occur at higher levels of tissue architecture.
LOSS OF TIMP1 AND TIMP3 MAINTAINS YOUTHFUL STEM CELL ACTIVITY IN AGING MICE
Thursday, April 9, 2015
Stem cell activity declines with age, an evolutionary trade-off that reduces the risk of death by cancer at the cost of increasing frailty and a slower death due to failure of tissue maintenance. This is just one of the many contributing factors that together determine the present human life span and the course of failing health for most people. Researchers would like to be able to restore youthful stem cell activity in old people without significantly increasing the risk of cancer, as continued tissue maintenance would greatly reduce the impact of aging and incidence of age-related disease.
At present this line of work is still in the comparatively early stages: much of the research community involved is searching for the signals and mechanisms responsible for stem cell decline, changes in the tissue environment that are most likely reactions to rising levels of cellular and molecular damage produced over the course of aging. Some points of potential intervention have been found in recent years, such as altering levels of GDF-11 to improve stem cell function in aged mice. Here is news of another potential basis for therapies, discovered by chance during cancer research:
Think of tissue as a building that is constantly under renovation. The contractors would be metalloproteinases, which are constantly working to demolish and reconstruct the tissue. The architects in this case, who are trying to reign in and direct the contractors, are known as tissue inhibitors of metalloproteinases - or TIMPs. When the architect and the contractors don't communicate well, a building can fall down. In the case of tissue, the result can be cancer. To understand how metalloproteinases and TIMPs interact, medical researchers bred mice that have one or more of the four different types of TIMPs removed. The team examined the different combinations and found that when TIMP1 and TIMP3 were removed, breast tissue remained youthful in aged mice.
In the normal course of aging, your tissue losses its ability to develop and repair as fast as it did when you were young. That's because stem cells, which are abundant in your youth, decline with the passing of time. The team found that with the TIMP1 and TIMP3 architects missing, the pool of stem cells expanded and remained functional throughout the lifetime of these mice. "Normally you would see these pools of stem cells, which reach their peak at six months in the mice, start to decline. As a result, the mammary glands start to degenerate, which increases the risk of breast cancer occurring. However, we found that in these particular mice, the stem cells remained consistently high when we measured them at every stage of life." The team also found that despite large number of stem cells, there was no increased risk of cancer. "It's generally assumed that the presence of a large number of stem cells can lead to an increased cancer risk. However, we found these mice had no greater predisposition to cancer." The next step in this research is to understand why this is happening.
HOW LIPOFUSCIN DISRUPTS AUTOPHAGY IN THE RETINA
Friday, April 10, 2015
One of the contributing causes of aging is the accumulation of metabolic waste products that are hard or impossible for our biochemistry to break down. Cells undertake numerous forms of housekeeping, one of which is autophagy: in this process, unwanted or damaged proteins and cellular components are tagged and shuttled to the nearest lysosome where they are broken down for recycling. Waste products that cannot be broken down remain in the lysosome, however, to form a mix of various compounds known as liposfusin. Over time the lysosomes in long-lived cells of the nervous system, such as those of the retina, become bloated and dysfunctional, and the cells begin to malfunction and die as a result.
The SENS rejuvenation research approach to this part of the aging process is the find ways to safely break down lipofuscin constituents, with a starting point of mining the natural world of bacteria to find those capable of consuming lipofuscin. It is well understood in the research community that lipofuscin accumulation is a cause of age-related retinal degeneration and consequent blindness, and so SENS researchers are far from the only people looking for ways to get rid of lipofuscin or blunt its effects. This paper looks into mechanisms involved in the disruption of autophagy caused by lipofusin and suggests one potential form of amelioration:
Autophagy is an essential mechanism for clearing damaged organelles and proteins within the cell. As with neurodegenerative diseases, dysfunctional autophagy could contribute to blinding diseases such as macular degeneration. However, precisely how inefficient autophagy promotes retinal damage is unclear. In this study, we investigate innate mechanisms that modulate autophagy in the retinal pigment epithelium (RPE), a key site of insult in macular degeneration. High-speed live imaging of polarized adult primary RPE cells and data from a mouse model of early-onset macular degeneration identify a mechanism by which lipofuscin bisretinoids, visual cycle metabolites that progressively accumulate in the RPE, disrupt autophagy.
We demonstrate that bisretinoids trap cholesterol and bis(monoacylglycero)phosphate, an acid sphingomyelinase (ASMase) cofactor, within the RPE. ASMase activation increases cellular ceramide, which promotes tubulin acetylation on stabilized microtubules. Live-imaging data show that autophagosome traffic and autophagic flux are inhibited in RPE with acetylated microtubules. Drugs that remove excess cholesterol or inhibit ASMase reverse this cascade of events and restore autophagosome motility and autophagic flux in the RPE. Because accumulation of lipofuscin bisretinoids and abnormal cholesterol homeostasis are implicated in macular degeneration, our studies suggest that ASMase could be a potential therapeutic target to ensure the efficient autophagy that maintains RPE health.
REVIEWING IMMUNE CHECKPOINT TARGETING IN CANCER RESEARCH
Friday, April 10, 2015
The cancer research establishment is not a single monolithic entity, but rather consists of many diverse fields and approaches to treatment. Researchers in one area may or may not be paying all that much attention to other areas. This is an important issue in modern scientific development, where there is simply too much information and too much going on for any one person to know everything of relevance to the work at hand. There is need for at least a few scientists in every field to spend much of their careers in synthesis and knowledge exchange, bringing together research groups who would otherwise not know that they might benefit from collaboration:
The prospect of combining genomically targeted therapies with drugs that free the immune system to attack cancer suggests "we are finally poised to deliver curative therapies to cancer patients." While individual researchers and pharmaceutical companies are studying and developing both types of drugs, a major initiative is needed to understand how both drug types might best work together. "Without a major initiative, it will be harder to make progress because the groups focused on genomically targeted therapy and the checkpoint blockade researchers will largely stay in their own camps."
Drugs that hit a specific genomic defect that drives a patient's cancer provoke good initial responses in most patients, the review notes. For example, drugs that target a specific BRAF gene mutation commonly found in melanoma shrink tumors in about half of patients with the mutation. However, resistance almost always develops because tumors harbor multiple genomic defects capable of driving the disease after a targeted drug knocks down one driver. BRAF inhibitors prolonged median survival in clinical trials by about seven months.
Checkpoint blockade is an approach that treats the immune system, rather than the tumor directly, by blocking molecules on T cells that shut those attack cells down, protecting tumors from immune response. Knowing that the immune system is capable of recognizing distinctive features of cancer cells and launching a T cell attack against those tumor antigens, and that checkpoint blockade removes a roadblock to that attack, it's logical that these drugs should work against many tumor types. But the impact varies across cancers.
There's a school of thought that combining multiple genomically targeted therapies might prove effective. However, evidence suggests that tumor genomic diversity might still defeat such combinations, and that it's axiomatic in oncology that side effects increase in number and intensity as more drugs are added to treatment. Targeted therapies might act as effective cancer vaccines, killing tumor cells and releasing new target antigens for T cells to identify and associate with tumors. And they might vary in their ability to enhance or inhibit immune response, because little is known right now about how targeted agents affect the immune system.
Early efforts to combine approaches have yielded interesting results. One phase I trial of an immune checkpoint blockade drug combined with two established targeted therapies yielded 40-50 percent response rates among patients with metastatic kidney cancer. "At this stage, it does not seem a stretch to say that increasing funding to combination therapies will be key to development of new, safe treatments that may prove to be curative for many patients with many types of cancer."