FIGHT AGING! NEWSLETTER
June 15th 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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- Fundraising Posters: Do You Want to Suffer Alzheimer's?
- Pointing out Rejuvenaction
- A Look at Some of the Aging Research of Irina Conboy
- Faster Cures and the Costs of Medical Regulation
- Yet More Discussion of Programmed Aging
- Latest Headlines from Fight Aging!
- Evidence for Disruption of Autophagy in Sarcopenia
- Mitochondrial DNA Damage and Longevity in Rockfish
- Blood Type and Cognitive Decline
- The Decline of Memory with Aging is Complex
- Advanced Glycation End-Products Accelerate Cardiac Aging
- Maintaining TDP43 in Amyotrophic Lateral Sclerosis
- Regenerative Medicine and Idiopathic Pulmonary Fibrosis
- Stepping Towards Bioartificial Immune Systems
- Attacking Cancer Stem Cells in the Brain
- A Drug Candidate to Trigger Faster Regeneration
FUNDRAISING POSTERS: DO YOU WANT TO SUFFER ALZHEIMER'S?
People are very good at not thinking about the personal inevitability of aging and age-related disease. We all know what happens to the aged. It happens to those we know and care about. It is no big secret that aging causes pain, suffering, and death on a vast scale. Yet here we stand, you and I, consumed by the minutiae of day to day life, in which from moment to moment we put little thought into our future state of frailty and loss of dignity. Across a long history of being unable to greatly influence aging, and the pain and death it causes, this ability to put aside foreknowledge has proven a great strength. It let individuals work and prosper and build despite knowing all too well what was coming down the line. We live in a society of wealth and technology enabled by the toil of our ancestors, the majority of whom suffered and died because of aging.
And now? This talent for looking anywhere but ahead is killing us. What has changed? Medical technology. Unlike every past generation, we stand within reach of means to control and indefinitely delay the aging process. Aging is damage to cells and tissues, and for each of those types of damage researchers can envisage in detail at least one development program to produce a means of repair. The cost of getting to working prototypes in mice for all of these is probably in the vicinity of one or two billion spread over 10-20 years, not all that different from the amounts of time and money required to run a single drug candidate through the present regulatory process.
Yet to a first approximation this development isn't happening. Only a tiny amount of funding is presently devoted towards the development of means to repair the causes of aging and thus indefinitely postpone disease and death. There is little support among the public at large for such a goal, little awareness that any work is ongoing, or that there is the potential to strike out for great gains in health and longevity. Indeed there is little thought at all on the topic of medicine to treat and control the processes of aging, the root cause of so much pain and suffering for the old. Ignoring aging is no longer a good thing: it has now become a terrible strategy that is costing lives and costing health.
Ask someone you know today "do you want to suffer Alzheimer's disease?" Or heart disease. Or cancer. The answer is probably no. But why are they not doing something about it? Do they think it is out of their hands? None of their business? Or is it more a case of lapsing back into the daily grind wherever possible, avoiding uncomfortable existential thoughts about the future? The cancer and stem cell research establishments are examples of what should exist for aging: a research community of great size and vigor, aiming to extinguish disease and prevent disability. But it doesn't exist yet for aging, and the behavior of the people you know in response to these questions has a lot to do with that state of affairs. At the large scale and in the long term medical research funding follows the desire of the public. That 10-20 year countdown for treatments to prevent and reverse aging doesn't start at least the first shards of a massive research community do exist.
This is why we advocate and donate. So much is left to be done, and people are suffering and dying in vast numbers each and every day. This is why there must be people of vision leading the way, philanthropists of all stripes and means funding early stage research to bring greater attention to the best paths forward. The bootstrapping of the next generation of medical research for aging, the programs that will ultimately bring an end to all age-related disease, starts with us as much as with the researchers who see clearly enough to put forward their detailed plans in search of support and funding. We hold up the torch and guide the way, helping to bring greater resources to the research that deserves that support.
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Do Something About It Poster #2: 4200 x 2800px
POINTING OUT REJUVENACTION
A slowly growing group of people are setting forth to publish web sites that aim at similar goals to those of Fight Aging!: regular updates on aging research, advocacy for specific research programs, such as those of the SENS Research Foundation, and original opinion pieces. LifeMAG, the Longevity Reporter, and the Healthspan Campaign are a few of the comparatively recent additions, ranging from amateur to professional and single author to organizational publication. As the field of longevity science grows I expect its associated journalism to grow also, at one end from funded interests putting forward their positions and gathering public support, and at the other from ever more motivated individuals deciding that they cannot possibly remain silent in their support for bringing an end to aging.
Of course there are a very wide range of opinions regarding exactly what research we should be supporting in order to make the best possible progress. Just look at the SENS proposals versus the Hallmarks of Aging proposals, and then the Seven Pillars of Aging proposals from the Trans-NIH Geroscience Interest Group. That's just within some of the fairly well-trafficked portions of the aging research community. Then compare the Fight Aging! support for SENS rejuvenation research based on repair of cell and tissue damage to attain radical life extension versus the advocacy of sites like AgingSciences, which is very focused on near term pharmaceutical strategies to make very slight differences to aging.
Today I thought that I'd point out another new single author effort that is closer to the Fight Aging! position on advocacy and research, a site called Rejuvenaction. It always pleases me to see yet another person motivated to step up and speak out on this topic. Eventually there will be many more voices than is presently the case, no-one will miss mine when I finally sit back down, and that is exactly as it should be, a sign that we are making meaningful progress towards the goal of ending frailty and disease in aging:
Imagine a world where your well-being doesn't depend on your age - a world where your health as a 90-year-old is indistinguishable from your health as a 25-year-old. In this world, once you're an adult you can be whatever you wish whenever you wish. No need to worry about when is the "right time" to have a family or a career, or to leave everything behind and explore yourself. This is not a world where you need to worry about your limited lifespan or about the fact that the more you approach its end, the less able you will be to even just take care of yourself.
This is a world where biological ageing has been cured.
What is biological ageing?
No offense, but you probably don't know what biological ageing actually is; I didn't either, until not too long ago. And maybe just like me, you might never have given much thought about the matter before, or you may be one of those who think that we age because the body "wears out" somehow, or maybe that it's a genetic thing. It isn't any of these things, really. In order to properly understand the matter, we can make use of an example.
Imagine a clean, tidy bedroom. Books are on the shelves, the bed is made, the floor is clean and washed, everything smells nicely and is exactly where it is supposed to be. You can't really expect the room to stay like that forever if you use it, and it will undergo a certain degree of untidiness and dirt even if you don't use it. One day you will take a few books to read off the shelves, and put only two or three back because something distracted you and you left the rest hanging around on the desk. You've been busy and you didn't have time to dust the floor lately. You spilled a drink on the desk and you didn't clean it as thoroughly as you thought you had. And you will have no trouble believing, if your desk is anything like mine, that papers and pens and whatnot tend to accumulate on top of it, without you really knowing how you managed to go from a clear and usable desktop to a complete chaos where you can hardly find anything.
You get the hang of it: there comes a point when the room becomes gradually unusable. Using the room for what it was (more or less) designed has led to causing "damage" to the room itself. The room didn't "wear out" on its own, nor was this programmed. It's a side-effect of using the room in the first place. And you've got to do something about it, if you want to be able to use it again. Of course you might try to prevent havoc from wreaking, by being more tidy, trying to put things back in place as soon as you've done using them, perhaps not to drink anything in the bedroom, and so on; this preventative approach can work really well for some people, but in general, we all know there will come a time when a thorough clean-up of the room is called for, and it will come more than once. If we do it regularly and often enough, we can expect the room to reach only a certain amount of untidiness that still allows to use it comfortably: if we perform regular maintenance to fix up "damage" that has accumulated in the room over time, and we do it before the room becomes a complete mess, we can prevent it from ever reaching a threshold after which is unusable.
Our bodies aren't rooms; however, it's no matter of controversy that the human body is just a machine - a very complex one, with an astronomical amount of tiny moving parts, but still a machine. And just like any human-made machine, the human body does damage to itself, as a side-effect of its normal operations. These are carried out by our metabolism, the incredibly complex set of processes that keep us alive.
During these past few years in which I've been interested in negligible senescence, I've faced many objections to the possibility of human rejuvenation. I must say that the vast majority of people opposing it seemed to be acting out of a gut instinct: a feeling inside them that questioning the inevitability of ageing is somehow a threat to their own mental peace. This is probably due to the fact that all humans need to come to terms with what they consider inevitable, namely ageing and death, and once they've done it they don't really want to go through the trouble of re-examining the case, particularly for the sake of something that still feels like science fiction. Also, I suspect that people tend to repeat what is considered conventional wisdom rather acritically, probably assuming that if nearly everyone says it, it must be true; in addition, it seems that people feel they're being wise and experienced in life by accepting ageing and death as they are.
A LOOK AT SOME OF THE AGING RESEARCH OF IRINA CONBOY
Irina Conboy is on the SENS Research Foundation's advisory board and is one of the more frequently noted scientists presently working on heterochronic parabiosis and related research. These scientific programs aim at identifying age-related changes in important signal proteins circulating in the bloodstream, with parabiosis being where it all starts: link the circulatory systems of an old and a young animal and observe benefits to measures of health in the elder of the two. This happens because old tissues are exposed to a young blood environment. Once specific proteins in the blood are identified as being of interest, then researchers move on to attempts to alter amounts of these proteins in circulation in old animals. They are in search of the basis for therapies that might make cells and tissues in an old individual behave as if they were younger, despite the damage they have suffered.
The main thrust of this research could probably be considered a branch of stem cell medicine. The signals that differ between young and old tissue appear to be involved in regulating the activity of stem cell populations, and thus the degree to which tissues are maintained, kept supplied with fresh new cells. It is well known that stem cell activity declines with age. Much of the present panoply of stem cell therapies consists of what are, when it comes down to it, ways to bolster regeneration and tissue maintenance in old people. Stem cells transplanted into patients appear to achieve at least some of their beneficial effects by altering the balance of signal proteins in their environment. So why not a future in which the cells are done away with and the therapy consists of directly manipulating protein levels? The only thing needed for that to come to pass is a much better understanding of the signals themselves and how they control cell behavior.
The caveat for all of this is that as an approach it really doesn't address the underlying causes of aging at all. It addresses a consequence of cellular damage without repairing the damage itself. Revving up the activity of a damaged engine obviously bears risks. The greatest risk from a theory point of view is cancer: that damaged cells are doing more has an obvious consequence. In practice, more has been achieved in the field of stem cell medicine and with less cancer as the outcome that was feared at the outset. There may be a fair degree of room in our evolved biology for more regeneration in a damaged system, who knows. Equally these bounds and balances may be very different for short and long-lived species, and so it is an open question as to the degree to which we can trust results in laboratory mice today, even following on from consistency in past results in laboratory mice now translated into human stem cell therapies.
Still, we need stem cell medicine for the old. Stem cell populations will need restoration and repair regardless of success in the rest of the rejuvenation toolkit, as there will be old people awaiting treatment when these therapies are introduced. It is another open question as to whether sufficiently good prevention of other forms of damage will mean that stem cell populations never decline in an individual who has undergone period use of repair therapies since childhood, but that is hardly the most pressing issue in front of us. The first and initial goal of building treatments for aging is to save the people who are old when those treatments arrive.
Engineering the End of Aging
For over a decade, Conboy and her colleagues at UC Berkeley have been searching for ways to slow down or even reverse aging. Their latest discovery - a small-molecule drug that restored brain and muscle tissues to youthful levels in old mice through stem cells - signalled that the prospect of anti-aging therapy for humans may be on the horizon. Published this May, the discovery has been called "fountain of youth" or the "secret to eternal youth" by the media. Comfortably clad in an oversized hoodie, Conboy burst the bubble in her high-pitch, Eastern European accent: Sorry, the drug won't keep us young forever, and we will all eventually die. But what her research hopes to accomplish, Conboy said, is a painless, cost-effective way to live when we are old.
Aging-related diseases like adult-onset diabetes, cancer, Alzheimer's, and Parkinson's disease kill millions every year while draining the economy via health care costs, and a treatment that keeps people healthier in old age would cut the costs significantly down. A drug that tackles these diseases at its root would also give people more agency how they choose to live late in their lives. "Aging is a synonym with diseases," Conboy said. "When we are young, we don't have these diseases. But when we are old, it doesn't matter what background or gender or culture, we all have them. If we can better understand the aging process, then we don't need to have different hospitals, departments, and institutes that deal with each disease."
The drug, known as Alk5 kinase inhibitor, target a growth factor called TGF-beta1 pathway which, at old age, overproduce itself and inhibits other pathways to stimulate stem cells. As our body breaks down over time, stem cells - which are responsible for repairing the body and live huddled together in pockets called niches - are prevented by TGF-beta1 from doing its job. As the body ages, however, the TGF-beta1 begins to overexpress itself and become a deterrent for yet unknown reasons. What the Alk5 kinase inhibitor sought to do was not rid the body of the pathway but rather regulate it by attaching itself to the pathway and dulling its signal asking for more expression. Now with the TGF-beta1 down to youthful levels, stem cells are able to freely repair the body.
"I look at it as more promising than anything," said Hanadie Yousef, the lead author of the Oncotarget study and currently a postdoctoral scholar at Stanford University. "When I was starting graduate school five years ago, there was absolutely nothing known about how aging actually happened. The field is growing so rapidly that I would bet within the next decade we'll see effective anti-aging therapeutic methods." With the probability of anti-aging therapy on the horizon, death may take a different shape in the future. Death, as Conboy's team hoped to accomplish, would no longer come with pain or suffering at some hospital with wires and machines keeping the body alive. Instead, death will come by more natural causes such as cardiac arrest or a stroke - a relatively quick way to die than fighting years against cancer or similar diseases. "I hope we'll just die in our sleep with no cancer or disease eating up our organs," Yousef said. "The goals of my colleagues and I are not to live forever. Instead of becoming old and becoming a burden on society, we can age ourselves more with integrity."
Persuading researchers to work on treating aging at all has been the major battle of the past fifteen years. We've come a long way when postdocs can now talk in public about treating aging without fearing for their future careers. From here we can build, grow the number of researchers who are willing to aim higher - at rejuvenation, radical life extension, and a complete end to aging. No illness, no loss of vigor or health, and consequently no age-related deaths. That is the future we'd like to see more people working towards.
FASTER CURES AND THE COSTS OF MEDICAL REGULATION
I think that it's no great surprise that many people see the US Food and Drug Administration (FDA) and its ilk in other countries as a gargantuan ball and chain dragging down progress. Yet few of these take the fully libertarian position that the FDA should be removed and the demand for safety assurance provided by a marketplace of review and certification organizations. Instead most such advocates argue for a return to the smaller FDA and much less onerous review process that existed in the past. They note that FDA administrators have perverse incentives to block as much progress as possible, and that they have followed these incentives across recent decades to greatly increase the amount of time and money required to obtain approval for new medical technologies.
FDA bureaucrats are blamed for letting through any technology that causes even a tiny amount of harm, while receive no personal benefit for approving something that is safe, and receive no personal penalty from slowing down or blocking perfectly safe technologies from approval. There is no such thing as a perfectly safe medical technology: it is always a cost-benefit analysis for even the most beneficial technologies developed to date, and the mass media tends to inflate every harm done without taking account of the benefits. Everything else proceeds from that, and the consequence is that ever fewer new medicines are approved, there is less funding for development, and many lines of research are abandoned because the cost of regulatory compliance has become too great.
The situation is actually much worse for aging research, as the FDA doesn't recognize aging as a medical condition that can be treated; there is no path through the regulatory process to obtain approval for a treatment for aging, and that fact echoes back down the funding chain to make it much harder to raise money for projects such as SENS rejuvenation research. Potential technologies for the treatment of aging would at best have to be shoved through the approval process as narrow therapies for specific age-related conditions, which may well have a distorting effect on development. Some people are less concerned by this than I am, but changing what the FDA considers to be a disease is a long process of lobbying. This costs money and time that would be better spent on research. Just look at the years of attempts to get FDA bureaucrats to consider sarcopenia a medical condition: that is still going on, with no end in sight.
A number of political advocacy organizations have been founded in past years with the intent of trying to cut down the influence, size, and costs imposed on medical development by the FDA. In most cases they are focused on the time cost rather than the financial cost, possibly because that is an easier rallying cry. These organizations are one of the expressions of frustration with a regulatory process run wild, that serves only itself, and is causing far more harm than good. People don't see the invisible cost of medicines not development and technologies delayed for years. Faster Cures is one of the earlier organizations, now with interests in many approaches to speeding up research, including the venture philanthropy ideals that have been expressed by Peter Thiel for some years. But today I'll point out another lobbying organization created by those frustrated by the FDA and its baleful influence on the pace of medical development:
Tomorrow's Cures Today Foundation
Millions of Americans are in pain and suffer needlessly. Thousands of Americans die unnecessarily as they wait for promising new drugs to make their way through an unnecessarily long approval process. What we see is death and suffering that is attributed to approving drugs with dangerous side effects; but what we don't see is the death and suffering due to regulatory delay. Those victims are invisible.
The Pathway to Faster Cures
Rob Donahue used to ride horses. He was a modern-day cowboy until he was stricken with amyotrophic lateral sclerosis (ALS). Now his muscles are weak. He can't ride horses anymore. And his condition is worsening quickly. ALS will degenerate Donahue's neurons and nervous system, and he will probably die in less than five years. Another ALS sufferer, Nick Grillo, is trying to change all that. He's put together a petition on Change.org to urge the FDA to fast-track approval of a new drug, GM-604, that would help people like Donahue and others like him. "People can't wait five, ten, 15 years for the clinical trial process," said Grillo. "Things need to happen much quicker." But ALS is just one illness, and GM-604 is just one medicine. There are thousands of Americans suffering -- many with terminal illnesses -- while waiting on the FDA approval process.
A paradigm change is essential because FDA culture has led to a situation where it costs an average of one to two billion and 12 or more years of clinical testing to bring a new drug to market. Medical innovation cannot thrive when only very large firms can afford to research and develop new drugs. Another problem is that the FDA's first goal is not to maximize innovation, but to minimize the chances that an FDA-approved drug leads to unanticipated adverse side effects and negative publicity. In particular, the FDA's efficacy testing requirements have resulted in an ever-increasing load of money and time on drug developers. We can't count on FDA bureaucrats to fix the broken system they created. Even Congress, whose cottage industry is to regulate, admits that the current FDA system is a roadblock to fast-paced innovation.
The missing seat at the table is for someone who represents freedom -- that is, the right of patients, advised by their doctors, to make informed decisions as to the use of not-yet-FDA-approved drugs. Absent from the congressional hearings over health care, however, has been a freedom agenda, specifically one designed to eliminate the FDA's monopoly on access to new drugs. We hear very little about those who suffer and die because they were not able to access drugs stuck in the FDA's testing pipeline, or about drugs that were never brought to market because FDA procedures made the development costs too high. There is an invisible graveyard filled with people who have died because of drug lag and drug loss. The FDA's deadly over-caution is why venture capitalists shy away from investing in biopharmaceutical startup firms. Venture capitalists are willing to take big risks on ideas that may fail. But failure due to regulatory risk is just too big a hurdle to overcome. Capital providers have other opportunities, even if those opportunities don't involve cures for disease.
High costs and slow innovation are the hallmark of a monopoly. And, as medical science continues its rapid pace of innovation, the cost of lost opportunities for better health will increase even faster. The solution is to introduce consumer choice and competition. FDA proponents would bolster the fear that "unsafe" drugs could flood the marketplace. But the FDA cannot define what is "safe." Only patients with their unique health conditions, treatment profiles, and preferences for taking risk can define what is safe for them.
YET MORE DISCUSSION OF PROGRAMMED AGING
There are many theories of aging, a state of affairs that I would say is really due to past lack of resources put towards building means to treat aging in a targeted way, by addressing specific purported root causes. There has been a great deal of investigation of the biochemistry of aging, and will continue to be given its complexity, and all too little bold experimentation in means to extend healthy life spans. This was in large part cultural for the last generation of researchers, a way to reject any association with the fraud and self-deception of the "anti-aging" marketplace, and thus preserve reputations and the ability to raise funding for legitimate studies of aging. At the same time, however, this meant that greater progress towards longevity enhancement might have happened and did not: talk of treating aging became a threat to careers, an unfortunate state of affairs that has only recently abated.
Ways to increase longevity in laboratory species are the tools by which theories of aging can be winnowed and validated. Unfortunately all of the present means of slowing aging are far too general in their operation to serve as good tools in this sense. Take calorie restriction and its alleged mimetic drugs, for example: these approaches change near every measure of metabolism, to the point at which it remains an enormous puzzle to figure out how and why they act to slow aging. What is needed is a new generation of much more targeted therapies, things like clearance of senescent cells, or clearance of cross-links, or other proposed SENS biotechnologies based on the repair of one single type of tissue damage thought to cause aging. Build the treatment, run the experiment, and a lot will be learned from whether or not it does extend healthy life. If great progress is made by repairing forms of damage thought to cause aging, that tells us that theories painting aging as a process of damage accumulation are more robust and defensible. The types of damage being repaired and the results obtained will help separate out which theories on various types of damage are more robust and defensible.
Ultimately theories of aging matter today because they are used to steer investment in research. This will continue to be important until one group of theories wins out by weight of evidence obtained through extending life in laboratory animals. At the moment the division of greatest importance is between programmed aging theories and stochastic damage theories. Programmed aging theories would have us think that aging is the direct consequence of a set of evolved changes in (say) gene expression and protein levels and cellular operation, and these changes causes damage, dysfunction, and death. The right thing to do if this is true is to work to alter the operation of metabolism, change the gene expression levels, manipulate specific protein levels, to bring them back to a more youthful pattern. In contrast stochastic damage theories of aging tell us that aging is caused by what is effectively biochemical wear and tear, and our bodily systems react to the presence of that damage with altered gene expression and protein levels and cellular operation - but it is the damage that is the root cause of disease and dysfunction. The way forward if this is the case is to repair the damage.
Personally, based on my view of evidence to date, I'm in the latter camp: aging is stochastic damage accumulation. Repairing that damage if following the SENS proposals is very cost-effective, and producing full demonstrations of the various treatments in mice is a one to two billion, 10-20 year project at full scale funding. That's less than the cost of developing a single drug candidate in the Big Pharma world these days. Programmed aging on the other hand would direct us into a massive, unending project of trying to fully understand and safely alter swathes of our metabolism. That is a vast project. To give some idea of the scale, about a billion has been swallowed up on research of sirtuins in aging over the past decade or so - just a couple of genes out of thousands worth looking at, and nowhere near a full understanding of their role yet, and no meaningful treatments or ways to alter metabolism resulted from all of that work. So from my perspective, I see programmed aging theories as the road into an endless swamp, a course that might be averted at a low cost by making enough progress on SENS rejuvenation treatments in the laboratory to demonstrate their worth in extending healthy life spans, and thereby showing that aging is mostly likely a process of stochastic damage.
Here is a better than average popular science article that covers many of the aspects of this debate over theories of aging, using a recent paper on programmed aging as a springboard. You should read the whole thing, given that the author took the time to gather opinions from various researchers with different takes on aging, who think that this particular line of research is flawed, and goes on to examine the point I make above, which is that all this theorizing is far from idle and unimportant. It in fact determines the prospects for the near future development of effective means of treatment for degenerative aging, with both sides believing that their road is the more effective one, but only one of them being right:
Are Limited Lifespans An Evolutionary Adaptation?
That aging is a deliberate function of our genetics remains a controversial idea, but it's an idea that's steadily acquiring adherents. One of these adherents is NECSI president Yaneer Bar-Yam, who contends that popular approaches to the aging problem fail to address a very important constraint, namely the ways lifespans are genetically controlled according to the resource limitations of a given environment. Without genetically programmed aging, he argues, animals wouldn't be able to leave sufficient resources for their offspring. And this holds true for all animals, whether they be rabbits, dolphins, or humans.
Bar-Yam and his team reached this conclusion by developing a simple model that analyzed how the lifespans of simulated organisms would change and evolve over time under spatially constrained conditions. Fascinatingly, group selection -- the idea that natural selection acts at the group level -- was never a consideration in the model. Yet the simulations consistently showed that a built-in life expectancy emerged among the simulated organisms to preserve the integrity of their species over time. This is surprising because a pro-group result was produced via an individualized selectional process.
"Beyond a certain point of living longer, you over-exploit local resources and leave reduced resources for your offspring that inhabit the same area," Bar-Yam said. "And because of that, it turns out that it's better to have a specific lifespan than a lifespan of arbitrary length. So, when it comes to the evolution of lifespans, the longest possible lifespans are not selected for."
Programed Death is Favored by Natural Selection in Spatial Systems
Standard evolutionary theories of aging and mortality, implicitly based on mean-field assumptions, hold that programed mortality is untenable, as it opposes direct individual benefit. We show that in spatial models with local reproduction, programed deaths instead robustly result in long-term benefit to a lineage, by reducing local environmental resource depletion via spatiotemporal patterns causing feedback over many generations. Results are robust to model variations, implying that direct selection for shorter life span may be quite widespread in nature.
LATEST HEADLINES FROM FIGHT AGING!
EVIDENCE FOR DISRUPTION OF AUTOPHAGY IN SARCOPENIA
Monday, June 8, 2015
Sarcopenia is the name given to age-related loss of muscle mass and strength. Researchers here provide somewhat indirect evidence in support of defects in autophagy, a cellular housekeeping process, being involved in the development of sarcopenia. Autophagy is known to fail with age for reasons that include the accumulation of metabolic waste in cell lysosomes, the structures responsible for breaking down damaged structures to recycle their component parts. Improved autophagy shows up in many of the approaches demonstrated to slow aging in mammals. The practice of calorie restriction improves the state of both autophagy and sarcopenia, for example.
One should always be wary of correlations in aging, of course: aging is caused by damage, and various forms of damage and consequences build up in many tissues at a similar pace. There is no necessary reason for any two correlated aspects of aging to be directly connected simply because they are happening at the same time:
Sarcopenia is the aging-related loss of skeletal muscle mass and strength. Preventing sarcopenia is important for maintaining a high quality of life in the aged population. However, the molecular mechanism of sarcopenia has not yet been unraveled and is still a matter of debate. Determining whether the levels of autophagy-related mediators (e.g., p62/SQSTM1, LC3, etc.) in muscle change with ageing is important to understanding sarcopenia. Such information could enhance the therapeutic strategies for attenuating mammalian sarcopenia.
In previous studies, autophagic defects were detected in the sarcopenic muscle of mice, rats, and humans. However, all these studies involved only western blotting analyses of crude not cell-fractionated muscle homogenates. Thus, these data were insufficient to describe the adaptive changes in autophagy-linked molecules within sarcopenic muscle. Researchers found a marked accumulation of p62/SQSTM1 in the sarcopenic quadriceps muscle of mice using two different methods (western blotting of cell-fractionated homogenates and immunofluorescence). In contrast, the expression level of LC3, a partner of p62/SQSTM1 in autophagy progression, was not modulated. The found autophagic defect improves our understanding of the mechanism underlying sarcopenia. The researchers would like to further study this mechanism with an aim to attenuate sarcopenia by improving this autophagic defect using nutrient- and pharmaceutical-based treatments.
MITOCHONDRIAL DNA DAMAGE AND LONGEVITY IN ROCKFISH
Monday, June 8, 2015
Rougheye rockfish are one of the few species to show negligible senescence, a comparative lack of the usual evident consequences of aging. Other examples include lobsters, naked mole-rats, some tortoise species, and some clam species such as the ocean quahog. Individuals still die after a comparatively long life, and so there are evidently still processes of degeneration gnawing away, but for many of these species it is hard to measure age via the normal metrics of vigor, growth, reproduction, and changes in various aspects of biochemistry. There is little to no meaningful change and decline until close to the end.
Mitochondria are the power plants of the cell, responsible for generating chemical energy stores to power cellular processes. They are descended from symbiotic bacteria and contain a remnant of that bacterial DNA. Damage to this mitochondrial DNA is considered to contribute to aging via a complex chain of conseqeunces that leads to a growing number of malfunctioning cells overtaken by dysfunctional mitochondria. This study of mitochondrial damage and longevity is interesting for having been carried out in a negligibly senescent species:
The mitochondrial theory of ageing proposes that the cumulative effect of biochemical damage in mitochondria causes mitochondrial mutations and plays a key role in ageing. Numerous studies have applied comparative approaches to test one of the predictions of the theory: that the rate of mitochondrial mutations is negatively correlated with longevity. Comparative studies face three challenges in detecting correlates of mutation rate: covariation of mutation rates between species due to ancestry, covariation between life history traits, and difficulty obtaining accurate estimates of mutation rate.
We address these challenges using a novel Poisson regression method to examine the link between mutation rate and lifespan in rockfish (Sebastes). This method has better performance than traditional sister-species comparisons when sister species are too recently diverged to give reliable estimates of mutation rate. Rockfish are an ideal model system: they have long life spans with indeterminate growth and little evidence of senescence, which minimizes the confounding tradeoffs between lifespan and fecundity.
We show that lifespan in rockfish is negatively correlated to rate of mitochondrial mutation, but not the rate of nuclear mutation. The life history of rockfish allows us to conclude that this relationship is unlikely to be driven by the tradeoffs between longevity and fecundity, or by the frequency of DNA replications in the germline. Instead the relationship is compatible with the hypothesis that mutation rates are reduced by selection in long-lived taxa to reduce the chance of mitochondrial damage over its lifespan, consistent with the mitochondrial theory of ageing.
BLOOD TYPE AND COGNITIVE DECLINE
Tuesday, June 9, 2015
It is probably a good idea to be skeptical of links claimed between blood type and measures of degenerative aging. The evidence to date is either nebulous or shows little to no correlation. Where correlations are found the effects are not large, or are not reproduced in other study populations. Nonetheless, here is another paper on this topic:
Researchers claim that people with an 'O' blood type have more grey matter in their brain, which helps to protect against diseases such as Alzheimer's, than those with 'A', 'B' or 'AB' blood types. The researchers made the discovery after analysing the results of 189 Magnetic Resonance Imaging (MRI) scans from healthy volunteers. The researchers calculated the volumes of grey matter within the brain and explored the differences between different blood types. The show that individuals with an 'O' blood type have more grey matter in the posterior proportion of the cerebellum. In comparison, those with 'A', 'B' or 'AB' blood types had smaller grey matter volumes in temporal and limbic regions of the brain, including the left hippocampus, which is one of the earliest part of the brain damaged by Alzheimer's disease.
These findings indicate that smaller volumes of grey matter are associated with non-'O' blood types. As we age a reduction of grey matter volumes is normally seen in the brain, but later in life this grey matter difference between blood types will intensify as a consequence of ageing. "The findings seem to indicate that people who have an 'O' blood type are more protected against the diseases in which volumetric reduction is seen in temporal and mediotemporal regions of the brain like with Alzheimer's disease for instance. However additional tests and further research are required as other biological mechanisms might be involved."
THE DECLINE OF MEMORY WITH AGING IS COMPLEX
Tuesday, June 9, 2015
Memory is not a straightforward function of the brain. There are many different aspects to storing and recalling memories of various types, and all decline in different ways with advancing age, a reflection of the influence of damage on quite different structures and mechanisms in brain tissue.
Researchers conclude that the memory of older adults is not as deficient as has been thought until now. Elderly people remember fewer specific details than younger people and, in general, both groups retain concrete information about events experienced better than abstract information. The main difference is to be found in the capacity to remember more distant facts: youngsters remember them better. "The highly widespread belief that memory deteriorates as one approaches old age is not completely true. Various pieces of neuro-psychological research and other studies show that cognitive loss starts at the age of 20 but that we hardly notice it because we have sufficient capacity to handle the needs of everyday life.This loss is more perceptible between 45 and 49 and, in general, after the age of 75, approximately."
The deterioration does not tend to be either uniform or general: It takes place in certain memory types more than in others. In old age, deterioration appears in episodic memory but not in semantic memory. This type of memory (semantic) and procedural memory are maintained (in some cases they even improve) whereas episodic memory in which detailed memories are retained is reduced. Procedural memory is the one to do with 'skills', the one we need to 'do things' (to drive, for example). In general, it is maintained during old age. Semantic memory, on the other hand, is related to language, to the meaning of concepts and to repetitive facts. Finally, episodic memory preserves the facts (episodes) of the past in our personal life, and it is more specific in terms of time and space.
An individual, both an adult and a young person, has the capacity to remember information relating to facts in his/her private life in detail. The main difference between older adults and younger adults is as follows: the younger ones remember more episodic details. This research shows, however, that this difference only occurred in older recollections, such as of the previous year. No appreciable differences were found in the recollections of the previous month and the previous week, and the older adults were just as capable as the younger adults in providing episodic details relating to the facts.
ADVANCED GLYCATION END-PRODUCTS ACCELERATE CARDIAC AGING
Wednesday, June 10, 2015
Advanced glycation end-products (AGEs) of various forms are present in the diet, but also generated by our biochemistry as a form of metabolic waste. Some are short-lived and easily cleared by the body, but others are very persistent and form long-lasting cross-links that degrade tissue structure. Their growing presence is one of the contributing causes of degenerative aging, causing a range of effects such as inflammation, stiffening of blood vessels, loss of elasticity in skin, and loss of cartilage and bone strength.
Surprisingly, given how well this cause of aging is understood, there is comparatively little work on the development of therapies to clear the most prevalent AGEs, such as glucosepane in human tissues. Spurring progress in this field is one of the goals of the SENS Research Foundation, and the staff there coordinate early-stage research in a few laboratories, aiming to build the fundamental tools and methodologies needed to encourage a broader participation. The research linked below is one of many examples to demonstrate why we need AGE clearance as a part of any near-future rejuvenation toolkit, here focusing on the role of AGEs in encouraging cellular senescence and fibrosis:
The current study was carried out to evaluate the effect of advanced glycation end-products (AGE) on cardiac aging and to explore its underlying mechanisms. Neonatal rat cardiac fibroblasts were cultured and divided into four groups: control; AGE; AGE + receptor for AGE antibody and AGE + SB431542 (transforming growth factor-β [TGF-β]/Smad signaling pathway inhibitor, 10 μmol/L) group. After being cultured for 48 h, the cells were harvested and the senescence-associated beta-galactosidase expression was analyzed. Then the level of p16, TGF-β, Smad/p-smad and matrix metalloproteinase-2 was evaluated by western blot.
Significantly increased senescence-associated beta-galactosidase activity as well as p16 level was observed in the AGE group. Furthermore, AGE also significantly increased the TGF-β1, p-smad2/3 and metalloproteinases-2 expression in cardiac fibroblasts. Meanwhile, either pretreatment with receptor for AGE antibody or SB431542 significantly inhibited the upregulated cardiac senescence (beta-galactosidase activity and P16) and fibrosis-associated (TGF-β1, p-smad2/3 and metalloproteinases-2) markers induced by AGE. Taken together, all these results suggested that AGE are an important factor for cardiac aging and fibrosis, whereas the receptor for AGE and TGF-β/Smad signaling pathway might be involved in the AGE-induced cardiac aging process.
MAINTAINING TDP43 IN AMYOTROPHIC LATERAL SCLEROSIS
Wednesday, June 10, 2015
Cellular quality control mechanisms and their failure modes are important in aging and many diseases. A large number of distinct mechanisms are involved in keeping cell structures in good condition, clearing damaged or unwanted proteins, and other related tasks. Many of these mechanisms are exceedingly complex and far from fully cataloged or understood. It is expected in the research community that therapies will emerge in the near future based on enhancing quality control processes, but while new discoveries are made on a regular basis, I can't say there has been much material progress towards actual treatments over the decade I've been watching the field.
Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig's disease, is a debilitating neurodegenerative disorder that leads to paralysis and death due to the loss of motor neurons in the brain and spinal cord. A primary feature of ALS is an accumulation of the protein TDP43, too much of which is toxic to cells. In the current study, the researchers identified another protein, hUPF1, that keeps TDP43 in check, thereby preventing cell death. "TDP43 is a 'Goldilocks' protein: too much, or too little, can cause cellular damage. Over 90% of ALS cases exhibit TDP43-based pathology, so developing a treatment that keeps protein levels just right is imperative."
Previous investigations had identified hUPF1 as a potential therapeutic target for ALS, but it was unclear how this protein prevented cell death. In the current study, the scientists tested hUPF1's ability to protect against neurodegeneration using a cellular model of ALS. They discovered that genetically increasing levels of hUPF1 extended neuron survival by 50-60%. Digging deeper, the researchers revealed that hUPF1 acts through a cellular surveillance system called nonsense mediated decay, or NMD, to keep TDP43 levels stable and enhance neuronal survival.
This protective mechanism (NMD) monitors messenger RNA (mRNA). If a piece of mRNA is found to be defective, it is destroyed so that it cannot go on to produce dysfunctional proteins that can harm the cell. It now appears that NMD also helps control the levels of proteins, like TDP43, that bind to RNA and regulate splicing. Since hUPF1 is a master regulator of NMD, altering it has a trickle-down effect on TDP43 and other related proteins. "Cells have developed a really elegant way to maintain homeostasis and protect themselves from faulty proteins. This is the first time we've been able to link this natural monitoring system to neurodegenerative disease. Leveraging this system could be a strategic therapeutic target for diseases like ALS and frontotemporal dementia."
REGENERATIVE MEDICINE AND IDIOPATHIC PULMONARY FIBROSIS
Thursday, June 11, 2015
There are hundreds of discrete lines of research within the broad field of regenerative medicine; projects that can be divided up by tissue type, organ, and approach to building therapies. The open access paper quoted below can be taken as an example of the complexity of ongoing work on just one age-related disease in one organ. The large scale funding devoted to stem cell medicine starts to look less large when you multiply the amount of work required to make progress here by all of the varied organs and tissues in the body:
Idiopathic pulmonary fibrosis (IPF) is a progressive, irreversible disease of the lung that has no lasting option for therapy other than transplantation. It is characterized by replacement of the normal lung tissue by fibrotic scarring, honeycombing, and increased levels of myofibroblasts. The underlying causes of IPF are still largely unknown, but this disease preferentially affects adults older than 60 years. The focus of the current review is the possible use of stem cell therapy, specifically mesenchymal stem cells (MSCs), a multipotent stromal cell population, which have demonstrated promising data in multiple animal models of pulmonary fibrosis (PF). The most studied source of MSCs is the bone marrow, although they can be found also in the adipose tissue and umbilical cord, as well as in the placenta. MSCs have immunomodulatory and tissue-protective properties that allow them to manipulate the local environment of the injured tissue, ameliorating the inflammation and promoting repair.
Animal models have shown the success of MSC therapy in mitigating the fibrotic effects of bleomycin-induced PF. However, bleomycin, the most commonly used model for PF, is imperfect in mimicking IPF as it presents in humans, as the duration of the illness is not parallel or reversible, and honeycombing is not produced. Furthermore, the time of MSC dosage has proven to be critical in determining whether the cells will ultimately have a positive or negative effect on disease progression, since it has been demonstrated that the maximal beneficial effect of MSCs occurs during the early inflammatory phase of the disease and that there is no or negative effect during the late fibrotic phase. Therefore, all the current clinical trials of MSCs and IPF, though promising, should proceed with caution as we move toward true stem cell therapy for this disease.
Because IPF primarily affects older patients, the issue of aging is intrinsically linked to many aspects of the disease, including the age of the stem cells. In our opinion, an important weakness in the study of IPF is the lack of knowledge of lung aging, which is a main risk factor in IPF. Until now, most of the mouse models have included young animals (less than 3 months), and it is clear that in humans IPF is a pathology of the elderly, and as the association between aging, IPF, and stem cells is well developed, this variable must be taken into account in evaluating preclinical results and in translation to human applications.
STEPPING TOWARDS BIOARTIFICIAL IMMUNE SYSTEMS
Thursday, June 11, 2015
There is no necessary reason that an artificial organ has to look like or be structured in the same way as the evolved organ it is intended to replace or augment. There are good reasons to try different approaches, largely cost-effectiveness in research and development at the present time, such as by narrowing down work to replicating specific functions rather than trying to encompass everything that a natural organ accomplishes. Further down the line researchers will be aiming to produce improvements on the capabilities of natural biology, however.
This is all especially true of the immune system: so long as it is possible to produce the desired end result of the correct balance of signals in tissues and competent immune cells roaming the body to defend it from pathogens and malfunctioning cells, then it doesn't really matter what the controlling organs look like or where they are in the body. Since immune function can readily be divided up into discrete but interacting portions, there is considerable leeway for researchers to build and augment a bioartificial immune system piece by piece in the years ahead. This sort of work is promising when considering the importance of age-related declines in immune function in frailty and disease. Any means of safely recreating youthful immune system activity in the old is likely to bring considerable benefits.
Beyond that, why shouldn't we all have immune systems that support twice or ten times as many active immune cells, or which are pre-immunized against every known disease, or have other capabilities far beyond the evolved system we're presently stuck with? These and other options are very plausible for the near future:
Engineers have created a functional, synthetic immune organ that produces antibodies and can be controlled in the lab, completely separate from a living organism. The engineered organ has implications for everything from rapid production of immune therapies to new frontiers in cancer or infectious disease research. The synthetic organ is bio-inspired by secondary immune organs like the lymph node or spleen. It is made from gelatin-based biomaterials reinforced with nanoparticles and seeded with cells, and it mimics the anatomical microenvironment of lymphoid tissue. Like a real organ, the organoid converts B cells - which make antibodies that respond to infectious invaders - into germinal centers, which are clusters of B cells that activate, mature and mutate their antibody genes when the body is under attack. Germinal centers are a sign of infection and are not present in healthy immune organs.
The engineers have demonstrated how they can control this immune response in the organ and tune how quickly the B cells proliferate, get activated and change their antibody types. According to their paper, their 3-D organ outperforms existing 2-D cultures and can produce activated B cells up to 100 times faster. The organ could lead to increased understanding of B cell functions, an area of study that typically relies on animal models to observe how the cells develop and mature. "You can use our system to force the production of immunotherapeutics at much faster rates. In the long run, we anticipate that the ability to drive immune reaction ex vivo at controllable rates grants us the ability to reproduce immunological events with tunable parameters for better mechanistic understanding of B cell development and generation of B cell tumors, as well as screening and translation of new classes of drugs."
ATTACKING CANCER STEM CELLS IN THE BRAIN
Friday, June 12, 2015
Many types of cancer have been shown to be driven by the existence of a small population of cancer stem cells. This is what leads to the recurrence of cancer following apparently successful treatments to remove tumors, for example: therapies targeting cells making up the bulk of the cancer may not be effective in clearing out the cancer stem cells. On the other hand for cancer types wherein cancer stem cells can be clearly identified, there is an opportunity to strike at the root by attacking these cells:
Some brain tumors are notoriously difficult to treat. Whether surgically removed, zapped by radiation or infiltrated by chemotherapy drugs, they find a way to return. The ability of many brain tumors to regenerate can be traced to cancer stem cells that evade treatment and spur the growth of new tumor cells. But some brain tumor stem cells may have an Achilles' heel, scientists have found. The cancer stem cells' remarkable abilities have to be maintained, and researchers have identified a key player in that maintenance process. When the process is disrupted, they found, so is the spread of cancer.
Scientists have realized in recent years that some cancer cells in glioblastomas and other tumors are more resistant to treatment than others. Those same, more defiant cells also are much better at re-establishing cancer after treatment. "These tumor stem cells are really the kingpins of cancers - the cells that direct and drive much of the harm done by tumors." Researchers identified a protein, known as SOX2, that is active in brain tumor stem cells and in healthy stem cells in other parts of the body. The researchers found that the tumor stem cells' ability to make SOX2 could be turned up or down via another protein, CDC20. Increasing SOX2 by boosting levels of CDC20 also increased a tumor's ability to grow once transplanted into mice. Eliminating CDC20, meanwhile, left tumor stem cells unable to make SOX2, reducing the tumor stem cells' ability to form tumors. "The rate of growth in some tumors lacking CDC20 dropped by 95 percent compared with tumors with more typical levels of CDC20."
When the scientists analyzed human tumor samples, they found that a subset of patients with glioblastomas that had the highest CDC20 levels also had the shortest periods of survival after diagnosis. The researchers are exploring methods to block CDC20 in brain tumors, including RNA interference, an approach in which the production of specific proteins is blocked. That general approach is in clinical trials as a therapy for other cancers, viral infections and other illnesses.
A DRUG CANDIDATE TO TRIGGER FASTER REGENERATION
Friday, June 12, 2015
Based on what we know of the mechanisms by which stem cell therapies produce benefits, it shouldn't be surprising to find that there are signals that can be provided to tissues that enhance the pace of regeneration. We are still in the comparatively early days of the identification and understanding of those signals, but some efforts are further ahead than others:
"We have developed a drug that acts like a vitamin for tissue stem cells, stimulating their ability to repair tissues more quickly. The drug heals damage in multiple tissues, which suggests to us that it may have applications in treating many diseases." The institutions collaborating on this work next hope to develop the drug - now known as SW033291 - for use in human patients. Because of the areas of initial success, they first would focus on individuals who are receiving bone marrow transplants, individuals with ulcerative colitis, and individuals having liver surgery. The goal for each is the same: to increase dramatically the chances of a more rapid and successful recovery.
The key to the drug's potential involves a molecule the body produces that is known as prostaglandin E2, or PGE2. It is well established that PGE2 supports proliferation of many types of tissue stem cells. Researchers had demonstrated that a gene product found in all humans, 15-hydroxyprostaglandin dehydrogenase (15-PGDH), degrades and reduces the amount of PGE2 in the body. The researchers hypothesized that inhibiting 15-PGDH would increase PGE2 in tissues. In so doing, it would promote and speed tissue healing. When experiments on mice genetically engineered to lack 15-PGDH proved them correct, the pair began searching for a way to inactivate 15-PGDH on a short-term basis.
The preliminary work began in test tubes. Researchers developed a test where cells glowed when 15-PGDH levels changed and then combed through a library of 230,000 different chemicals. Ultimately they identified one chemical that they found inactivated 15-PGDH. A series of experiments showed that SW033291 could inactivate 15-PGDH in a test tube and inside a cell, and, most importantly, when injected into animal models. When investigators treated diseased mice, the SW033291 drug again accelerated tissue recovery. In a mouse model of ulcerative colitis SW033291 healed virtually all the ulcers in the animals' colons and prevented colitis symptoms. In mice where two-thirds of their livers had been removed surgically, SW033291 accelerated regrowth of new liver nearly twice as fast as normally happens without medication.
The investigators believe the pathway by which SW033291 speeds tissue regeneration is likely to work as well for treating diseases of many other tissues of the body. However, the next stages of the research will concentrate on diseases where SW033291 already shows promise to provide dramatic improvement.