FIGHT AGING! NEWSLETTER
August 5th 2013
The Fight Aging! Newsletter is a weekly email containing news, opinions, and happenings for people interested in aging science and engineered longevity: making use of diet, lifestyle choices, technology, and proven medical advances to live healthy, longer lives. This newsletter is published under the Creative Commons Attribution 3.0 license. In short, this means that you are encouraged to republish and rewrite it in any way you see fit, the only requirements being that you provide attribution and a link to Fight Aging!
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- A New Step in Targeted Therapies: Molecular Automata Add Surface Labels to Cells
- Profiles of Scientists Working on Rejuvenation Biotechnology at the SENS Research Foundation
- Society For Venturism Cryonics Conference, October 2013
- The Intersection of Kickstarter-Style Fundraising for Research and Distributed Development in Complex Problems
- Opposing the Argument that Increased Longevity Will Slow Progress, and is Therefore Undesirable
- Latest Headlines from Fight Aging!
- The LongevityMap Online Database
- Living Longer, Living Healthier
- Towards Transferring the Cellular Benefits of Calorie Restriction
- Calorie Restriction Produces Benefits via Increased Autophagy
- Exercise Versus Alzheimer's Disease
- Protyping a Tissue Engineered Ear
- Surviving Lethal Chemotherapy by Boosting Stem Cell Activity
- The Cost of Being Tall is a Shorter Life Expectancy
- Steps Towards a Tissue Engineered Thymus
- Considering State Opposition to Life Extension Technologies
A NEW STEP IN TARGETED THERAPIES: MOLECULAR AUTOMATA ADD SURFACE LABELS TO CELLS
The coming generation of medical therapies will be distinguished from those of the past decades by their specificity: they will target only those cells that need to be destroyed, altered, or reprogrammed, rather than being indiscriminately infused into the body to hit all cells. In a world in which researchers cannot target specific cells, the development of therapies is focused on finding things that won't kill the patient. Treatments are deployed because they are just a bit more harmful to, say, cancer cells than they are to all other cells. This is, needless to say, no walk in the park for the patient.
A targeted therapy, on the other hand, will by design have few side effects. The method of destroying or altering targeted cells can be ramped up to optimal levels of effectiveness because it won't bleed over to impact many other cells. Indeed, with the addition of some form of targeting and delivery mechanism such as nanoparticles even the old chemotherapies for cancer can be turned into highly effective, low impact treatments that kill only cancer cells and don't make the patient sick at all.
This is the future, and not just for cancer treatments. So it's worth keeping an eye on research in the field of targeting and delivery, as any new methodology with a broad application has the potential to greatly impact the effectiveness of many types of medical therapy over the next ten to twenty years.
I noticed an example of this sort of thing today, wherein researchers are engaged in the first steps of building a generic cell labeling platform. Instead of incorporating the ability to detect surface markers into a delivery mechanism, it might be possible to standardize delivery systems to identify cells by a small set of constructed labels. Labeling technologies would perform the work of identifying specific cell types by their (very varied, very complex) surface chemistry, and then applying labels to those cells. So a treatment would be a two-step process in which cells are labeled, that result is validated, and then the therapy is applied, targeted to those labels. With these technologies, a standard set of labels becomes an API of sorts, enabling specialization of research and development into labeling and delivery camps, something that always speeds progress and reduces costs where it occurs.
Molecular robots can help researchers build more targeted therapeutics
In the new study, scientists have designed molecular robots that can identify multiple receptors on cell surfaces, thereby effectively labeling more specific subpopulations of cells. The molecular robots, called molecular automata, are composed of a mixture of antibodies and short strands of DNA. These short DNA strands, otherwise called oligonucleotides, can be manufactured by researchers in a laboratory with any user-specified sequence.
The researchers conducted their experiments using white blood cells. All white blood cells have CD45 receptors, but only subsets have other receptors such as CD20, CD3, and CD8. In one experiment, [researchers] created three different molecular robots. Each one had an antibody component of either CD45, CD3 or CD8 and a DNA component. The DNA components of the robots were created to have a high affinity to the DNA components of another robot. DNA can be thought of as a double stranded helix that contains two strands of coded letters, and certain strands have a higher affinity to particular strands than others.
The researchers mixed human blood from healthy donors with their molecular robots. When a molecular robot carrying a CD45 antibody latched on to a CD45 receptor of a cell and a molecular robot carrying a CD3 antibody latched on to a different welcoming receptor of the same cell, the close proximity of the DNA strands from the two robots triggered a cascade reaction, where certain strands were ripped apart and more complementary strands joined together. The result was a unique, single strand of DNA that was displayed only on a cell that had these two receptors.
The addition of a molecular robot carrying a CD8 antibody docking on a cell that expressed CD45, CD3 and CD8 caused this strand to grow. The researchers also showed that the strand could be programmed to fluoresce when exposed to a solution. The robots can essentially label a subpopulation of cells allowing for more targeted therapy. The researchers say the use of increasing numbers of molecular robots will allow researchers to zero in on more and more specific subsets of cell populations.
"The automata trigger the growth of more strongly complementary oligonucleotides. The reactions occur fast. In about 15 minutes, we can label cells." In terms of clinical applications, researchers could either label cells that they want to target or cells they want to avoid. "This is a proof of concept study that it works in human whole blood. The next step is to test it in animals."
PROFILES OF SCIENTISTS WORKING ON REJUVENATION BIOTECHNOLOGY AT THE SENS RESEARCH FOUNDATION
With yearly budget of several million dollars, the SENS Research Foundation has grown a long way beyond the founding group of a few advocates and researchers. Life scientists in laboratories around the world, including the Foundation's research center in California, presently work on the foundations of human rejuvenation detailed in the Strategies for Engineered Negligible Senescence (SENS). There are forms of cellular and intracellular damage that harm us and cause degenerative aging, and in every case researchers can clearly describe what needs to be accomplished in order to repair that damage. The only obstacles to rapid progress towards the medical control of aging are (a) funding and (b) obtaining the widespread public support and understanding needed to generate that funding.
Aging is the greatest form of harm to humanity that presently exists: it causes more death and suffering than all forms of disease, violence, and accident combined. The golden future of medicine involves finding ways to reduce the cost of aging, and preferably eliminate it altogether through periodic repair procedures. Curing degenerative aging will save more lives than any other human endeavor to date, and more lives than any other endeavor can possibly save. Research into human rejuvenation is the most important activity presently taking place in the world today by any rational measure.
(And yet it is also probably the least funded in comparison to its importance. Little medical research is well funded of course, in comparison to the benefits it can produce, but that is the way of the world. We spend billions on circuses and war, billions more on trying to cope with the consequences of sickness and aging, but next to nothing on ways to dramatically improve the human condition by eliminating that sickness and aging. Given how small a sliver of economic activity is devoted to improving medicine, it's amazing that progress is as fast as it is).
The SENS Research Foundation is presently running a series of profiles of the researchers and interns who are helping to push forward the boundaries of the possible in medical science. Few people are doing work that is more important than that funded by the Foundation:
The Youngest Thiel Finalist: SRF's Thomas Hunt
Before I joined SRF, I started out as a curious and active member of the Do-It-Yourself (DIY) bio community. As a young teen, I got involved with BioCurious in its earliest days to help build the BioCurious lab. I also participated in other organizations like the Health Extension Salon and Thiel Fellowship Under20 Summits before applying for a 20Under20 Fellowship this past year.
Currently I volunteer at SRF four days a week. I spend my time conducting research to understand a poorly understood pathway that plays a key role in cancer cell immortality called alternative lengthening of telomeres, or ALT. I keep current with new developments in my field by reading scientific papers at the cutting edge of ALT work, and I am currently in charge of studying POT1, a protein that could negatively affect ALT activity. I am also performing experiments on cancer cells to test for ALT activity.
When I'm not at SRF, I've designed my own home schooling curriculum, where I get to choose which subjects I want to study. I take local college classes that I feel will assist me in my research goals, like chemistry and public speaking. I love telling people about the latest discoveries in science, and have spoken at The University of California, Santa Cruz (UCSC) about genetic modification.
Amutha Boominathan: Moving vulnerable mitochondrial genes to the safety of the nucleus
After moving to the Bay Area I was looking for mitochondria research labs that would fit my experience and expertise where I could further my career. I came across the MitoSENS project at SRF's Research Center and was very excited. It seemed like 'the' perfect place, almost like an extension of what I was doing in my postdoc lab. So I sent my CV, cold, to the info address listed, and Daniel forwarded my CV to Oki [Matthew O'Connor, SRF's Principal Investigator]. We had a good talk about the project and I volunteered for a short bit before coming on full-time this year.
We all know that mitochondria are the cell's "powerhouse" for energy. One interesting fact about these organelles is that they have their own DNA in addition to the nuclear DNA that we are all aware of. However, the mitochondrial DNA is prone to mutations due to constant exposure from ROS (reactive oxygen species) generated through the OX-PHOS system. This is because the mitochondrial DNA is not encased in a nuclear envelope nor does it have efficient repair mechanisms to correct mutations as they occur. To mitigate this weakness, our goal here at SRF is to move the mitochondrial genes to the nucleus, where it's safer to express them for function. This would let mitochondria keep producing energy normally, even after mitochondrial mutations have occurred.
Jayanthi Vengalam: Engineering backup mitochondrial genes
Here at SRF, we're working to engineer expressions of "backup" copies of vulnerable mitochondrial genes, located in the safer location of the cell's nucleus. To explore and refine methods to safely accomplish this, we've taken four cell lines from patients suffering from inherited mitochondrial mutations, and made stable lines that express their improved mitochondrial gene constructs. We've begun collecting data which confirms the targeting of gene transcripts and proteins, as well as the functional activity of the mitochondrial energy system.
Our two primary goals this year are to definitively confirm the localization of allotopically-expressed proteins at the inner membrane of mitochondria, and to demonstrate that our allotropic expression systems can functionally rescue cells with each of several missing or severely mutated mitochondrial genes. I spend most of my time engineering different targeting tags on the various proteins we are trying to target to the mitochondrial OxPhos system and testing the engineered genes in the cell lines.
Aging is a sad thing, and it's important to me to contribute to research that helps understand and alleviate suffering. Mitochondrial abnormalities contribute to general problems of aging most people traditionally think of as inevitable, but also affect acute diseases such as diabetes, Parkinson's and Alzheimer's. Our mission is a noble one.
Mission isn't everything, though; you have to like the people your work with, too. I really like that everyone here is not only abstractly passionate about SRF's mission, but also truly committed to uncovering the real scientific truths in what they want to accomplish. Some more traditional workplaces have such a product or hierarchically-oriented management focus that it's hard to get real research done; here, if I have a question or a research problem, it's really natural to just go talk to someone about it honestly face-to-face.
SOCIETY FOR VENTURISM CRYONICS CONFERENCE, OCTOBER 2013
The Society for Venturism has been a part of the cryonics advocacy community since the 1980s, and so is one of the older portions of the modern transhumanist movement. The cryonics industry, which has existed in a rigorous form since the 1970s, focuses on preserving the brain and thus the structure of the mind following death, so as to offer a chance at restoration to life and health by future medical technologies, such as those that might be built on a foundation of molecular nanotechnology and medical nanorobotics. The chance of success is unknown, but very much greater than zero, which are the odds you'll get when opting for the traditional choice of grave, gravestone, and oblivion. Over the decades cryonics providers have moved from simple freezing and its attendant issues of tissue damage to the modern process of vitrification and a practiced procedure of standby and support for terminal patients.
Cryonics is an important part of the longevity science community, for all that it garners far too little attention from the world at large: billions will die before methods of rejuvenating the old and preventing age-related frailty become widespread throughout the world even under the best case scenarios of funding and public support. Cryonics is a way for those who will age to death too soon to have a shot at the future of greatly extended lives and youth.
Still, while the cryonics community has grown and become more professional and research-oriented with time, it has failed to find the footing and support for an earnest transition into the mainstream. The number of people cryopreserved to date is around 250 or so, a miniscule fraction of those who have died over the past four decades and who had the funds to hand to choose cryopreservation. In recent years, the public and press view of cryonics has become less hostile and much more understanding, however. New cryonics organizations have been established or are in the process of establishment outside the US. So there is hope that the process of growth and improvement will continue at a faster pace in the future.
Venturist Society FAQ Cryonics Conference
The convention this year has a lineup of prominent and inspirational speakers in the fields of cryonics, radical life extension and transhumanism, including Aubrey de Grey, Ph.D., Max More, Ph.D. and experts in other areas.
The name of the convention will be the FAQ Cryonics Convention. FAQ, as most people know, stands for Frequently Asked Questions. This convention will be open to people who are already signed up for cryonics, and for prospects for cryonics as we also we expect a good turnout from people who are thinking about joining. [It is] to be held at Don Laughlin's Riverside Resort in Laughlin, Nevada on October 25, 26 & 27, 2013.
Aubrey de Grey, of the SENS Research Foundation, will be giving this presentation:
A biologist's view on why cryonics is feasible: Many non-biologists presume that cryonics must be fantasy because it is not mainstream. This is a reasonable inference for those who do not appreciate how appallingly balkanised biology is, with almost all biologists being expert in only a very narrow area and having no time to study other areas. Since a field's reputation for infeasibility is a reason not to pay attention it, this parlous situation is self-fulfilling. In this talk I will see to rectify it.
THE INTERSECTION OF KICKSTARTER-STYLE FUNDRAISING FOR RESEARCH AND DISTRIBUTED DEVELOPMENT IN COMPLEX PROBLEMS
The success of Kickstarter and conceptually similar entities (IndieGoGo, AngelList, and so forth) as fundraising communities has more than adequately demonstrated that crowdfunding works very well in an environment of low-cost, ubiquitous communication and open data. All the old centralized time-proven activities of fundraising in for-profit business can in fact be distributed, turned inside out, and disintermediated. New middle men arise in this process of disruptive change, such as Kickstarter, but the future will see their dominance vanish in favor of open protocols and marketplaces with some sort of an ecosystem of optional gatekeepers and reviewers. This is exactly the same as the transition from early dial-up services and their walled gardens to the open internet, and seems to be something of an inevitability.
Can this be made to work for science and research? Therein lies the question. At the high level, it seems as though the answer is obviously yes: it's all just money, and money is presently invested in research. But at the detail level research is a very different thing from funding a new artwork or widget: it has a much longer time horizon, a far greater degree of uncertainty, and the funders don't walk away at the end with a new widget. A number of companies are presently attempting to find the magic recipe by which crowsourced science funding can be made work in a Kickstarter-like fashion.
Clearly crowdfunding for specific research goals is possible. There are numerous examples of success in the past decade beyond those I'll mention here. The Methuselah Foundation and SENS Research Foundation grew out of crowdfunding initiatives, raising money from hundreds of donors from the transhumanist community and other supporters of longevity science. The advocacy community of Longecity raises modest sums for specific life science research projects connected to longevity and related medical technologies. But these are tailored projects, integrated with specific interest communities: not the same thing at all as building a successful marketplace for diverse forms of project and community.
Crowdfunding intersects with another important trend that arises with ubiquitous, low-cost communication and openly accessible data, which is the distribution of effort in large projects. Complex initiatives can now be undertaken piecemeal by geographically dispersed groups who share a common interest. The open source software development community is far ahead of the rest of the world in this respect: many vital and important software projects have evolved in a worldwide fashion, with self-organizing collaborators who will never meet in person. Science is moving in the same direction: lots of data, lots of complex software, data becoming more open, and more distributed collaboration between researchers in different parts of the world.
What medical science has that the software industry does not is a vast and pervasive edifice of regulation, wherein largely unaccountable regulators insist on centralization and the imposition of enormous costs on research and its application in the form of new therapies and medical technologies. Regulation opposes movement to a more distributed research and development industry in which even exceedingly rare diseases will be worked on by someone, somewhere with a vested interest. Higher costs always mean that marginal work suffers, vanishes entirely, or takes place in black and grey markets with all their attendant issues. It is enormously harmful, and that harm is largely invisible: the technologies not developed, the progress not made, the dead in their millions who might have had a chance at longer lives.
The article quoted below offers some thoughts on all of this in the context of cancer research and proto-crowdfunding efforts that have aimed to spur research and development in therapies for very rare forms of cancers, those that present regulation makes it unprofitable to work on. The points raised are also applicable to the situation for aging and rejuvenation research, however, which is also a collection of related minority fields that are shut out from clinical application by the decisions of regulators.
Can We Build A Kickstarter For Cancer?
Building large analytical databases to mine clinical and molecular data, and scan the scientific literature to identify better treatments for cancer patients is happening today. But what about patients who fall outside what we already know - whose cancer subtypes haven't been discovered yet, and who don't have access to the technologies that could make a difference in unraveling the aberrations driving their cancers? The technology to unravel the molecular drivers of cancer is, for the most part, available today: "-omics" technologies for screening tumor samples from patients and comparing them to healthy tissue samples to pick out cancer-specific mutations; diagnostics that can track patients' response to treatment in real time at a molecular level; and Web-based tools and apps [that] patients and community oncologists can use to guide treatment decisions (and feed those outcomes, good and bad, back into the research process).
Our current research approach - one drug, one clinical trial, one cancer type at a time - won't generate enough of the information we need to unravel cancer's molecular mysteries at the patient level. And it is too slow, too bureaucratic, and too expensive to be sustainable, given the number of compounds we have to test and the limited pool of patients who participate in clinical trials. Only about 3% of all cancer patients participate in cancer clinical trials, and those patients - because of restrictive inclusion/exclusion criteria - are often very different (i.e., healthier) than the average cancer patient, who is likely to be in poorer health and have one or more co-morbidities (obesity, diabetes, etc.). This limits the applicability of even the best drug guidelines based on classical trials for real-world patients. Classical clinical trials lead to a "tyranny of the averages," rather than helping us to - as in the case of cancer - disassemble complex diseases that might share the same clinical symptoms (and which we happen to call cancer or diabetes) but which are really molecularly distinct and thus require different treatment approaches.
In short, we won't develop the drugs or complex treatment regimens we need to for truly personalized cancer treatment regimens for patients if we keep doing business as usual. The patients who have the most to gain from this approach are those who have the most to lose today - patients with rare or hard-to-treat cancers, who fail rapidly on standard or even targeted treatments. And it's exactly these patients who will, in all likelihood, be most eager to embrace the risks and promise of Kickstarting their own cancer research.
It's not just cancer: all of modern medicine would benefit from an overturning of the present centralized regulatory structures in order to allow unfettered diversity in fundraising, research, and clinical application. This is exactly the sort of approach that modern communication technologies enable: let there be far more in the way of researchers connecting to the interested small communities among the broader public - as was the case for the Strategies for Engineered Negligible Senescence - and the best of these initiatives, those that manage to obtain support from both the public and the scientific community, will prosper. This, I think, is a far more promising model for the future of research than the stasis, obstructions, and failures of highly regulated, state-funded scientific and medical monoliths.
OPPOSING THE ARGUMENT THAT INCREASED LONGEVITY WILL SLOW PROGRESS, AND IS THEREFORE UNDESIRABLE
Some opponents of increased human healthy longevity argue that if we begin to live for far longer than the present human life span then progress in technology will slow to a crawl. This is often presented as a variation on the stagnation argument: that long-lived people will cling to their ideas and their positions for decades or centuries, resisting all change. It is true that human nature comes with a strong conservative streak, and all change is opposed. But despite that fact change nonetheless happens on a timescale quite short in comparison to human life spans: leaders come and go, like fashions, and revolutions, and changes of opinion, and sweeping redefinitions in culture and society. Rare indeed are those that manage to last for a couple of decades, never mind longer. This pace of change in human affairs is essentially the same as that of the ancient world, despite our much greater adult life expectancy in comparison to the classical Greek period or Roman empire.
If we want to look at raw correlations on the other hand, it seems that the technologies needed to extend healthy life go hand in hand with an increased rate of technological progress. Longevity has made the human world become wealthier and run faster, opening doors of opportunity rather than closing them. The only way to increase the healthy human life span is through the creation of a broad pyramid of enabling technologies that in turn lead to faster progress in all fields, not just medicine. Computing is the present dominant enabler, for example, not just for biotechnology but also for almost all other fields of endeavor. If human nature to date has failed to hold back the tide of progress, I'd say it has little chance at doing so in the future: progress is only speeding up.
As is pointed out in the article excerpted below, people change throughout their lives. This also is the same as in the times of antiquity, despite much longer life spans. Human nature is human nature, and the caricature of inflexible, static old people is just that: a caricature. Minds change, and where the elderly are in fact forced into smaller and smaller circles it is largely through disability and frailty, not choice: the failing body and mind narrow the accessible vista, not the lack of will.
Combatting the "Longer Life Will Slow Progress" Criticism
We are all still children. As far as the Centenarian is concerned, the only people to have ever lived have been children - and we have all died before our coming of age. What if humans only lived to age 20? Consider how much less it would be possible to know, to experience, and to do. Most people would agree that a maximum lifespan of 20 years is extremely circumcising and limiting - a travesty. However, it is only because we ourselves have lived past such an age that we feel intuitively as though a maximum lifespan of 20 years would be a worse state of affairs than a maximum lifespan of 100. And it is only because we ourselves have not lived past the age of 100 that we fail to have similar feelings regarding death at the age of 100. This doesn't seem like such a tragedy to us - but it is a tragedy, and arguably one as extensive as death at age 20.
The current breadth and depth of the world and its past are far too gargantuan to be encompassed by a mere 100 years. If you really think that there are only so many things that can be done in a lifetime, you simply haven't lived long enough or broadly enough. There is more to the wide whorl of the world than the confines and extents of our own particular cultural narrative and native milieu.
Luckily, functional decline as a correlate of age is on the way out. We will live to 100 not in a period of decline upon hitting our mid-twenties, but in a continuing period of youthfulness. There are no longevity therapies on the table that offer to truly prolong life indefinitely without actually reversing aging. Thus, one of the impediments preventing us from seeing death at 100 as a tragedy, as dying before one's time, will be put to rest as well. When we see a 100 year old die in future, they will have the young face of someone who we feel today has died before their time. We won't be intuitively inclined to look back upon the gradual loss of function and physiological-robustness as leading to and foretelling this point, thereby making it seem inevitable or somehow natural. We will see a terribly sad 20 year old, wishing they had more time.
It seems to me a truism that we get smarter, more ethical and more deliberative as we age. To think otherwise is in many cases derivative of the notion that physiology and experience alike are on the decline once we "peak" in our mid-twenties, downhill into old age - which does undoubtedly happen, and which inarguably does cause functional decline. But longevity therapies are nothing more nor less than the maintenance of normative functionality; longevity therapies would thus not only negate the functional decline that comes with old age, [but also] the source of the problem arguably at the heart of the concern that longer life will slow progress.
Increasing longevity will not bring with it prolonged old-age, a frozen decay and decrepit delay, but will instead prolong our youthful lives and make us continually growing beings, getting smarter and more ethical all the time.
Lastly, this thought: so what if increased life spans did slow progress? Even in the hypothetical world in which that did look even remotely plausible, it is still the case that for so long as the pace of longevity is greater than the slowdown, everyone still comes out ahead. Being alive and in good health is the important thing: given that, the only thing that matters with regard to further technological progress is whether it is happening fast enough to keep you alive and in good health. Everything else in life is what you make of it.
LATEST HEADLINES FROM FIGHT AGING!
THE LONGEVITYMAP ONLINE DATABASE
Monday, July 29, 2013
The senescence.info team recently added a new online database to the collection available at the site:
The LongevityMap is based on manually-curated data from over 200 genetic association studies of longevity. Each entry includes a brief description of the study and major findings, as well as the specific population studied and other relevant information. Entries are mapped (if appropriate) to genes, chromosomal regions and SNP ID which can be queried.
Negative results are also included in the LongevityMap to provide visitors with as much information as possible regarding each gene and variant previously studied in context of longevity. As such, the LongevityMap serves as a repository of genetic association studies of longevity and reflects our current knowledge of the genetics of human longevity.
LIVING LONGER, LIVING HEALTHIER
Monday, July 29, 2013
If aging is a matter of accumulating damage, then we would expect all successful efforts to improve health to also result in some degree of extended healthy life. Biology is very complex, and so the situation on the ground inside an aging body isn't as simple as the accumulation of damage in a non-self-repairing entity such as a chair or a building, but the fact that human life span and health in old age are both steadily increasing alongside general improvements in medical technology supports the view of aging as damage.
With the exception of the year or two just before death, people are healthier than they used to be. Effectively, the period of time in which we're in poor health is being compressed until just before the end of life. So where we used to see people who are very, very sick for the final six or seven years of their life, that's now far less common. People are living to older ages and we are adding healthy years, not debilitated ones. The study results are based on data collected between 1991 and 2009 from nearly 90,000 individuals who responded to the Medicare Current Beneficiary Survey (MCBS).
"There are two basic scenarios that people have proposed about the end of life. The first argues that what medical science is doing is turning us into light bulbs - that is, we work well until suddenly we die. This is also called the rectangularization of the life curve, and what it says is that we're going to have a fairly high quality of life until the very end. The other idea says life is a series of strokes, and medical care has simply gotten better at saving us. So we can live longer because we've prevented death, but those years are not in very good health, and they are very expensive - we're going to be in wheelchairs, in and out of hospitals and in nursing homes."
While researchers have tried to tackle the question of which model is more accurate, different studies have produced competing results. One reason for the confusion [is] that such efforts are simply looking at the wrong end of someone's life. "Most of our surveys measure health at different ages, and then use a model to estimate how long people have to live. But the right way to do this is to measure health backwards from death, not forwards. We should start when someone dies, then go back a year and measure their health, then go back two years, three years, and so on."
"There seems to be a clear relationship between some conditions that are no longer as debilitating as they once were and areas of improvement in medicine. The most obvious is cardiovascular disease - there are many fewer heart attacks today than there used to be, because people are now taking cholesterol-lowering drugs, and recovery is much better from heart attacks and strokes than it used to be. A person who suffered a stroke used to be totally disabled, but now many will survive and live reasonable lives. People also rebound quite well from heart attacks."
TOWARDS TRANSFERRING THE CELLULAR BENEFITS OF CALORIE RESTRICTION
Tuesday, July 30, 2013
You might recall research involving parabiosis, in which researchers joined the circulatory systems of an old and a young mouse to measure the effects of signaling changes in the cellular environment that occur with age - and to see what the results would be if changes in the old environment were reversed. Prior investigations were conducted in cell cultures, exposing old cells to young blood or vice versa, which is how the fact that this resulted in interesting changes was noted in the first place.
Researchers here are walking down the same path with calorie restriction: it seems that changes are observed if you take blood serum from a calorie restricted individual and expose cells to it. This suggests that one component of the mechanisms by which calorie restriction extends life and improves health involves changes to the chemical makeup of the cellular environment, as one might expect:
Calorie restriction (CR) without malnutrition is the most robust intervention to slow aging and extend healthy lifespan in experimental model organisms. Several metabolic and molecular adaptations have been hypothesized to play a role in mediating the anti-aging effects of CR, including enhanced stress resistance, reduced oxidative stress and several neuroendocrine modifications. However, little is known about the independent effect of circulating factors in modulating key molecular pathways.
In this study, we used sera collected from individuals practicing long-term CR and from age- and sex-matched individuals on a typical US diet to culture human primary fibroblasts and assess the effects on gene expression and stress resistance. We show that treatment of cultured cells with CR sera caused increased expression of stress-response genes and enhanced tolerance to oxidants. Cells cultured in serum from CR individuals showed a 30% increase in resistance to H2O2 damage. Consistently, SOD2 and GPX1 mRNA, two key endogenous antioxidant enzymes, were increased by 2 and 2.5 folds respectively in cells cultured with CR sera. These cellular and molecular adaptations mirror some of the key effects of CR in animals, and further suggest that circulating factors contribute to the CR-mediated protection against oxidative stress and stress-response in humans as well.
CALORIE RESTRICTION PRODUCES BENEFITS VIA INCREASED AUTOPHAGY
Tuesday, July 30, 2013
It is fairly well established by this point that calorie restriction boosts the cellular housekeeping processes known as autophagy. Damaged components, broken proteins, and other issues are more readily dealt with, destroyed, and recycled when an individual is on a low calorie rather than high calorie diet. Increased levels of autophagy are known to be associated with many of the methods of slowing aging demonstrated in laboratory animals, which leads some researchers to think that it is one of the more important aspects of the way in which metabolism determines variations in longevity. With that in mind, here is one of a range of studies that confirm the association between calorie restriction and increased autophagy:
Diet has been long recognized as a modulator of kidney health in both humans and experimental models. Calorie restriction (CR) can retard the progression of many age-associated molecular, physiological, and pathological processes which occur in tissues with high oxidative demand, such as kidney, skeletal muscle, heart, and brain. In contrast, feeding mice with a high-calorie diet results in age-related obesity, cardiovascular diseases, and other metabolic disorders, and it shortens lifespan. A high-calorie (HC) diet induces renal injury and promotes aging, and calorie restriction (CR) may ameliorate these responses. However, the effects of long-term HC and CR on renal damage and aging have been not fully determined.
Autophagy is an evolutionarily conserved process in eukaryotic organisms. Cytoplasmic constituents are sequestered in double-membrane structures to form autophagosomes, which fuse with lysosomes to form autolysosomes. The cytoplasmic components are degraded by acid hydrolases, and the degradation products are released into the cytosol and recycled into biological structures or to supply energy during periods of starvation. Autophagy is critical for survival during nutrient deprivation, as it enables recycling of macromolecules to provide new nutrients and energy in yeast and mammals. Another key function of autophagy is to remove damaged organelles such as mitochondria and aberrant macromolecules, to prevent further injury to cells. Therefore, impairment of autophagy will lead to a progressive accumulation of damaged macromolecules and organelles in somatic cells, increased oxidative damage and accelerated aging.
We evaluated the expression of [markers of autophagy] in the kidneys of 24-month-old Fischer 344 rats. We also observed mitochondrial structure and autolysosomes by transmission electron microscopy. Expression of the autophagosome formation marker LC3/Atg8 and markers of mitochondrial autophagy (mitophagy) were markedly decreased in the kidneys of the HC group, and markedly increased in CR kidneys. Transmission electron microscopy demonstrated that HC kidneys showed severe abnormal mitochondrial morphology with fewer autolysosomes, while CR kidneys exhibited normal mitochondrial morphology with numerous autolysosomes. Markers of aging, such as p16 and senescence-associated-galactosidase, were increased significantly in the HC group and decreased significantly in the CR group. The study [suggests] that HC diet inhibits renal autophagy and aggravates renal oxidative damage and aging, while CR enhances renal autophagy and ameliorates oxidative damage and aging in the kidneys.
EXERCISE VERSUS ALZHEIMER'S DISEASE
Wednesday, July 31, 2013
Exercise is known to reduce the risk of suffering Alzheimer's disease, but it also brings reliably greater benefits to Alzheimer's patients than any presently available medical technology. Exercise is in general very beneficial for elderly people, all too few of whom undertake enough exercise these days. The future of medical science will ultimately make lifestyle choices such as a calorie restricted diet and regular moderate exercise irrelevant as determinants of health and longevity, but for now they are the best available option to slow degeneration and improve long-term health.
New research [shows] that exercise may improve cognitive function in those at risk for Alzheimer's by improving the efficiency of brain activity associated with memory. Memory loss leading to Alzheimer's disease is one of the greatest fears among older Americans. While some memory loss is normal and to be expected as we age, a diagnosis of mild cognitive impairment, or MCI, signals more substantial memory loss and a greater risk for Alzheimer's, for which there currently is no cure. The study [is] the first to show that an exercise intervention with older adults with mild cognitive impairment (average age 78) improved not only memory recall, but also brain function, as measured by functional neuroimaging (via fMRI).
Two groups of physically inactive older adults (ranging from 60-88 years old) were put on a 12-week exercise program that focused on regular treadmill walking and was guided by a personal trainer. Both groups - one which included adults with MCI and the other with healthy brain function - improved their cardiovascular fitness by about ten percent at the end of the intervention. More notably, both groups also improved their memory performance and showed enhanced neural efficiency while engaged in memory retrieval tasks.
Tests and imaging were performed both before and after the 12-week exercise intervention. Brain scans taken after the exercise intervention showed a significant decrease in the intensity of brain activation in eleven brain regions while participants correctly identified famous names. The brain regions with improved efficiency corresponded to those involved in the pathology of Alzheimer's disease, including the precuneus region, the temporal lobe, and the parahippocampal gyrus.
PROTYPING A TISSUE ENGINEERED EAR
Wednesday, July 31, 2013
Simpler forms of exterior soft tissue are among the first candidates for tissue engineering, and work continues on ways to produce tissue structures such as ears:
Scientists have built an artificial human ear by combining living tissues from cows and sheep and growing them around a flexible wire frame that retains the correct anatomical shape of the organ. It is the latest development in 3D tissue engineering where substitute organs are made in the laboratory in the hope of using them to replace the damaged or missing body parts of patients. The artificial ear is described as a "proof of concept" prototype, and further research and development will be needed before it could be used in clinical transplants on patients.
A key feature of the artificial ear is a cartilage scaffold with an embedded titanium wire which retains the shape of the structure as well as maintaining its flexibility. "The technology is now under development for clinical trials, and thus we have scaled-up and redesigned the prominent features of this scaffold to match the size of an adult human ear and to preserve the aesthetic appearance after implantation."
Collagen connective tissue from a cow was formed into the shape of a human pinna - the fleshy visible part of the ear - and held in place by titanium wire. The porous collagen was then "seeded" with ear cartilage cells taken from a sheep and the cells grew within the porous collagen fibres. The scientists grew the ear on mice and rats lacking an immune system to show that it was possible for it to be connected to a blood supply without tissue rejection. In a human transplant, the ear would have to be either made from a patient's own stem cells or used with anti-rejection drugs. An important feature of the technology is that the ear can be designed to look as natural as possible by pulling the skin taut over the wire and cartilage frame using vacuum suction.
SURVIVING LETHAL CHEMOTHERAPY BY BOOSTING STEM CELL ACTIVITY
Thursday, August 1, 2013
Increasing chemotherapy tolerance, so as to allow greater harm to be caused to cancerous tumors while the patient still survives the treatment, is a strategy that will be eclipsed by the next generation of cancer therapies. They will target cancer cells and have few to no side effects, and will certainly not be a case of flooding the body with poisons that are just a little more toxic to cancer than to the rest of the patient's cells. So the discovery made by these researchers will, I think, be something that finds application in regenerative medicine instead: a way to greatly boost stem cell activity in specific tissues should have many uses.
Treating a cancerous tumor is like watering a houseplant with a fire hose - too much water kills the plant, just as too much chemotherapy and radiation kills the patient before it kills the tumor. However, if the patient's gastrointestinal tract remains healthy and functioning, the patient's chances of survival increase exponentially. Recently, [researchers] discovered a biological mechanism that preserves the gastrointestinal tracts in mice who were delivered lethal doses of chemotherapy.
"It's our belief that this could eventually cure later-staged metastasized cancer. People will not die from cancer, if our prediction is true. All tumors from different tissues and organs can be killed by high doses of chemotherapy and radiation, but the current challenge for treating the later-staged metastasized cancer is that you actually kill the patient before you kill the tumor."
[Researchers] found that when certain proteins bind with a specific molecule on intestinal stem cells, it revs intestinal stem cells into overdrive for intestinal regeneration and repair. [Researchers have] worked with these molecules, called R-spondin1 and Slit2, for more than a decade. In the study, 50-to-75 percent of the mice treated with the molecule survived otherwise lethal doses of chemotherapy. All of the mice that did not receive the molecule died. "The next step is to aim for a 100-percent survival rate in mice who are injected with the molecules and receive lethal doses of chemotherapy and radiation."
Stem cells naturally heal damaged organs and tissues, but so-called "normal" amounts of stem cells in the intestine simply cannot keep up with the wreckage left behind by the lethal doses of chemotherapy and radiation required to successfully treat late-stage tumors. However, the phalanx of extra stem cells protect the intestine and gastrointestinal tract, which means the patient can ingest nutrients, the body can perform other critical functions and the bacterial toxins in the intestine are prevented from entering the blood circulation.
THE COST OF BEING TALL IS A SHORTER LIFE EXPECTANCY
Thursday, August 1, 2013
This popular science piece outlines some of the evidence for greater height to come with a penalty to longevity. I believe that the most plausible contribution to this effect has to do with growth hormone metabolism, given the degree to which it is linked to longevity in laboratory animals. Broadly speaking less growth hormone means a longer life in species such as mice. Larger individuals with more growth hormone accumulate damage and dysfunction at a faster pace in all areas: they age more rapidly.
One of the goals for future medicine is to make all such correlations in long term health irrelevant. Advanced medical technology, sufficient to repair the causes of aging, will sweep away the effects of differences in genetics and circumstances. This is something to look forward, as with suitable levels of funding and support the first of these new therapies of rejuvenation might be developed and rolled out by the late 2030s.
Physicians and epidemiologists began studying the link between height and longevity more than a century ago. Early researchers believed that tall people lived longer, [but] in fact in the early 20th century height was [a] reflection of better nutrition and hygiene, which increased longevity. Once the studies were limited to otherwise homogeneous populations, a consensus emerged that short people are longer-lived.
Among Sardinian soldiers who reach the age of 70, for example, those below approximately 5-foot-4 live two years longer than their taller brothers-in-arms. A study of more than 2,600 elite Finnish athletes showed that cross-country skiers were 6 inches shorter and lived nearly seven years longer than basketball players. Average height in European countries closely correlates to the rate of death from heart disease. Swedes and Norwegians, who average about 5-foot-10, have more than twice as many cardiac deaths per 100,000 as the Spaniards and Portuguese, who have an average height just north of 5-foot-5. Tall people rarely live exceptionally long lives. Japanese people who reach 100 are 4 inches shorter, on average, than those who are 75. The countries in the taller half of Europe have 48 centenarians per million, compared to 77 per million in the shorter half of the continent.
Setting aside simple mortality, individual diseases are also more common among tall people. American women above 5-foot-6 suffer recurrent blood clots at a higher rate. Among civil servants in London, taller people have been shown to suffer from more respiratory and cardiovascular illness. And then there's cancer. Height is associated with greater risk for most kinds of cancer, except for smoking-induced malignancies.
Unlike intelligence, which has a merely coincidental relationship with height, there are plausible biological explanations for why short people live longer. Researchers have found that the lungs of taller people don't function as efficiently, relative to their bodies' demands, as those of short people. Explanations for the link between height and other disorders are slightly more speculative, but largely credible. Tall people have more cells, which may increase the chances that some of them will mutate and lead to cancer. The hormones involved in rapid growth may also play a role in cancer development. It's even possible that the foods that lead to fast growth during childhood may increase the likelihood that a person will eventually develop cancer. The link between height and clots probably has to do with the length and weight of the columns of blood that travel between the heart and the body's extremities.
STEPS TOWARDS A TISSUE ENGINEERED THYMUS
Friday, August 2, 2013
The thymus helps to generate the cell populations of your immune system when young, but it atrophies - a process called involution - quite early in adult life. Many of the frailties of aging have their roots in the age-related decline of the immune system. It fails with age in large part because it is a size-limited population of cells, and ever more of those cells become inappropriately configured and unable to respond to new threats. One of the proposed methods for dealing with this issue is to restore the thymus, and therefore create a stream of new immune cells to take up the slack. Transplanting a thymus from a young mouse into an old mouse improves the immune system and extends life, for example.
For human medicine, the focus is on finding ways to tissue engineer a new thymus from the patient's own cells, or spur regrowth of the existing involuted thymus. Here is an example of progress in the research and development needed for thymic tissue engineering - if you want to build a thymus, you first have to be able to reliably generate large numbers of the right sort of cells. Work on that goal is still in progress:
Thymus transplantation has great clinical potential for treating immunological disorders, but the shortage of transplant donors limits the progress of this therapy. Human embryonic stem cells (hESCs) are promising cell sources for generating thymic epithelial cells. Here, we report a stepwise protocol to direct the differentiation of hESCs into thymic epithelial progenitor-like cells (TEPLCs) by mimicking thymus organogenesis with sequential regulation of Activin, retinoic acid, BMP, and WNT signals.
The hESC-derived TEPLCs expressed the key thymic marker gene FOXN1 and could further develop in vivo into thymic epithelium expressing the functional thymic markers MHC II and AIRE upon transplantation. Moreover, the TEPLC-derived thymic epithelium could support mouse thymopoiesis in T-cell-deficient mice and promote human T cell generation in NOD/SCID mice engrafted with human hematopoietic stem cells (hHSCs). These findings could facilitate hESC-based replacement therapy and provide a valuable in vitro platform for studying human thymus organogenesis and regeneration.
CONSIDERING STATE OPPOSITION TO LIFE EXTENSION TECHNOLOGIES
Friday, August 2, 2013
It is human nature to be capable of committing acts of great evil or economic self-destruction for years on end, and especially in groups. We are not at all far removed at the moment from large-scale genocides, collapsed kleptocracies, meaningless prohibitions, and more. So it's probably unsafe to assume that no state will outright ban the extension of healthy life via medicine in the future: there are more than enough examples of human collectives acting against the long-term self-interest of all their members for decades, and that becomes ever more likely if those at the top invent the means to profit personally from a widespread destruction of life and wealth.
For all that, I do think it's an unlikely outcome. The more plausible outcome is the one that is taking place right now: great economic harm to the pace and breadth of medical development through heavy, centralized regulation. Enormous, entirely unnecessary costs and very high barriers to entry are imposed on clinical applications of medicine, which ensures that a great deal of possible, plausible research and development never happens. Worse, in a system in which all that is not expressly permitted is forbidden - which is exactly the case for the FDA and similar regulatory bodies elsewhere in the world - radically different new technologies such as the means to treat aging are restricted by default, without any politician or bureaucrat having to raise a finger. The entire system of regulation must be changed to even allow them to be considered: which means more cost, more delay, and more work suppressed because it isn't cost-effective to undertake.
Here the possibility of future restrictions on rejuvenation therapies is considered by someone who is more supportive of the existence of a large state than I am. They see the solution as working within the system, being a petitioner to power to beg for the chance to be free enough to make the world a better place. I'm not sure that this has ever had a good record of success over the long term, certainly not when compared to revolution or the establishment of new colonies far enough distant from the state to be largely free from its bureaucracy:
Most laypeople with an opinion [on] biogerontology assume "[life extension] treatments will be centuries in the future", actual specialists with a medical background tend to be more 'optimistic' and postulate some for of accessibility of these treatments somewhere later this century. I'll abbreviate "Life Extension" as LE and Rejuvenation as RE.
The human that has singlehandedly saved most lives world wide may very well have been Maurice Hilleman. In the late 19th to mid 20th century there was a small number of cynics who insisted that vaccinations (and other treatments intended to make people live longer lives) would contribute to Malthusian overpopulation. It is interesting to realize that many of these objections were based on class-prejudice and racism. People who objected to child vaccinations tended to not like poor people very much, and didn''t want 'their' world overrun by the kind of people they took offense to. These sentiments are by no means dead. A very common objection to the mere realization of RE/LE treatments is that "the world would quickly overpopulate". When quizzed strikingly many people today insist that RE/LE might "have to be declared illegal to avoid an overpopulation disaster". These people seem to be unable to infer comparisons from earlier Life Extension treatments (clean drinking water, sanitation, healthy diets, environmental protection laws, vaccinations) from which they benefited, and regard Biogerontological Life Extension as something different altogether.
The process of development of actual "biological immortality" is likely to be a long trajectory of dead ends and catastrophes. The beta stage of life extension may come with painful episodes and failures. Early adopters may end up forking out large sums of private capital for treatments that may or may not work. If earliest stage regenerative treatments were to emerge in the 2020s it may be decades before these treatments would end up safe, affordable, comfortable and easy to use. What is worse - such treatments don't have a convenient fit in the current medical corporate sector. What does a LE or RE treatment actually do? Does it make people less dependent on other medical treatments? If that is the case many established medical conglomerates may very well vehemently object against these treatments, and declare them "snake oil" or "pseudoscience". It is thus quite likely that on the earliest years of emerging LE/RE many consumers may reject these treatments basing their choices on vicious and deceptive media campaigns.