FIGHT AGING! NEWSLETTER
March 31st 2014
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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- The Years in Which Gene Therapy Finally Escapes the Labs and Trials
- Some of the Details Involved in Creating Heart Tissue That Beats
- A Little Recent Research on Exercise and Calorie Restriction
- To Accept Aging and Death is to Choose Aging and Death
- Pointing out Ašţal Journal
- Latest Headlines from Fight Aging!
- Work on Allotopic Expression of Mitochondrial Genes is Spreading
- Digging into the Details of Why a Young Environment Restores the Activity of Old Cells
- Life Extension in Mice via FAT10 Knockout
- Considering Histone H1 in Age-Related Neurodegeneration
- A Different Take on the Evolution of Longevity Through Calorie Restriction
- A Reality Check on Dietary Supplements
- Microglial Dysfunction as a Contributing Cause of Macular Degeneration
- AGEs Accumulate With Age in Tooth Dentin
- A Popular Press Article on Cryonics UK
- Engineered Organs Don't Have to Look Like Existing Organs
THE YEARS IN WHICH GENE THERAPY FINALLY ESCAPES THE LABS AND TRIALS
The costs of biotechnologies relating to gene therapy and genetic analysis have fallen steeply in the last ten years, even as the capabilities of a well-equipped laboratory have increased by leaps and bounds over the same period of time. A graduate student today has more power at his or her fingertips than an entire laboratory staff of the early 90s. This has matched the economics of computing hardware, as much of biotechnology is essentially a matter of building direct interfaces between that computing hardware and the nanoscale life science world of proteins and cells. This said, until just the past year or two the available options for gene therapy and most genetic analysis remained still remained too challenging and expensive for growth into the market. They have long been practical for the work of a laboratory or research institution, but not for most potential uses in the mass market, where a single provider would be expected to churn through thousands or tens of thousands of samples in a week, with high reliability and at a minimal expense per item.
The present leap in capacity and fall in cost promises to change all of that, however, given time to work its way through the pipeline. The latest methods and technologies are so far proving to be cheap enough and reliable enough to form the basis for the mass commercialization of genetic analysis and alteration in the years ahead. This will certainly have a great impact on many areas of medicine, though we'll probably all be surprised by many of the specific outcomes. The best thing that can happen for progress in the long term is for the cost of research to fall greatly, as is presently happening. The lower the cost of entry to a field, the more experimentation and development that will take place - and this is why it is helpful to keep an eye on progress in fundamental technologies, not just on specific applications of interest, such as in the area of aging and longevity.
New DNA-editing technology spawns bold UC initiative
The technology, precision "DNA scissors" referred to as CRISPR/Cas9, has exploded in popularity since it was first published in June 2012 and is at the heart of at least three start-ups and several heavily-attended international meetings. Scientists have referred to it as the "holy grail" of genetic engineering. "The CRISPR/Cas9 technology is a complete game changer. With CRISPR, we can now turn genes off or on at will."
The new genomic engineering technology significantly cuts down the time it takes researchers to test new therapies. CRISPR/Cas 9 allows the creation in weeks rather than years of animal strains that mimic a human disease, allowing researchers to test new therapies. The technique also makes it quick and easy to knock out genes in human cells or in animals to determine their function, which will speed the identification of new drug targets for diseases.
Using the Cas9 technique, UC Berkeley immunologist Russell Vance disabled a gene in mice that regulates fur color and in just six weeks had a strain of mice with white coats instead of brown. Similar research in animal models ranging from rodents to primates is being done in labs around the world using the CRISPR/Cas9 technology. Other researchers have already adapted the technology to reprogram stem cells to regenerate damaged organs, such as the liver, and made attempts to reprogram immune cells to cure AIDS in HIV-positive patients.
Innovative technique provides inexpensive, rapid and detailed analysis of proteins
Mass Spectrometric Immunoassay (MSIA) [is] a high-throughput protein quantification technique that also provides detailed protein information. In a new study [researchers] demonstrate the power of the MSIA platform, with a vision towards clinical adoption. The research reports a high-throughput method for quantifying and characterizing insulin-like growth factor 1 (or IGF1) at a rate of more than 1,000 human samples a day.
Mass spectroscopy can readily identify genetic variants that are expressed on the protein level (for example single-nucleotide polymorphisms). Such changes may alter or disable the function of the resulting protein. Further, mass spectroscopy can pinpoint changes that may occur to the protein after it has already been produced from the gene template - so-called post-translational modifications.
SOME OF THE DETAILS INVOLVED IN CREATING HEART TISSUE THAT BEATS
In recent years a number of research groups have made progress towards building heart tissue that is capable of beating. This is obviously quite necessary if the end goal is a completely functional heart, produced from a patient's stem cells alone, but even if considering the production of small tissue patches for an injured heart researchers must be able to produce muscle fibers that behave in the right way, otherwise it is just as likely that a treatment would prove to be harmful rather than helpful.
Decellularization is still well ahead of other approaches in terms of the ability to produce large amounts of tissue for transplant or testing, as well as in the production of tissue that accurately reproduces the complex structure of an organ. Creating the blood vessel network needed to support larger tissue sections is perhaps the greatest present challenge facing tissue engineers, though once past that a whole range of other issues related to organ structure will be next in line. The structural challenges are precisely why decellularization is out in front in terms of technical outcomes: a donor organ scaffold with all its cells stripped neatly provides the guiding structure and chemical cues needed to reconstruct the blood vessels and other details required for full function. At some point it will be necessary to break free from the need for donor organs, however. Decellularization is only a stepping stone between today and a world in which organs can be printed to order from a simple skin sample.
Here is news of recent work on the details of heart tissue engineering, with a focus on improving the electrical aspect associated with the beating of a living heart. The fine details of muscle structure are absolutely vital here, and hard to get right. There is a still a great deal of experimentation between here and a functional heart grown from cells or bioprinted, and there is a need for flexible, reliable technology platforms to enable that experimentation:
Building heart tissue that beats
When a heart gets damaged, such as during a major heart attack, there's no easy fix. But scientists working on a way to repair the vital organ have now engineered tissue that closely mimics natural heart muscle that beats, not only in a lab dish but also when implanted into animals. To tackle the challenge of engineering heart muscle, Khademhosseini and Annabi have been working with natural proteins that form gelatin-like materials called hydrogels. "The reason we like these materials is because in many ways they mimic aspects of our own body's matrix," Khademhosseini said. They're soft and contain a lot of water, like many human tissues.
His group has found that they can tune these hydrogels to have the chemical, biological, mechanical and electrical properties they want for the regeneration of various tissues in the body. But there was one way in which the materials didn't resemble human tissue. Like gelatin, early versions of the hydrogels would fall apart, whereas human hearts are elastic. The elasticity of the heart tissue plays a key role for the proper function of heart muscles such as contractile activity during beating. So, the researchers developed a new family of gels using a stretchy human protein aptly called tropoelastin. That did the trick, giving the materials much needed resilience and strength.
But building tissue is not just about developing the right materials. Making the right hydrogels is only the first step. They serve as the tissue scaffold. On it, the researchers grow actual heart cells. To make sure the cells form the right structure, Khademhosseini's lab uses 3-D printing and microengineering techniques to create patterns in the gels. These patterns coax the cells to grow the way the researchers want them to. The result: small patches of heart muscle cells neatly lined up that beat in synchrony within the grooves formed on these elastic substrates. These micropatterned elastic hydrogels can one day be used as cardiac patches. Khademhosseini's group is now moving into tests with large animals. They are also using these elastic natural hydrogels for the regeneration of other tissues such as blood vessels, skeletal muscle, heart valves and vascularized skin.
Hybrid hydrogels containing vertically aligned carbon nanotubes with anisotropic electrical conductivity for muscle myofiber fabrication
Biological scaffolds with tunable electrical and mechanical properties are of great interest in many different fields, such as regenerative medicine, biorobotics, and biosensing. In this study, dielectrophoresis (DEP) was used to vertically align carbon nanotubes (CNTs) within methacrylated gelatin (GelMA) hydrogels in a robust, simple, and rapid manner.
Skeletal muscle cells grown on vertically aligned CNTs in GelMA hydrogels yielded a higher number of functional myofibers than cells that were cultured on hydrogels with randomly distributed CNTs and horizontally aligned CNTs, as confirmed by the expression of myogenic genes and proteins. In addition, the myogenic gene and protein expression increased more profoundly after applying electrical stimulation along the direction of the aligned CNTs. We believe that platform could attract great attention in other biomedical applications, such as biosensing, bioelectronics, and creating functional biomedical devices.
A LITTLE RECENT RESEARCH ON EXERCISE AND CALORIE RESTRICTION
The amassed scientific evidence of decades tells us that regular moderate exercise and the practice of calorie restriction with optimal nutrition are both very beneficial for long term health. There is no other presently available option that will result in a better expected outcome for the average basically healthy individual. That in turn suggests that we should be putting much more effort and attention into research that will generate better ways to extend the healthy span of life available to us. Exercise and calorie restriction are free, but speeding up longevity research requires organization, effort, and above all funding.
At present a great deal more research relating to exercise and calorie restriction takes place than that relating to means of extending life to a far greater degree. Rejuvenation biotechnology is the outcast poor cousin of the research community, for all that it is the best path forward towards radical life extension. That will have to change, but in the meanwhile here are a few recent examples of mainstream research, offered without comment, but similar to studies that come and go in volume month by month:
Exercise Training Improves Health Outcomes of Women with Heart Disease More Than of Men
The clinical trial randomized 2,331 patients with heart failure and a left ventricular ejection fraction of less than or equal to 35 percent to either a formal exercise program plus optimal medical therapy, or to optimal medical therapy alone. Prior to randomization, patients underwent symptom-limited cardiopulmonary exercise tests to assess exercise capacity, as measured by peak oxygen uptake (VO2). Patients randomized to the exercise treatment arm participated in supervised walking, or stationary cycling for 30 minutes three days a week for six weeks. After completing 18 sessions, patients added 40 minutes of home-based exercise two days per week. After completing 36 supervised sessions, patients were fully transitioned to a five day per week, 40 minutes a day home-based exercise program.
The primary outcome of this analysis was a composite of all-cause mortality or hospitalization, stratified by gender. Women randomized to exercise training saw a 26 percent reduction in risk of all-cause mortality or hospitalization compared with a 10 percent reduction in risk of these outcomes for men randomized to exercise.
The Benefits of Staying Active in Old Age: Physical Activity Counteracts the Negative Influence of PICALM, BIN1, and CLU Risk Alleles on Episodic Memory Functioning
PICALM, BIN1, CLU, and APOE are top candidate genes for Alzheimer's disease, and they influence episodic memory performance in old age. Physical activity, however, has been shown to protect against age-related decline and counteract genetic influences on cognition. The aims of this study were to assess whether (a) a genetic risk constellation of PICALM, BIN1, and CLU polymorphisms influences cognitive performance in old age; and (b) if physical activity moderates this effect.
Data from the SNAC-K population-based study were used, including 2,480 individuals (age range = 60 to 100 years) free of dementia at baseline and at 3- to 6-year follow-ups. Tasks assessing episodic memory, perceptual speed, knowledge, and verbal fluency were administered. Physical activity was measured using self-reports. Individuals who had engaged in frequent health- or fitness-enhancing activities within the past year were compared with those who were inactive. High genetic risk was associated with reduced episodic memory performance, controlling for age, education, vascular risk factors, chronic diseases, activities of daily living, and APOE gene status. Critically, physical activity attenuated the effects of genetic risk on episodic memory. Our findings suggest that participants with high genetic risk who maintain a physically active lifestyle show selective benefits in episodic memory performance.
A novel kinase regulates dietary restriction-mediated longevity in Caenorhabditis elegans
Although dietary restriction (DR) is known to extend lifespan across species, from yeast to mammals, the signalling events downstream of food/nutrient perception are not well understood. In Caenorhabditis elegans, DR is typically attained either by using the eat-2 mutants that have reduced pharyngeal pumping leading to lower food intake or by feeding diluted bacterial food to the worms. In this study, we show that knocking down a mammalian MEKK3-like kinase gene, mekk-3 in C. elegans, initiates a process similar to DR without compromising food intake.
This DR-like state results in upregulation of beta-oxidation genes through the nuclear hormone receptor NHR-49, a HNF-4 homolog, resulting in depletion of stored fat. This metabolic shift leads to low levels of reactive oxygen species (ROS), potent oxidizing agents that damage macromolecules. Increased beta-oxidation, in turn, induces the phase I and II xenobiotic detoxification genes, through PHA-4/FOXA, NHR-8 and aryl hydrocarbon receptor AHR-1, possibly to purge lipophilic endotoxins generated during fatty acid catabolism.
The coupling of a metabolic shift with endotoxin detoxification results in extreme longevity following mekk-3 knock-down. Thus, MEKK-3 may function as an important nutrient sensor and signalling component within the organism that controls metabolism. Knocking down mekk-3 may signal an imminent nutrient crisis that results in initiation of a DR-like state, even when food is plentiful.
Maternal caloric restriction partially rescues the deleterious effects of advanced maternal age on offspring
While many studies have focused on the detrimental effects of advanced maternal age and harmful prenatal environments on progeny, little is known about the role of beneficial non-Mendelian maternal inheritance on aging. Here, we report the effects of maternal age and maternal caloric restriction (CR) on the life span and health span of offspring for a clonal culture of the monogonont rotifer Brachionus manjavacas.
Mothers on regimens of chronic CR (CCR) or intermittent fasting (IF) had increased life span compared with mothers fed ad libitum (AL). With increasing maternal age, life span and fecundity of female offspring of AL-fed mothers decreased significantly and life span of male offspring was unchanged, whereas body size of both male and female offspring increased. Maternal CR partially rescued these effects, increasing the mean life span of AL-fed female offspring but not male offspring and increasing the fecundity of AL-fed female offspring compared with offspring of mothers of the same age. Both maternal CR regimens decreased male offspring body size, but only maternal IF decreased body size of female offspring, whereas maternal CCR caused a slight increase.
TO ACCEPT AGING AND DEATH IS TO CHOOSE AGING AND DEATH
It is in the nature of things for people to become more accepting of the imperfect state of the world and the flawed human condition with advancing age, to lose that youthful indignation and urge to change all that causes suffering and injustice. We can blame a range of things for this, but I suspect that it has a lot to do with the growth in wealth and connections that occurs over the years for most individuals. Whatever your starting level, on average the 50-year-old you will be in a better place than the 20-year-old you. The gains you have amassed merge with nostalgia in a slow erosion of the desire to tear down walls and shake up your neighbors: things are better for you, and isn't that a good thing? Not everyone is this way, of course, but it is a dynamic to be aware of in your relationship with the world. It is human nature to measure today against yesterday, and feel good about gains that are relatively large but absolutely small.
Acceptance of death and aging is the mindset I am thinking in particular here. The unpleasant ends of life are dim and distant myths when you are young and vigorous in your search for world-changing causes. It is the rare young individual who is willing to devote his or her life in preparation for a time half a century down the road. The older folk who feel the pressures of time and encroaching frailty are those who have become more accepting, however. To fight aging and work on rejuvenation treatments is an intrinsically hard sell in comparison to many other ventures. The youth think they have time to focus on other matters first, and the old have come to terms.
Nonetheless, with rapid progress in biotechnology year after year the number of people needed to get the job done is falling rapidly. Ten million supporters willing to put in a little time or money (rather than just a wave and a good word) and the careers of a few thousand scientists and biotechnicians is probably more than is needed at this point, a level of support that lies in a similar ballpark to that of the cancer or stem cell research communities. We are not there yet, though support for scientific, medical approaches to the treatment and prevention of aging has grown in a very encouraging fashion over the past decade. At any time in the next year or so you might see mainstream press articles in noted publications favorably mention the SENS Research Foundation, regenerative medicine, Google's Calico initiative, and progress in genetic science all in the same few paragraphs.
We are here, where we are, precisely because numerous people retained a youthful fire and verve, and indignation and horror of aging and death. Despite the ever-present opposition from a mainstream that once mocked aging research, these iconoclasts put in the work that has raised funds, created organizations, and changed minds: all seeds for tomorrow's grand rejuvenation research community. This is a work in progress. But let us take a moment to admire some of the fire from those driving things along at the grassroots level:
Those Critical of Indefinite Life Extension Fear Life
Accepting death is in fact choosing it. In the face of recent discoveries and progress in science, medicine, technology - it is a matter of choice. Pretending to be fearless in the face of death isn't some form of heroism. It isn't reasonable or courageous. It is quite the opposite. It is taking the easy way out. Let's repeat it - death really is the easy way out. You fall asleep; you get a bullet; cancer kills you; some choose suicide; some accept aging and its effects as an inexorable given. The hard truth here that we should be prepared to acknowledge is: accepting death is the true cowardice, no matter the circumstances. Fighting it and choosing life is the true courage.
Critics of indefinite life extension, don't put on a snide, condescending face and tell me that you aren't afraid of death, because you are, too.
By your own knee-jerk flippancy, reactionary admission, you are also afraid of life. You're afraid of death, and you're afraid of life. You say, right to us, all the time, that you don't want to bear to deal with the drastic changes, you don't want to live without all your friends and family around, you don't want to live with war still being a reality anywhere. You can't stand all the jerks and the dangerous people, and rich people, or tyrants, controlling you for one decade longer than a traditional lifespan. The thought of it makes you want to jump into your grave right now to get away from this big, bad, scary life.
You, my friend, are afraid of life. Living scares you. You think of life and you cower. You see the challenges of life and you're too scared to face them. You wouldn't dare form and join teams and initiatives to meet those challenges on the intellectual combat fields of dialectics and action. You don't have what it takes. Life isn't for you. It's not your thing. So love your death, fear your life. Do that if that's what you want.
I am afraid of death. It scares me to think of losing my life. I value my life. I have no shame in that. That is the reasonable thing to do. What I have shame for is that anybody would think that being afraid of death might possibly be something to mock.
You mock us for being afraid of death. We are afraid of death; it's a logical and positive thing to be afraid in the face of it. It reminds a person to take action against danger. It's your being afraid of life that is to be mocked. So stand up and tell us how afraid you are of living. We promise not to look upon you with too much shame, and we promise to lend you a hand if you need help crossing over to the land of reason.
POINTING OUT AšţAL JOURNAL
Today I'll point out the Ašţal Journal as something that might be of interest. The name is apparently taken from the constructed language of Ithkuil, and represents the sudden realization of possibilities when someone conveys to you an idea you've never considered before:
This is a journal of ideas that eagerly hopes to act as a place of open discussion about the intersection between longevity, overpopulation, and space exploration, as well as a general discourse on a broad range of other subjects. Through it, we wish to inform anyone interested about new and exciting developments in these fields, as well as ways in which they can contribute to the leading-edge research being carried out around the world.
The general position in the longer articles seems to be that overpopulation is a real concern, but one that can be controlled and evaded with foresight. That isn't a position I agree with at all, on the grounds that I don't see that overpopulation or the threat of it actually exists, and no more foresight is needed to maintain that state of affairs that is ordinarily deployed by every participant in the broad market of human society - just the sort of everyday economic foresight that led to the broad and successful efforts to radically improve agricultural techniques in the 1960s and 1970s in response to perceived opportunities in the market brought about by advancing technology.
There is no shortage of suffering in the world, but realize that everywhere that plague, famine, and utter poverty still exists it is maintained and enforced by avaricious, ruinous governance. Every populous region presently poor and dangerous could have had a trajectory just like that of South Korea over the past 60 years or so, from a largely agrarian to a largely information economy. That this did not happen universally is not a matter of how many people live in a region, or its level of natural resources: look instead to war, looting by political leaders, and other deliberate barriers to the growth of market economies. The inhumanity of man is the root cause of what most people casually label as overpopulation. Sufficient resources exist to support many more people than are currently alive, and those resources are constantly growing and changing with advances in technology.
A couple of items from the Ašţal Journal that are worth a glance are quoted below:
A Q&A with Aubrey de Grey
Ašţal: What are the main obstacles to reaching faster decisive breakthroughs in rejuvenation research?
Aubrey de Grey: Money, money and money. Originally there were two other obstacles: there was no plan, and there were far too few top scientists interested in the problem. One of the things I'm proudest of is that I've been able both to come up with a concrete, plausible plan (SENS itself) and also to bring a large number of world-leading scientists on board to implement it - just so long as the resources necessary to do so are available.
Ašţal: How much of an impact do you reckon private initiatives like the Calico project will have on the future landscape of longevity research?
Aubrey de Grey: Calico has the potential to be a complete game-changer, simply because their budget is so large. It's a hugely encouraging start that they've hired awesome people outside the field, such as Art Levinson and David Botstein, to head it up: that makes me pretty sure that they won't make the mistake that the Ellison Medical Foundation did of just following the failed strategies of the past. It may not work out, of course, but all the omens are really encouraging.
Ašţal: What kind of public policies would best support the goal of longevity?
Aubrey de Grey: The single most important change in public policy that is needed is to restructure medical research funding in a manner that takes account of the inextricable linkage between aging and the diseases of old age. At present, huge sums are wasted on the futile attempt to treat the diseases of old age as if they could be eliminated from the body, like infections. Once it is properly recognised that the diseases of old age are simply aspects of the later stages of a lifelong process of damage accumulation, it will also be recognised that the best way to combat those diseases is by preventative maintenance at the molecular and cellular level. Then we will see an appropriate prioritisation of research themes and a great acceleration of progress.
The Necessity of Longevity
In essence, the prejudice toward understanding senescence and death as intrinsic properties of life, together with a misconstrued notion of the goals of longevity research, are biases which have yet to be eradicated from the collective mentality. We have told each other stories for so long, that those stories have become reality and our intuitions myths. Our common sense has been demoted to second-rank reasoning, and in the process we have become the victims of our own bemusement. Of course, as long as a viable option is not brought forward we are likely to continue opposing obvious scientific progress in light of a mitigating ideal.
Notwithstanding these initial fears, the outlines of a solution are unequivocally beginning to take shape, but as long as we continue to adopt the question of longevity as a moral issue, and not a scientific one, we will not gain purchase on the far shore. There is no way to predict whether these technologies will be useful in the long-run until we try them out, but we must stop thinking about longevity and rejuvenation through the lens of individual prejudices and work towards integrating it as a viable long-term goal for the advancement of the species. I am willing to argue here that the pursuit of viable rejuvenation is the most desirable course of action in terms of the active prevention of senescence, disease, and eventually, death.
Overpopulation and Its Discontents
Overpopulation abides as the poor relation of the great world problems, eternally relegated behind the saraband of food shortages, endemic wars, diseases and epidemics, and now climate change, although all of these issues ostensibly spring from the same root cause: the very object of this essay.
Overpopulation puts humanity at existential risk, most notably at the meso-level where it threatens the life of large groups of people, both of its individual members (as a direct life threat) and of the form of life they embody (as a cultural threat). On the one hand, there is a strong case for overpopulation as a major political and philosophical issue as it will shape the problems à-venir. On the other hand, most of our current understanding remains flawed, regrettably confining it to a demographic and economic problem.
LATEST HEADLINES FROM FIGHT AGING!
WORK ON ALLOTOPIC EXPRESSION OF MITOCHONDRIAL GENES IS SPREADING
Monday, March 24, 2014
Gene expression is the process of generating proteins from the blueprints encoded in DNA. Most DNA is in the cell nucleus, but thirteen genes can be found in the mitochondria, the powerplants of the cell that were once, long ago, symbiotic bacteria. Alloptic expression is a form of genetic engineering wherein one or more of those mitochondrial genes is copied into nuclear DNA, and the resulting proteins transported back to the mitochondria where they are needed. It is that transportation that is the hard part, not yet accomplished for more than a couple of mitochondrial genes.
Why should we care about allotopic expression as anything more than a technical curiosity? Because mitochondrial DNA damage is one of the root causes of aging. Mutations that disable some mitochondrial genes, thus depriving mitochondria of necessary protein machinery, lead to a chain of unfortunate events that progressively produces ever more dysfunctional cells and damage to tissues and organs over the years. If researchers could create a backup source of the necessary proteins in the cell nucleus, then this contribution to aging could be completely removed - and even reversed in its later stages.
The SENS Research Foundation is more or less the only group coordinating work on allotopic expression for the treatment of aging, but a number of unaffiliated labs are using the approach in a more limited way in an attempt to address the genetic disease of Leber hereditary optic neuropathy (LHON). LHON is caused by a defective mitochondrial gene, so many of the efforts taken to cure it are also somewhat applicable to the issue of mitochondrial mutations in aging. Here researchers demonstrate effectiveness and safety of allotopic expression in this case:
We developed a novel strategy for treatment of Leber hereditary optic neuropathy (LHON) caused by a mutation in the nicotinamide adenine dinucleotide dehydrogenase subunit IV (ND4) mitochondrial gene. In a series of laboratory experiments, we modified the mitochondrial ND4 subunit of complex I in the nuclear genetic code for import into mitochondria. The protein was targeted into the organelle by agency of a targeting sequence (allotopic expression). The gene was packaged into adeno-associated viral vectors and then vitreally injected into rodent, nonhuman primate, and ex vivo human eyes that underwent testing for expression and integration.
We tested for rescue of visual loss in rodent eyes also injected with a mutant G11778A ND4 homologue responsible for most cases of LHON. We found human ND4 expressed in almost all mouse retinal ganglion cells by 1 week after injection and ND4 integrated into the mouse complex I. In rodent eyes also injected with a mutant allotopic ND4, wild-type allotopic ND4 prevented defective adenosine triphosphate synthesis, suppressed visual loss, reduced apoptosis of retinal ganglion cells, and prevented demise of axons in the optic nerve. Injection of ND4 in the ex vivo human eye resulted in expression in most retinal ganglion cells. Primates undergoing vitreal injection with the ND4 test article and followed up for 3 months had no serious adverse reactions.
DIGGING INTO THE DETAILS OF WHY A YOUNG ENVIRONMENT RESTORES THE ACTIVITY OF OLD CELLS
Monday, March 24, 2014
Heterochronic parabiosis is the unwieldy name given to the process of linking the circulatory systems of an old and a young individual. Over the past decade, researchers have used this technique in mice to demonstrate that the declining activity of many types of old stem cells is driven more by changing protein levels in the environment than by any damage inherent to the cells themselves. Restore a youthful environment to some degree, and stem cells pick up their activities.
The decline in stem cell activity with aging, the loss of tissue maintenance and resulting frailty and dysfunction, is thought to be an evolutionary adaptation to reduce cancer risk, with the later stages of life painted as a balancing act between risk of cancer due to the activities of damaged cells on the one hand versus the need to maintain tissue function on the other. As the medical community becomes ever better at controlling cancer, there may be no real objection to removing the environmental triggers that are turning down stem cell activity. That of course requires the identification of these triggers, which is presently an ongoing topic of research.
I see this as a stop-gap approach, however. It might prove fairly beneficial, but it doesn't address the underlying reasons as to why the environment within the body has changed. That change is presumably a response to higher levels of damage to cells and macromolecules. Thus the development of rejuvenation treatments that repair that damage will lead to a restoration of the environment to youthful patterns of protein levels and cellular responses to those protein levels.
Although commonly considered a disease of white matter, gray matter demyelination is increasingly recognized as an important component of multiple sclerosis (MS) pathogenesis, particularly in the secondary progressive disease phase. Extent of damage to gray matter is strongly correlated to decline in memory and cognitive dysfunction in MS patients. Aging likewise occurs with cognitive decline from myelin loss, and age-associated failure to remyelinate significantly contributes to MS progression.
However, recent evidence demonstrates that parabiotic exposure of aged animals to a youthful systemic milieu can promote oligodendrocyte precursor cell (OPC) differentiation and improve remyelination. In the current study, we focus on this potential for stimulating remyelination, and show it involves serum exosomes that increase OPCs and their differentiation into mature myelin-producing cells - both under control conditions and after acute demyelination.
Environmental enrichment (EE) of aging animals produced exosomes that mimicked this promyelinating effect. Additionally, stimulating OPC differentiation via exosomes derived from environmentally enriched animals is unlikely to deplete progenitors, as EE itself promotes proliferation of neural stem cells. We found that both young and EE serum-derived exosomes were enriched in miR-219, which is necessary and sufficient for production of myelinating oligodendrocytes by reducing the expression of inhibitory regulators of differentiation. Accordingly, protein transcript levels of these miR-219 target mRNAs decreased following exosome application to slice cultures. Finally, nasal administration of exosomes to aging rats also enhanced myelination. Thus, peripheral circulating cells in young or environmentally enriched animals produce exosomes that may be a useful therapy for remyelination.
LIFE EXTENSION IN MICE VIA FAT10 KNOCKOUT
Tuesday, March 25, 2014
Visceral fat is harmful to long term health, such as through its promotion of chronic inflammation, among other mechanisms. It is known that surgical removal of visceral fat in mice can extend life, for example. So it is plausible that the mechanism of action for the genetic alteration noted in the paper quoted below is in fact lower levels of fat, but as for all such things it will require much more work to determine whether or not this is the case. So many aspects of metabolism are changed, they all impact one another, and picking apart individual mechanisms is a challenging process. There are many ways to extend life in mice through metabolic alteration, and it is fair to say that none are yet fully understood.
The HLA-F adjacent transcript 10 (FAT10) is a member of the ubiquitin-like gene family that alters protein function/stability through covalent ligation. Although FAT10 is induced by inflammatory mediators and implicated in immunity, the physiological functions of FAT10 are poorly defined.
We report the discovery that FAT10 regulates lifespan through pleiotropic actions on metabolism and inflammation. Median and overall lifespan are increased 20% in FAT10ko mice, coincident with elevated metabolic rate, preferential use of fat as fuel, and dramatically reduced adiposity. This phenotype is associated with metabolic reprogramming of skeletal muscle (i.e., increased AMP kinase activity, β-oxidation and -uncoupling, and decreased triglyceride content). Moreover, knockout mice have reduced circulating glucose and insulin levels and enhanced insulin sensitivity in metabolic tissues, consistent with elevated IL-10 in skeletal muscle and serum. These observations suggest novel roles of FAT10 in immune metabolic regulation that impact aging and chronic disease.
If the role of FAT10 in humans is similar to mice, then targeting of FAT10 may hold promising therapeutic impact for the treatment of various diseases including obesity and obesity-related diseases and aging associated diseases.
CONSIDERING HISTONE H1 IN AGE-RELATED NEURODEGENERATION
Tuesday, March 25, 2014
Like all tissues, the brain and nervous system become damaged and dysfunctional with age. While the underlying root causes, the differences between old tissue and young tissue, are well cataloged, how this process unfolds to create specific age-related diseases is still a matter for debate and investigation. If you care about rejuvenation and repair, you don't need to know much more than we do today in order to work on treatments to reverse the differences, but most researchers aim at greater understanding of the process, rather than actually doing something about it. Here researchers look at a small slice of the process of aging and damage in one type of tissue:
In neurodegenerative conditions and following brain trauma it is not understood why neurons die while astrocytes and microglia survive and adopt pro-inflammatory phenotypes. We show here that the damaged adult brain releases diffusible factors that can kill cortical neurons and we have identified histone H1 as a major extracellular candidate that causes neurotoxicity and activation of the innate immune system. Extracellular core histones H2A, H2B, H3 and H4 were not neurotoxic.
Innate immunity in the central nervous system is mediated through microglial cells and we show here for the first time that histone H1 promotes their survival, up-regulates MHC class II antigen expression and is a powerful microglial chemoattractant. We propose that when the central nervous system is degenerating, histone H1 drives a positive feedback loop that drives further degeneration and activation of immune defences which can themselves be damaging. We suggest that histone H1 acts as an antimicrobial peptide and kills neurons through mitochondrial damage and apoptosis.
A DIFFERENT TAKE ON THE EVOLUTION OF LONGEVITY THROUGH CALORIE RESTRICTION
Wednesday, March 26, 2014
Calorie restriction with optimal nutrition involves reducing the level of calories in the diet by up to 40% or so while still maintaining sufficient intake of micronutrients. This has been shown to slow aging and extend maximum life span in most species tested to date, with most mammal studies having used mice and rats. In primate studies while calorie restriction is definitely shown to significantly improve health and reduce incidence of age-related disease, the evidence isn't so good for meaningful extension of life span.
Why would calorie restriction reliably extend life span in short lived species but not in longer-lived species? The current thinking is that this response evolved because it allows individuals better odds of surviving seasonal famines, such that they can procreate later. When you are a mouse a seasonal famine is a large fraction of a life span, but this is not the case for humans, so it makes sense to see greater plasticity of life span in response to environmental circumstances in mice. There is selection pressure for this outcome in a short-lived species that isn't present for a long-lived species.
This researcher has a different take on the origin of the calorie restriction response, in which extension of life span is not the effect being selected for. Instead enhanced longevity is a side-effect of the actual selected trait, which is greater cellular recycling and repair that enables the ability to better reproduce when food is scarce. This still leaves the open question of why life extension is large in short-lived animals but not in humans, given that the short-term measures of the effects of calorie restriction on metabolism are remarkably similar between mice and humans.
Scientists have known for decades that severely restricted food intake reduces the incidence of diseases of old age, such as cancer, and increases lifespan. This effect has been demonstrated in laboratories around the world, in species ranging from yeast to flies to mice. There is also some evidence that it occurs in primates. The most widely accepted theory is that this effect evolved to improve survival during times of famine. "But we think that lifespan extension from dietary restriction is more likely to be a laboratory artefact."
Lifespan extension is unlikely to occur in the wild, because dietary restriction compromises the immune system's ability to fight off disease and reduces the muscle strength necessary to flee a predator. "Unlike in the benign conditions of the lab, most animals in the wild are killed young by parasites or predators. Since dietary restriction appears to extend lifespan in the lab by reducing old-age diseases, it is unlikely to have the same effect on wild animals, which generally don't live long enough to be affected by cancer and other late-life pathologies."
Dietary restriction, however, also leads to increased rates of cellular recycling and repair mechanisms in the body. [The] new theory is that this effect evolved to help animals continue to reproduce when food is scarce; they require less food to survive because stored nutrients in the cells can be recycled and reused. It is this effect that could account for the increased lifespan of laboratory animals on very low nutrient diets, because increased cellular recycling reduces deterioration and the risk of cancer.
A REALITY CHECK ON DIETARY SUPPLEMENTS
Wednesday, March 26, 2014
As a rule most people interested in health and longevity lavish far too much of their attention on dietary supplements, misled by the loudest voices in the room. No supplement or combination of supplements have been shown to reliably produce even a fraction of the benefits of exercise and calorie restriction, and none of these line items will give you a good chance of living past 90. Three quarters of the most health-obsessed people die before reaching that age, despite the fact that those who exercise and remain thin usually suffer a lower incidence of disease and medical expense in later life. The only shot at a much longer healthy life available to all of us is faster progress in medical technology, an area in which comparatively small donations now can have a large effect in the decades ahead by allowing today's small disruptive initiatives in human longevity to succeed and grow.
Back to supplements, here is a reality check from someone who does spend too much time thinking about supplements and longevity:
Stephen Spindler, biochemistry prof at UC Riverside, has been warning us for years that supplements, herbal extracts and neutraceuticals are, on the whole, ineffective for healthy adults, and that some may actually shorten life expectancy. Spindler's lab has done many life extension studies on mice, almost always with negative results. One of the themes in his papers is that caloric restriction is the only thing that works consistently, and that many of the treatments that seem to offer life extension are subtley inducing caloric restriction, (and this goes unreported by the investigators). But there are so many substances to test, and each lifespan test in mice is so expensive, that Spindler has suggested gene expression profiles as a shortcut to identifying candidates for further testing.
Another approach is to test many substances at once in a mouse life extension cocktail. Another rationale for this kind of testing is that we know that natural fruits and vegetables contribute to a long and healthy life, so perhaps it takes a complex combination of nutrients to be effective. Late last year, Spindler reported on his experiments, feeding commercial "life extension" mixes to hybrid mice. The results are a bracing cold shower for those of us who take a variety of carefully-chosen supplements each day - the mice that ate the supplements and the mice that ate ordinary mouse chow had exactly the same pattern of mortality.
MICROGLIAL DYSFUNCTION AS A CONTRIBUTING CAUSE OF MACULAR DEGENERATION
Thursday, March 27, 2014
Age-related macular degeneration involves damage to the retina and consequent encroaching blindness. One of the contributing causes is a buildup of metabolic waste products in long-lived retinal cells to form lipofuscin, something that the SENS Research Foundation focuses on in their lysoSENS program. Here researchers review the evidence for a different proximate cause, the malfunction of nervous system immune cells:
In the healthy retina, microglial cells represent a self-renewing population of innate immune cells, which constantly survey their microenvironment. Equipped with receptors, a microglial cell detects subtle cellular damage and rapidly responds with activation, migration, and increased phagocytic activity.
While the involvement of microglial cells has been well characterized in monogenic retinal disorders, it is still unclear how they contribute to the onset of retinal aging disorders including age-related macular degeneration (AMD). There is evidence, that microglial activation is not solely a secondary manifestation of retinal tissue damage in age-related disorders. Thus, work in the aging rodent and human retina suggests that long-lived and genetically predisposed microglia transform into a dystrophic state, with loss of neuroprotective functions. In this concept, malfunction of aging microglia can trigger a chronic low-grade inflammatory environment that favors the onset and progression of retinal degeneration.
AGES ACCUMULATE WITH AGE IN TOOTH DENTIN
Thursday, March 27, 2014
Resilient forms of advanced glycation endproduct accumulate in the body with age as a byproduct of the operation of metabolism, particularly glucosepane in tissues such as skin. Our biochemistry struggles to remove these compounds, and they cause progressively greater harm in soft tissues by damaging tissue structure so as to reduce elasticity and generating higher levels of inflammation. This is why efforts to develop the means to remove AGEs are important. The types and effects of AGEs in harder tissues are not so well understood, however:
Cross-linking of collagen by Advanced Glycation End-products (AGEs) occurs by non-enzymatic glycation (Maillard reaction). The purpose of this study was to examine whether AGEs are formed in human dentinal collagen, and to consider any possible influence of AGEs on dentinal physiology.
Mechanical characteristics, fluorescence spectra and immunohistochemical analyses of demineralized dentine sections from young subjects were compared with those of aged ones. The same investigations were performed with young dentine artificially glycated by incubation in ribose solution. Indentation measurement indicated that the sections from aged dentine were mechanically harder than those from young dentine. The hardness of young dentine increased after incubation in ribose solution. Fluorescence peak wavelength of the young dentine was shorter than that of the aged one, but shifted towards the peak wavelength of the aged one after incubation in ribose solution.
These changes were considered to be due to accumulation of AGEs. Existence of AGEs in dentinal collagen was confirmed by immunohistochemical analysis. The obtained results suggest that AGEs accumulation occurs in dentinal collagen and is affected by both human age and physiological conditions such as glucose level in blood because dentinal collagen receives nourishment via dental pulp and tubules.
A POPULAR PRESS ARTICLE ON CRYONICS UK
Friday, March 28, 2014
The small cryonics industry has developed the means of long-term low temperature preservation of tissue over the past few decades, presently using a form of vitrification that minimizes ice crystal formation. For people who will die before the advent of rejuvenation therapies, this is the only option other than the grave: a way to preserve the structure of the brain and mind until such time as more advanced medical technologies can reverse the process, remove the signs of aging, and provide a newly tissue engineered body. None of this is impossible, just challenging and a way off into the future.
Only a few cryonics providers exist, most of which are in the US. In countries without cryonics providers there are support organizations, however, to aid the process of managing cryopreservation at the end of life for the few people who choose this option:
It's a small red-brick house just like any other, lost in the suburbs of Sheffield, in central England. The only thing that sets it apart is the yellow-and-green ambulance parked on the gravel driveway - for inside that vehicle, two men and a woman are training in the craft of defeating death itself, on the presumed road to eternity. Every three months, some 15 members of the Cryonics UK association meet for a weekend around the refrigerated container that will one day be the home of their long hibernation. They have already spent thousands of pounds sterling so that, when the day comes, their bodies will be kept at very low temperature until scientific techniques will allow for them to be "brought back to life."
Like some 2,000 people around the world, the 35 British members of Cryonics UK have applied to join the quest for immortality. With a calm smile on her face, Victoria Stevens, 38, explains that she managed to convince her husband and her two children that death was not irreversible. "When we love life, there's no shame in wanting to make it last longer."
Former engineer Mike Carter shares her point of view, and has become one of the cornerstones of the association since his retirement. "I know that the chances of being resuscitated are very slim. But apart from a bit a money for my children, there's nothing to lose. But you can't win the lottery if you don't buy a ticket!"
Cryonics UK is not a service provider, but merely a cooperative of mutual aid. Its job is to take care voluntarily of transporting the frozen bodies to the United States. "Whenever one of our members is about to die, we hurry to his house with the ambulance to be there as soon as possible," explains Carter. In such cases, a handful of volunteers put the body "on standby," which will prevent it from deteriorating during the transport across the Atlantic.
ENGINEERED ORGANS DON'T HAVE TO LOOK LIKE EXISTING ORGANS
Friday, March 28, 2014
Tissue engineering offers the opportunity to augment the function of an organ without necessarily recreating the evolved natural structure of that organ. There may be numerous paths forward in which it is much easier to create a pseudo-organ or tissue sections that perform only some of the necessary functions of the real organ rather than engineer a full replica. This is more evidently the case for tissues intended to generate regulatory proteins or other biochemicals: it often isn't necessary that these tissues exist in the exact location evolution has placed them. So for example functions of the thyroid or pancreas could be augmented with tissues implanted into lymph nodes - and that is an easier prospect than recreating the whole organ in question.
Here researchers demonstrate that it is also feasible to consider distributing some of the mechanical duties of the heart. They aim to produce novel small organs that wrap blood vessels to aid blood flow:
[Researchers have] invented a new organ to help return blood flow from veins lacking functional valves. A rhythmically contracting cuff made of cardiac muscle cells surrounds the vein acting as a 'mini heart' to aid blood flow through venous segments. The cuff can be made of a patient's own adult stem cells, eliminating the chance of implant rejection. "We are suggesting, for the first time, to use stem cells to create, rather than just repair damaged organs. We can make a new heart outside of one's own heart, and by placing it in the lower extremities, significantly improve venous blood flow."
The novel approach of creating 'mini hearts' may help to solve a chronic widespread disease. Chronic venous insufficiency is one of the most pervasive diseases, particularly in developed countries. Its incidence can reach 20 to 30 percent in people over 50 years of age. It is also responsible for about 2 percent of health care costs in the United States. Additionally, sluggish venous blood flow is an issue for those with diseases such as diabetes, and for those with paralysis or recovering from surgery.
[The researchers have] demonstrated the feasibility of this novel approach in vitro and are currently working toward testing these devices in vivo.