FIGHT AGING! NEWSLETTER
June 2nd 2014
The Fight Aging! Newsletter is a weekly digest of news and commentary for thousands of subscribers interested in the latest longevity science: both the road to future rejuvenation and the present understanding of what works and what doesn't work when it comes to extending healthy life. Expect to see summaries of recent advances in medicine, news from the longevity science community, advocacy and fundraising initiatives to help advance rejuvenation biotechnology, links to online resources, and much more.
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- A World of Inadvertently Held Stoic Views
- Arterial Stiffening is Enough to Explain Hypertension
- A Report from the Third International Conference on Genetics of Aging and Longevity
- A Future of Living in Health for Decades Beyond 100: Getting the Message Out
- Against a Duty to Die for the Elderly and the Sick
- Latest Headlines from Fight Aging!
- The Researcher Who Wants to Cure Old Age
- Calorie Restriction Improves Cancer Outcomes
- Conceptualizing Medical Nanorobots For Lipofuscin Removal
- The Role of Mitochondria in Longevity and Healthspan
- Genetically Modified Pigs as a Temporary Transplant Source
- Slowing Atherosclerosis Development By Interfering in the Reaction to Disturbed Blood Flow
- Laser Light Spurs Stem Cell Activity to Regenerate Dentin
- Progress Towards Understanding the Discrete Mechanisms of Calorie Restriction
- The Three Genetics of Longevity
- Comparing Heat Shock Protein Levels Between Similar Species of Different Longevity
A WORLD OF INADVERTENTLY HELD STOIC VIEWS
Most people don't really care as to how many years of life they have left. It isn't an interesting topic for them, and is thought about rarely if at all. If pushed for preferences, the average follow reverts to not wanting to rock the boat, to go with the observed defaults: to live as long as his grandparents, or just a little bit more than his peers, enough to make the point without being crass. But this is not really an expression of preference, it is simply going with the flow, the knee-jerk desire for conformity and hierarchy. Of course most people are in relatively good health and a demise by aging is still decades away, which might as well be never given the human psychology of time preference. Life is busy and it is easy to push future concerns to one side in favor of the day to distractions, needs, and pleasures.
You can conduct a survey of such views yourself. If you are reading this post, the odds are good that you have a very different view on the future of your life than do your friends and family. If you talk to healthy people you'll find that most are surprisingly indifferent to the length of time they have left before aging greatly harms and then kills them. It only becomes a pressing concern when that time remaining drops into territory that instinctively makes a person uncomfortable: a month or a year, perhaps.
One of the aspects of ancient Stoic philosophy is that length of life and even present health is of little concern when it comes to happiness. Will triumphs over circumstance, as present state of mind is under the control of anyone who strives for that goal. To quote Epictetus, the stoic can be "sick and yet happy, in peril and yet happy, dying and yet happy, in exile and happy, in disgrace and happy." In times when life was far more perilous and fraught with sickness and discomfort than is the case now, these sorts of considerations were not academic exercises.
Is a Longer Life a Happier Life? Stoicism and Happiness
My faltering commitment to stoicism was brought to the forefront of my mind quite recently when I read an article by Eyjolfur Emilsson entitled "On the length of a good life". The article outlines and advocates the stoic (and Epicurean) view that "a life, once happy, does not become any happier by lasting longer". That is to say: we don't need long or indefinite lives in order to be truly happy and content.
There is far more to stoicism than this small slice relating to happiness and length of life. It certainly isn't the "philosophy of what I'd do anyway," but this small slice does more or less reflect the default view of the public at large. Most people strive for happiness in the moment and ignore their future longevity, which one might argue is some mix of (a) following the example set by the norms of past behavior, (b) a response to lack of certainty and control over the future value of money and other forms of wealth, and (c) that all-too-short human time preference again.
But so what if we have a world of people who hold stoic views with respect to longevity and years of health remaining, but without any real intent of doing so. Why does this matter? It matters because defeating aging and age-related disease is a grand goal in medicine. Even if the prototype technologies might be pushed to the point of demonstration in mice for a billion dollars and ten to twenty years of work, well within the purchasing power of a large multinational research company or collaboration of billionaire philanthropists, vast resources and many hands will be needed to translate that into a full, mature, worldwide clinical industry. At this sort of scale at least a sizable minority of the population must support the goal in question for it to have a hope of moving from possibility to reality. There are many grand engineering projects and industries that might already exist in a different world but which in ours have too little public support to move forward rapidly: irrigating the Sahara, a low-cost orbital lift industry, commercial small-scale nuclear reactors, and so forth.
The near future of human longevity is not just a matter of research and building the tools needed to repair the damage of aging, but it is also, vitally, a process of convincing enough people that this is even worth doing. Anyone who has spent time looking at exactly what it means to be old, at the drawn out pain and suffering inherent in the age-related failure of all organs and bodily systems, might be forgiven for thinking that we live in a madhouse. But nonetheless, most people simply don't care about research, medicinal science, progress in clinical applications of medicine, or the future of their health, or how long they will live. These things are not important to them, and won't be until such time as they are in the clinical system asking how their pain and lost function can be assuaged - which is far too late.
ARTERIAL STIFFENING IS ENOUGH TO EXPLAIN HYPERTENSION
Many and varied are the harmful medical conditions that emerge with increasing age. The consensus position in the research community is that tracing back the biochemical chains of cause and effect to root causes, something that is not yet possible for many common medical conditions, will show that all age-related conditions and their complexities are the consequences of a comparatively small number of types of cellular and molecular damage. That damage accumulates with age to cause secondary effects, which in turn cause further issues, and by the time the process of dysfunction rises to the level of being called a disease it has become a huge mess of broken mechanisms, confusion, and dead ends. With that as the starting point for research into treating age-related disease it is no wonder that all too many conditions are not yet fully understood in terms of a clear chain of consequences from top to bottom.
Hypertension, you might think, is such a simple medical condition that it couldn't possibly be stuck in this situation. It is quite simply high blood pressure, something that places all sorts of physical, mechanical stress on important parts of the circulatory system. Pretty much every fatal thing that can go wrong with your heart and blood vessels is aggravated by hypertension. Yet the root causes and middle region of the chain of cause and effect for the rising incidence of hypertension with age are not nailed down at this point: it is all very much up for debate.
Here researchers take a different strategy to the normal approach of painstakingly tracing relationships between proteins in cells, starting at the end point of full blown disease and working backwards one step at a time. They are instead using computer modeling to try to constrain the bounds of the possible, to narrow down the region of study for those who will come afterwards to piece together mechanisms and interactions. Their argument, in short, is that you don't need anything more than the process of arterial stiffening that occurs with aging to explain the observed effects of hypertension:
Arterial Stiffening Provides Sufficient Explanation for Primary Hypertension
Hypertension is highly age-related and affects more than 1 billion people worldwide. It is a major source of morbidity and mortality as it makes us more prone to experience heart failure, stroke, and kidney disease. Despite intense research efforts over several decades, there is still no consensus on what are the primary causes of this disorder.
Here we present a computational physiology model which shows that the increase in arterial stiffness that follows with age is sufficient to account for an overwhelming amount of experimental and clinical data on hypertension. We demonstrate quantitatively that the stiffening causes the baroreceptors, the blood-pressure sensors located in the arterial wall, to misinform the highly complex machinery responsible for blood pressure regulation. This misinformation occurs because the baroreceptors are strain sensitive, not pressure sensitive, and with stiffening the aortic wall strain ceases to be a good proxy for aortic blood pressure.
Contrary to wide-held conceptions, the blood pressure regulation may thus become compromised without any other detrimental physiological change of the regulatory machinery. Our results therefore suggest that arterial stiffness represents a major therapeutic target by which an otherwise intact physiological machinery may be exploited for blood pressure regulation.
Aha, you might say, but assuming this research pans out it just swaps one unknown chain of cause and effect for another that is only one item shorter. Instead of working to figure out what is going on in hypertension, scientists are instead figuring out what is going on in arterial stiffening. As it happens this is actually a good swap, as much more is known of the causes of blood vessel stiffening with age.
For example, the formation of advanced glycation end product (AGE) cross-links shackles layered proteins in tissues and is one well-researched direct cause of age-related stiffness in blood vessel walls and loss of elasticity in skin. In humans just one type of cross-linking compound called glucosepane accounts for almost all such cross-links in the most studied tissues. Getting rid of glucosepane and removing its contribution to degenerative aging requires only a single successful drug development program to produce a safe means of breaking down the compound. Unfortunately this has yet to see much interest from pharmaceutical companies, despite the great size of the market for an effective AGE-breaker drug.
If you spend much time watching the research and development community, you'll see many areas like this, in which obvious near term goals of great potential benefit are little pursued. Progress, sad to say, isn't always ruthless and rational, and gaping holes of this nature can last for decades. Thus in the field of glucosepane research the only initiatives of note at the present time are set in motion by philanthropic funding, such as the programs coordinated by the SENS Research Foundation.
A REPORT FROM THE THIRD INTERNATIONAL CONFERENCE ON GENETICS OF AGING AND LONGEVITY
At the highest level one can measure the health and pace of progress in a field by counting conferences. Conferences are not where advances happen, but they are an inevitable byproduct of progress and growth in research. When more researchers are focused on a field and their output of significant new scientific results flows faster, then more conferences will tend to take place.
The field of aging research is, sad to say, still a small adjunct office to the great edifice of medical science. The pursuit of enhanced longevity through treating aging as a medical condition is just one small corner desk in that office. We'll see this sorry state of affairs change in our lifetimes, judging by the way things are going, but that process of growth can never proceed fast enough for my liking. Thus there are still all too few conferences devoted to the science of aging and longevity in comparison to those taking place for any truly large section of the medical research community. Nonetheless, they do exist. Last month, for example, the third International Conference on Genetics of Aging and Longevity was held in Sochi, Russia. As for the earlier conferences in the series it was well attended by noted names in aging research. Maria Konovalenko of the Science for Life Extension Foundation attended and offers this report from the event:
Third International "Genetics of Aging and Longevity" Conference Featured Research on Multiple Ways to Combat Aging
More than 200 participants from North America, Europe and Asia met in post-Olympic Sochi for five days this April, as world-famous anti-aging researchers exchanged ideas at the third International Conference on Genetics of Aging and Longevity. They discussed progress and remaining obstacles, in their efforts to deepen our understanding of this complex phenomenon and develop strategies for interventions.
The central themes of the conference included (1) identification of molecular targets for lifespan-extending drugs, (2) understanding the protective genotypes of centenarians and exceptionally long-lived animal species, (3) the complex roles and interactions of genetic determinants, epigenetic regulation, metabolism, gut microbiota, lifestyle and environment in shaping the aging process, (4) developing technologies for artificial growth, cryopreservation and transplantation of organs, and (5) new technologies, including gene-editing nanoparticles and artificial chromosomes, as prospective anti-aging tools.
Some of the few dozen presentations are worth noting, though much of this might be old news for readers here:
Judith Campisi (Buck Institute for Research on Aging) presented a new transgenic mouse model to visualize and eliminate senescent cells in mice based on their elevated expression of the p16INK4a gene.
Shay Soker (Wake Forest School of Medicine) presented recent advances in growing of organs in bioreactors. Simple organs like cornea, blood vessels and bladder are relatively easy to grow, whereas growing of complex organs like liver, kidney and pancreas requires scaffolds. Bioscaffolds can be isolated for the purpose of study by decellularisation of naturally grown organs.
Gregory Fahy (21st Century Medicine, Inc.) presented achievements and difficulties in vitrification of organs. Sophisticated cryoprotective cocktails, and protocols for tissue perfusion at high pressure prior to freezing, and rapid warming methods were developed. Nevertheless, the main problem that remains is different optimal cooling rate for different cell types and organ zones.
A FUTURE OF LIVING IN HEALTH FOR DECADES BEYOND 100: GETTING THE MESSAGE OUT
Most people are completely unaware of the great discontinuity in medical science that lies just ahead. They look back, and project forward based on what they see in the past - and no matter that we are in an era of sweeping, rapid change and progress. The average fellow in the street is laboring under the delusion that his future life will look much like that of his parents. But nothing could be further from the truth.
For centuries advances in medicine have provided a gradual increase in adult life expectancy, so slow that there really isn't a large enough gap to remark upon between the life spans of parent and child. The pace today is about a year gained every decade, and this despite very impressive recent advances in preventing and patching over the late stage consequences of cardiovascular aging. When the patching becomes more effective for one facet of aging, at the moment that just means that more people have the chance to be killed by something else, just a little further down the line. Aging is a global phenomenon in the body, and everything declines and fails at roughly the same time, give or take. If not heart failure, then dementia. If neither of those, then cancer. Or stroke, or atherosclerosis, or eventually poorly studied forms of amyloidosis that clog the heart and blood vessels.
If the approach to medicine continues to be a process of picking late stage dysfunction and failure, one item at a time, and producing marginally better ways of patching it up, then sure, this trend in increased longevity will continue very slowly, a year every decade. None of these gains in healthy life span are deliberate; they are all unintentional side-effects. Why should we expect a side-effect to be anything other than small? The only reason it is steady and continuing is that aging is damage, and medicine cannot be anything other than a process of repairing damage.
The coming discontinuity in medicine is this: researchers are going to start actually trying to treat aging directly as the medical condition it is. They will pin it down, produce ways to slow it or, far better, repair its root causes. They will at some point stop fumbling around with poor initial directions and marginally useful dead ends, such as calorie restriction mimetics, and start to produce effective therapies, such as implementations of SENS-like regenerative medicine. The business of "life extension" and "anti-aging" will be clawed back from the frauds and the cranks and the supplement sellers and the cosmetics companies and handed over to legitimate medical developers who produce procedures that actually do what it says on the label: reverse the course of degenerative aging.
The point here is that there is a world of difference between not trying at all to treat aging, the underlying cause of all age-related disease, and putting the weight of the medical research community behind deliberate attempts to treat aging. The present slow trend in life expectancy is the outcome of not trying. The future trend, based on thousands of researchers working hard to defeat aging and its causes, is going to look very different indeed.
These are exciting times to be in medical research. Yet the public at large is oblivious, and perhaps even disinterested. The view of aging in our culture is in no way similar to the view of cancer: that urge to do something about it is missing. Without widespread support funding at the large scale rarely emerges, however. At this time, then, it is very important for researchers to stand up on their soapboxes, a thing that scientists are notoriously reluctant to do, and make the case for the coming era of treatments for aging and all age-related disease. This is an example of the the sort of thing I mean, from a fellow who has been quite vocal on this topic in recent years:
The Coming Age of Unprecedented healthy Life Extension and Why You Should Be Cheering It On!
Have you given serious thought to what it would be like to live to age 120 plus? Recent polls in the US and Canada revealed that a large majority of people were decidedly not in favour of using biomedical interventions to be able to live past 120. No surprise you say? After all, why would anyone want to extend the part of our lives that we would rather avoid? Why prolong an old age that brings loss of independence, painful debilitating illnesses, mental decline - not to mention huge medical bills! Over eighty percent of our lifetime medical expenses occur in the last few years of life.
But wait! What if you could be in better physical and mental health in 20 years, than you are now? Would that change your view towards what is called by futurists and aging researchers "radical life extension"?
Imagine yourself in your late 80's happily playing tennis, in your 90's hiking around Machu Picchu, getting a second masters degree in literature and then in your 100's writing a best-selling novel (something you never thought of doing until you were 97!). What if this could all be done while helping the planet develop into a more sustainable, healthy place to live?
Sound too futuristically phantasmagoric? Maybe not! Consider that retirement planning is about the future - your future. And given the acceleration of change in our world, consider that your future will be dramatically different than your past. Perhaps the most important feature about your future is that radical healthy life extension is coming. Just how soon it arrives is up to us, our openness to it, our actions supporting it: we are all invited to embark on a grand new exploration into a never-before-seen-world of radical healthy life extension enabled by technology. But for it to manifest fully is a choice, our choice.
AGAINST A DUTY TO DIE FOR THE ELDERLY AND THE SICK
Freedom absolutely implies the freedom to die: if you don't own your own life, then what do you own? If you wish to assign yourself a duty to die, because you feel a burden, or for whatever reasons you have, then go right on ahead. The people you're doing it for won't be anywhere near as moved as you'd like to think, but euthanasia of all sorts should have far more respect as a personal choice than is presently the case. One of the most offensive interventions enforced by most modern states is to make it next to impossible for a person to safely and painlessly end his life in the manner and time of his own choosing.
But that is choice. A duty to die in the other sense of duty, that of an obligation imposed upon you by an often nebulous collection of other people, folk who are not in fact signed up to die right now themselves, is a whole other outrage. It is a particularly banal form of evil that oozes through the broadening debate on medical costs and rationing. This debate will only grow while dysfunctional centralized medical systems persist: you can either have a near-as-possible free market in which people are responsible for their costs and providers have to compete ruthlessly for customers, or you can have terrible service, shortages, and waste. Pick one. No-one has to worry about the availability or fit of shoes in the US, but the current medical system bears more semblance to the provision of shoes in the old USSR than it does to the modern US shoe marketplace - and the consequences of that command and control structure are plain to see.
The growth in biotechnology and the concurrent need for radical new advances in medicine for a growing number of comparatively wealth elderly should be an unparalleled opportunity for researchers, businesses, and consumers alike, the incentive for a great leap forward in the same manner as the recent decades-long burn of accelerating computing power. Instead, via the dark alchemy of heavy government regulation, this opportunity has been transformed into waste and the standard issue tragedy of the commons that attends any trough of public funds, its battles argued in the language of entitlement.
So as the pigs root around the trough, their incentives are not to develop better means and technologies, not to expand the set of paying customers by better serving those customers, but rather to find ways to cut costs, to deliver less, to push some of the other pigs away from the feed. Perverse incentives lead to perverse outcomes, and hence we are back to the duty to die, and that rhetoric is usually explicitly linked with costs of entitlement, as in the "fair innings" argument that has been taking place in the UK for some years.
Against a Duty To Die
In a 2008 interview, Baroness Mary Warnock, a leading moral philosopher, said that people suffering from dementia had a duty to commit suicide: "If you're demented, you're wasting people's lives - your family's lives - and you're wasting the resources of the National Health Services". Warnock also claimed that there was "nothing wrong" with helping people to die for the sake of their loved ones or society. Well known for her support of euthanasia, Warnock expressed in the interview the hope that people will soon be "licensed to put others down" if they are unable to look after themselves.
While such claims are controversial, they are persistent and seem to crop up from time to time in public debates and scholarly literature. In the United States, former Colorado Governor Richard Lamm expressed a similar view almost 30 years ago. Referring to the elderly as "leaves falling off a tree and forming humus for the other plants to grow up," he told a meeting of the Colorado Health Lawyers Association, "you've got a duty to die and get out of the way" and "let the other society, our kids, build a reasonable life".
Social scientists have noted that the elderly often worry about being a burden on others, especially family members. In the period leading up to their deaths, elderly people who subsequently committed suicide reported that their lives had been lived and that they were now a burden on others. Little is known about the experiences of elderly people who live and die alone, but in one qualitative study of this population, participants characterized a good death as being able to die without becoming a burden to others. There is a small but growing body of evidence suggesting that worry about creating a burden on others is common among people of all ages who are near the end of life.
As is the case for most ethics viewpoints this quoted piece above takes the state of medical science as it is, and only asks how bad behavior might change for the better within this environment (while largely ignoring the regulatory causes of the economic incentives that lead to this behavior). This is woeful but widespread. In an age of change such as ours we should always ask first and foremost how technology might be developed to alleviate suffering, because the answer is usually that meaningful results can be obtained comparatively rapidly, in a handful of years given broad support.
The behavioral change that I'd like to see is for more people to wake up and support greater funding and development in the life sciences, as this is the key to eliminating the greatest causes of pain, suffering, and death. Along the way that would also steamroller the apparently thorny ethics issues that accompany that pain, suffering, and death, but that is hardly the point of the exercise. If you don't like the color of the wall, don't analyze it or work around it, but instead go out and buy some paint. The world is what we make of it.
But that point aside, it is hard to use technology to solve the consequences of regulation that slows progress and even diminishes the incentives to create progress in science - unless it is technology that helps you travel far enough away that regulatory bodies can't keep up. I think that medical tourism will the way in which most of the newest possibilities in medicine arrive over the next few decade. Not every region has yet become as hostile to progress in medicine as the UK or the US, and many of these regions also lack the steady stream of semi-officially propagated nonsense that there is a duty to die if you are old and in ill health.
LATEST HEADLINES FROM FIGHT AGING!
THE RESEARCHER WHO WANTS TO CURE OLD AGE
Monday, May 26, 2014
Vice here interviews Aubrey de Grey of the SENS Research Foundation, an organization that coordinates and funds work on the necessary foundations for rejuvenation treatments, near future therapies that will repair the known cellular and molecular damage that causes aging:
Aubrey de Grey has been called many things. "Transhumanist" is one of them, but one he dislikes. "Immortalist" is the tag used to describe him and his colleague Bill Andrews in a documentary shown at South by Southwest this March, though de Grey rolls his eyes when someone drops the word "immortality."
The British gerontologist considers himself a "simple medical researcher," but his research is about fiddling with cells to stop ageing in human beings, and potentially postponing death indefinitely. If it's not immortality (in de Grey's world, you could still be dispatched by an infectious disease or a shotgun), it's quite a close beast.
He believes that tackling the individual illnesses that haunt old people's lives is a fundamentally flawed strategy; the right course of action is to act at the cellular level to prevent ageing from setting off those illnesses in the first place. His Silicon Valley-based foundation-cum-laboratory, the SENS Research Foundation, is completely devoted to this feat.
In the past, de Grey's views were often met with skepticism or hostility, when not openly guffawed at. That has not completely changed, but the idea that ageing should actually be regarded as a disease, and that it might even be treated as such, is increasingly gaining ground. Recently, that's been given a boost by research into tackling ageing on a genetic level. He initiated me in the science and doctrine of which he's the standard-bearer, most of which can be summarized in one question: If we could really wipe old age and death off the planet, why shouldn't we?
CALORIE RESTRICTION IMPROVES CANCER OUTCOMES
Monday, May 26, 2014
The practice of calorie restriction reduces the risk of suffering cancer, just as it reduces risk of suffering all other common age-related conditions. However if you do become unlucky and develop cancer, calorie restriction tends to improve the outcome, shifting the odds in your favor: there is a range of research to demonstrate that calorie restriction augments the effectiveness of cancer treatments, for example.
According to a study [the] triple negative subtype of breast cancer - one of the most aggressive forms - is less likely to spread, or metastasize, to new sites in the body when mice were fed a restricted diet. [When] mouse models of triple negative cancer were fed 30 percent less than what they ate when given free access to food, the cancer cells decreased their production of microRNAs 17 and 20 (miR 17/20). Researchers have found that this group of miRs is often increased in triple negative cancers that metastasize. This decrease in turn increased the production of proteins involved in maintaining the extracellular matrix. "Calorie restriction promotes epigenetic changes in the breast tissue that keep the extracellular matrix strong. A strong matrix creates a sort of cage around the tumor, making it more difficult for cancer cells to escape and spread to new sites in the body."
In theory, a drug that decreased miR 17 could have the same effect on the extracellular matrix as calorie restriction. However, targeting a single molecular pathway, such as the miR17 is unlikely to be as effective as calorie restriction. Triple negative breast cancers tend to be quite different genetically from patient to patient. If calorie restriction is as effective in women as it is in animal models, then it would likely change the expression patterns of a large set of genes, hitting multiple targets at once without toxicity. Breast cancer patients are often treated with hormonal therapy to block tumor growth, and steroids to counteract the side effects of chemotherapy. However, both treatments can cause a patient to have altered metabolism which can lead to weight gain. In fact, women gain an average of 10 pounds in their first year of treatment. Recent studies have shown that too much weight makes standard treatments for breast cancer less effective, and those who gain weight during treatment have worse cancer outcomes. "That's why it's important to look at metabolism when treating women with cancer."
In order to test that this hypothesis is true in humans, [the researchers are] currently enrolling patients in the CaReFOR (Calorie Restriction for Oncology Research) trial. As the first trial like it in the country, women undergoing radiation therapy for breast cancer receive nutritional counseling and are guided through their weight loss plan as they undergo their treatment for breast cancer.
CONCEPTUALIZING MEDICAL NANOROBOTS FOR LIPOFUSCIN REMOVAL
Tuesday, May 27, 2014
For some years a number of researchers, such as Robert Freitas, have modeled and proposed designs for nanomechanical robots capable of interacting with and repairing cells or replacing some of the tasks of cells so as to conduct those tasks far more efficiently. This is early groundwork in a field that has yet to exist beyond concepts and models: the actual construction of such things still lies in the future. On this topic Frank Boehm, the author of a comparatively recent book on medical nanorobot design, pointed me in the direction of an interesting piece on the design of medical nanorobots to remove lipofuscin from cells, which is quoted below.
Lipofuscin is made up of metabolic wastes that cells cannot break down, and it clogs up the cellular recycling system, leading to a deterioration of cellular function as damage builds up. Where it happens in long-lived cells this process contributes to a range of age-related conditions. Liposfuscin removal will be a going concern in the years ahead if the SENS Research Foundation does well with its research programs and in persuading other organizations to join in, but the near future of this project won't involve nanorobotics. It will be a matter of adapting bacterial enzymes that are both safe to introduce to the body and highly effective at breaking down the various compounds that make up lipofuscin. Still, we should look farther ahead as well, as mechanical medical nanomachinery will almost certainly be plausible to manufacture and control effectively twenty to thirty years from now.
It is conceivable that the future development of nanomedical robotics [might] enable the capacity for the therapeutic removal of lipofuscin from individual cells in massively parallel fashion. Conceptual dedicated autonomous nanodevices (~200 nm in diameter - where one nanometer is a billionth of a meter) might penetrate the cell membranes of neurons and other cells and undertake the removal of lipofuscin through various means.
Advanced autonomous nanodevices might precisely locate lipofuscin granules by exploiting its strong fluorescence signatures [to] match with onboard reference spectral profiles. The prospective armamentarium at the disposal of these autonomous diamondoid "defuscin" class nanodevices [might] allow for the complete eradication of lipofuscin aggregates utilizing a feedthrough digestive strategy. These entities may be propelled by arrays of oscillating piezoelectric "fins" or via integrated magnetic nanoparticles, which might be activated and controlled externally. The conical inlet port of the nanodevice would be lined with molecules that possess high affinities for A2E [a primary lipofuscin constituent] and other lipofuscin elements.
Once a lipofuscin granule has been captured it would proceed to be drawn into the core, where it would be digested by potent encapsulated enzymes or nanomechanically minced into a liquid state and subsequently purged from the outlet port. This functionality would be similar to Freitas's microbivore artificial mechanical phagocytes, which operate under a "digest and discharge" protocol"
THE ROLE OF MITOCHONDRIA IN LONGEVITY AND HEALTHSPAN
Tuesday, May 27, 2014
An editorial from the Longevity and Healthspan journal:
Mitochondria are indispensable for aerobic life. Depending on the tissue and species, they normally occupy 2-20% of the volume of a cell, and it can be up to 50%. They have their own DNA and undergo constant motion, fusion and fission. They provide the cell with ATP formed during the oxidation of carbohydrate, proteins and fats and are involved in a range of metabolic pathways. They help regulate cellular calcium levels, trigger apoptosis, and can generate reactive oxygen species that are used in cellular signalling and can cause oxidative damage.
The role of mitochondria in aging and disease remains contentious more than 40 years after the mitochondrial free radical theory of aging was first proposed. The hallmark of a useful hypothesis is that it stimulates further work and drives progress in its field. The free radical theory of aging has certainly done that since Harman proposed it in its general form in 1956 and in a more mitochondrially-oriented form in 1972. This theory proposes that the primary cause of aging is mitochondrial production of free radicals and the mitochondrial damage that ensues. The evidence that has been gathered over the years has led to adjustments and refinements in the formulation of the hypothesis as different authors have attempted to articulate it more precisely and to square it with experimental observations; as a result there have been numerous updates and overviews. Many of these have been very influential. However, the perspective has become increasingly critical as the predicted beneficial effects of many antioxidant treatments and genetic manipulations have failed to materialise.
Where does that leave us today? On the one hand, many of the manipulations that should decrease aging and increase longevity according to the classical versions of the mitochondrial free radical theory of aging have failed to do so, implying that the theory is wrong, or at best deeply flawed. On the other hand, some of these manipulations have been very successful, implying that that the theory refracts some underlying reality and still has significant value as a guide to thought and experiment.
GENETICALLY MODIFIED PIGS AS A TEMPORARY TRANSPLANT SOURCE
Wednesday, May 28, 2014
Xenotransplantation, the transplantation of tissue from animals to humans, is a potential stepping stone technology to bridge the gap between today and a future in which all tissues can be grown to order from a patient's own cells. Xenotransplantation is not yet a completely practical possibility, as it has greater issues of immune rejection than transplantation between humans, but several lines of research are bringing it closer. One of these is decellularization, stripping cells to leave the scaffold of the extracellular matrix that is then repopulated with the recipient's own cells. Another is to genetically alter the donor animal to remove proteins that will trigger rejection:
[Researchers have] been investigating ways to allow the human body to accept organ and tissue transplants from animals. [The] team developed a strain of inbred miniature swine with organs that are close in size to those of adult humans. Since pig organs implanted into primates are rapidly rejected due to the presence of the Gal (alpha-1,3-galactose) molecule, [they] used the strain [to] generate miniature swine in which both copies of the gene encoding GalT (galactosyltransferase), the enzyme responsible for placing the Gal molecule on the cell surface, were knocked out.
When insufficient undamaged skin is available for grafting, tissue from deceased donors is used as a temporary covering. But deceased-donor skin grafts are in short supply and expensive - disadvantages also applying to artificial skin grafts - must be carefully tested for pathogens and are eventually rejected by a patient's immune system. Once a deceased-donor graft has been rejected, a patient's immune system will reject any subsequent deceased-donor grafts almost immediately.
When [the researchers] used skin from these Gal-free pigs to provide grafts covering burn-like injuries on the backs of baboons - injuries made while the animals were under anesthesia - the grafts adhered and developed a vascular system within 4 days of implantation. Signs of rejection began to appear on day 10, and rejection was complete by day 12 - a time frame similar to what is seen with deceased-donor grafts and identical to that observed when the team used skin grafts from other baboons.
As with the use of second deceased-donor grafts to treat burned patients, a second pig-to-baboon graft was rapidly rejected. But if a pig-to-baboon graft was followed by a graft using baboon skin, the second graft adhered to the wound and remained in place for around 12 days before rejection. The researchers also showed that acceptance of a second graft was similar no matter whether a pig xenograft or a baboon skin graft was used first.
Clearly there is a way to go yet, but even just a better source of useful temporary grafts for burn victims is an improvement on the current situation, and the researchers are talking about organizing clinical trials based on this work.
SLOWING ATHEROSCLEROSIS DEVELOPMENT BY INTERFERING IN THE REACTION TO DISTURBED BLOOD FLOW
Wednesday, May 28, 2014
Much of modern medicine does not address root causes. If there is one clear item that has to change in order for the research community to effectively address degenerative aging, it is this. It is perhaps understandable as to how we find ourselves in this position: most research into specific diseases starts at the end point, with the full-blown late-stage manifestation of the condition, and works backwards from there. The role of the research has long been to understand what is going on at the level of cells and proteins in the late stages of disease, and then trace back the chain of relationships and interactions to earlier stages. Thus progress leads into the middle stages of cause and effect, and most potential treatments built using modern tools of biotechnology tend to be ways to interfere in proximate causes, not root causes. The people who catalog root causes and work on ways to repair them, aiming to prevent large numbers of medical conditions with a small number of treatments, are still a small minority in medical research, unfortunately.
This is a good example of the sort of thing I'm talking about here: it doesn't address the reasons why blood flow becomes disturbed, but seeks to decouple that from a raised risk of atherosclerosis.This will be beneficial if it works, but it does nothing to address the real issues or the other problems that said issues causes.
In atherosclerosis, plaques preferentially develop in arterial regions of disturbed blood flow (d-flow), which alters endothelial gene expression and function. Here, we determined that d-flow regulates genome-wide DNA methylation patterns in a DNA methyltransferase-dependent (DNMT-dependent) manner.
Induction of d-flow by partial carotid ligation surgery in a murine model induced DNMT1 in arterial endothelium. In cultured endothelial cells, DNMT1 was enhanced by oscillatory shear stress (OS), and reduction of DNMT with either the inhibitor 5-aza-2′-deoxycytidine (5Aza) or siRNA markedly reduced OS-induced endothelial inflammation. Moreover, administration of 5Aza reduced lesion formation in 2 mouse models of atherosclerosis.
We determined that d-flow in the carotid artery resulted in hypermethylation within the promoters of 11 mechanosensitive genes and that 5Aza treatment restored normal methylation patterns. Of the identified genes, HoxA5 and Klf3 encode transcription factors that contain cAMP response elements, suggesting that the methylation status of these loci could serve as a mechanosensitive master switch in gene expression. Together, our results demonstrate that d-flow controls epigenomic DNA methylation patterns in a DNMT-dependent manner, which in turn alters endothelial gene expression and induces atherosclerosis.
LASER LIGHT SPURS STEM CELL ACTIVITY TO REGENERATE DENTIN
Thursday, May 29, 2014
These researchers take an interesting approach to boosting the activity of stem cells so as to effect regeneration, demonstrating their approach in teeth. By the look of it this is effectively a means of induced hormesis, taking advantage of a very general cellular response to mild stress, but in a more controlled way than has been possible in the past:
The team used a low-power laser to trigger human dental stem cells to form dentin, the hard tissue that is similar to bone and makes up the bulk of teeth. What's more, they outlined the precise molecular mechanism involved, and demonstrated its prowess using multiple laboratory and animal models. It turns out that a ubiquitous regulatory cell protein called transforming growth factor beta-1 (TGF-β1) played a pivotal role in triggering the dental stem cells to grow into dentin. TGF-β1 exists in latent form until activated by any number of molecules.
Here is the chemical domino effect the team confirmed: In a dose-dependent manner, the laser first induced reactive oxygen species (ROS), which are chemically active molecules containing oxygen that play an important role in cellular function. The ROS activated the latent TGF-β1 complex which, in turn, differentiated the stem cells into dentin. Nailing down the mechanism was key because it places on firm scientific footing the decades-old pile of anecdotes about low-level light therapy (LLLT), also known as Photobiomodulation (PBM).
Since the dawn of medical laser use in the late 1960s, doctors have been accumulating anecdotal evidence that low-level light therapy can stimulate all kind of biological processes including rejuvenating skin and stimulating hair growth, among others. The clinical effects of low-power lasers have been subtle and largely inconsistent. The new work marks the first time that scientists have gotten to the nub of how low-level laser treatments work on a molecular level, and lays the foundation for controlled treatment protocols.
PROGRESS TOWARDS UNDERSTANDING THE DISCRETE MECHANISMS OF CALORIE RESTRICTION
Thursday, May 29, 2014
Calorie restriction increases life span and greatly improves health in almost all species tested to date. The relative degree of life extension is much greater in short-lived species, however. Human calorie restriction is not expected to improve life expectancy by more than 5-10% at most. Still, human studies have demonstrated that the practice of calorie restriction produces health benefits such as resistance to age-related disease to a degree that cannot be obtained through any other available technique or technology at the present time - though regular exercise comes close.
Researchers have shown that at least some of the response to calorie restriction stems from sensing levels of amino acids in the diet. In mammals similar results can be obtained by restricting dietary methionine without reducing calories, for example. It is still the early days when it comes to dissecting the calorie restriction response into its component parts, however, the better to understand and replicate it with drugs. Here is an example of this sort of research, in which scientists are working with flies to link calorie restriction and dietary amino acid level alterations to various known longevity-related aspects of metabolism:
Dietary restriction (DR) is an intervention whereby a considerable reduction of food intake, just short of malnutrition, extends lifespan. This has been demonstrated to be effective in a wide range of evolutionarily diverse organisms, from yeast to invertebrates and mammals, and is considered one of the most robust environmental interventions to extend lifespan in laboratory organisms. Moreover, the longevity promoting effects of DR are accompanied by a range of health benefits. DR rodents had a delayed onset or a lesser severity of age-related diseases such as cancer, autoimmune diseases and motor dysfunction and improved memory. In C. elegans, DR was shown to reduce proteotoxicity. DR rhesus monkeys were found to have improved triglyceride, cholesterol and fasting glucose profiles, and a reduced incidence of diabetes, cancer, cardiovascular disease and brain atrophy.
Reduced signalling through the insulin/IGF-like (IIS) and Target of Rapamycin (TOR) signalling pathways also extend lifespan. In Drosophila melanogaster the lifespan benefits of DR can be reproduced by modulating only the essential amino acids in yeast based food. Here, we show that pharmacological downregulation of TOR signalling, but not reduced IIS, modulates the lifespan response to DR by amino acid alteration. Of the physiological responses flies exhibit upon DR, only increased body fat and decreased heat stress resistance phenotypes correlated with longevity via reduced TOR signalling. These data indicate that lowered dietary amino acids promote longevity via TOR, not by enhanced resistance to molecular damage, but through modified physiological conditions that favour fat accumulation.
Some long-lived TOR and IIS pathway mutants [in other species] have increased fat levels. Given that not all fat mutants are long-lived, it is likely that if fat levels are causally involved in extending life, the quality of fat accumulated is important. It would be interesting in future work to determine how lipid profiles change under different dietary conditions, to identify the specific types of lipids that are altered, and whether experimental manipulation can enhance lifespan.
THE THREE GENETICS OF LONGEVITY
Friday, May 30, 2014
One can take the perspective a human is more like a city than an individual, where the noteworthy populace is of diverse origins. The cells of the body are just one demographic, and there are also the microbial population of the gut and the mitochondria to consider. All are joined into a symbiotic relationship, but one that is not completely free from acts of mutual antagonism among its membership.
Longevity is a complex trait whose genetics has been extensively studied since many years. Understanding the genetic makeup that predisposes to longevity is an urgent challenge owing to the explosion of the elder population in western as well as in emerging countries.
Usually the studies on the genetics of human longevity are restricted to the analysis of nuclear genome (nDNA). However, another essential genome, that is, the mitochondrial genome (mtDNA), is part of the genetic machinery of each cell. Despite its limited length, the mtDNA encodes for few genes that constitute a quantitatively relevant group because of the high copy number of mtDNA in each cell.
These two genomes do not work in the void and life/survival, as well as ageing and longevity, depends on their complex interaction with environment/lifestyle. To this scenario we have to add another level of genetic complexity represented by the microbiota, that is, the whole set of bacteria that live in different anatomical districts of our body with their whole set of genes (microbiome). Indeed, the most comprehensive view is to consider human being as a "metaorganism" resulting from the close relationship with symbiont microbial ecosystems. A particular attention has been recently devoted to the gut microbiome (GM). The GM probably represents the most adaptable genetic counterpart of the human metaorganisms, being extremely plastic in response to age-related physiological changes in diet and modification in lifestyle.
Thus, the result of the ageing process is defined by the sum of a number of factors both biological and nonbiological (environmental and stochastic). Therefore while the ageing research based on the study of animal models starts assuming the existence of major genes that determine longevity, in humans this assumption represents an oversimplification. The study of human model imposes a more holistic view of the genetics to grasp the complex dynamics of the interaction between the environment, stochasticity, and the three genetics of the host (nDNA, mtDNA, and GM).
COMPARING HEAT SHOCK PROTEIN LEVELS BETWEEN SIMILAR SPECIES OF DIFFERENT LONGEVITY
Friday, May 30, 2014
Heat shock proteins are involved in the hormetic response to mild levels of molecular damage, such as that induced by heat, in which cells increase their housekeeping and maintenance activities. If the damage is mild then the end result is a net gain: cells remain on alert and tissues are kept more free of damage and functional than would otherwise be the case. This ultimately translates into greater healthy longevity, and this effect can be observed by measuring levels of heat shock proteins in similar species with different life spans:
The longevity of an organism is directly related to its ability to effectively cope with cellular stress. Heat shock response (HSR) protects the cells against accumulation of damaged proteins after exposure to elevated temperatures and also in aging cells. To understand the role of Hsp70 in regulating life span of Daphnia, we examined the expression of Hsp70 in two ecotypes that exhibit strikingly different life spans.
Daphnia pulicaria, the long lived ecotype, showed a robust Hsp70 induction as compared to the shorter lived Daphnia pulex. Interestingly, the short-lived D. pulex isolates showed no induction of Hsp70 at the mid point in their life span. In contrast to this, the long-lived D. pulicaria continued to induce Hsp70 expression at an equivalent age.
We further show that the Hsp70 expression was induced at transcriptional level in response to heat shock. The transcription factor responsible for Hsp70 induction, heat shock factor-1 (HSF-1), although present in aged organisms did not exhibit DNA-binding capability. Thus, the decline of Hsp70 induction in old organisms could be attributed to a decline in HSF-1's DNA-binding activity. These results for the first time, present a molecular analysis of the relationship between HSR and life span in Daphnia.