FIGHT AGING! NEWSLETTER
August 26th 2013
The Fight Aging! Newsletter is a weekly email containing news, opinions, and happenings for people interested in aging science and engineered longevity: making use of diet, lifestyle choices, technology, and proven medical advances to live healthy, longer lives. This newsletter is published under the Creative Commons Attribution 3.0 license. In short, this means that you are encouraged to republish and rewrite it in any way you see fit, the only requirements being that you provide attribution and a link to Fight Aging!
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- Adding Healthy Decades to the Present Human Life Span
- Removing C1q in Mice Reduces Cognitive Decline With Aging
- Damaging the Biology of Mice to Make them Age More Rapidly Often Tells Us Little of Use
- A Two-Part Report on Global Futures 2045
- Latest Headlines from Fight Aging!
- A Human Interest Article on Cancer Immunotherapy
- The State of the Art in Misrepresenting Longevity Science
- David Sinclair on the Prospects for Longevity Science
- Arguing for Rapamycin to Slow Aging
- The Price of Complexity is a Loss of Superior Regeneration
- Considering Bat Longevity
- Restoring Autophagy as a Basis to Treat Macular Degeneration
- Calorie Restriction as a Means to Augment Cancer Therapies
- A Look Back at Some of the Roots of Modern Thought on Radical Life Extension
- The Next Few Years of Research Into Alzheimer's Disease
ADDING HEALTHY DECADES TO THE PRESENT HUMAN LIFE SPAN
With the recent publication of a fairly high profile survey on radical life extension, there has been more chatter than usual in the media and blogs on the topic of longevity science. That can only be a good thing: the more this subject is discussed, the more people will come to see healthy life extension through medical science as possible, plausible, and desirable. Greater public support is very much needed if we are to see the plausible means of human rejuvenation developed over the next few decades, soon enough to matter for those of us in the middle of life today.
Detailed plans for building therapies to lengthen the healthy human life span already exist, and a few organizations like the SENS Research Foundation are following those plans, but accomplishing this goal soon enough to matter is very much dependent on funding. There is little money for aging research in comparison to its importance to human health, let alone the small fraction of this research devoted to actually doing something about aging rather than just recording its effects or picking apart its mechanisms. Outside the work of the stem cell research community, some of which has relevance to reversal of aging, I'd be surprised to learn that more than $10 million / year is being spent on the foundations of rejuvenation therapies at this time.
(In comparison, efforts to slightly slow aging through drugs have probably consumed a billion dollars or more in the last decade, and with little to show for it. There are good reasons to think that rejuvenation research would be considerable less speculative and costly).
One thing I think that we'll see in the future is a growth in the number of media articles and public discussions that explicitly address one of the most important errors of belief regarding extending human life: people tend to think that medicine will make us older and decrepit for longer, rather than younger and healthier for longer, and this goes a long way towards explaining the lack of interest in extended life in the public at large. But this belief is false, as life extension is youth extension not old age extension. It has to be, because aging is damage at the level of cells and tissue structures, and the only meaningful ways to address aging involve repairing or preventing that damage. Less damage means that you are literally physically younger: less frail, with a lower risk of death, and greater vitality and function of your organs and biological systems.
More often these days I'm seeing media articles talk about this mistaken belief of extended frailty in the context of providing a correction: explaining that, no, researchers are in fact going to prolong youth or attempt to reverse the degenerations of aging by repairing the root causes of frailty and dysfunction. More of this sort of thing helps to lower the barrier presented by mistaken beliefs about longevity, opening the doors to greater growth in the number of people willing to materially support organizations like the SENS Research Foundation and their scientific work aimed at preventing and reversing aging and age-related disease. Here's a recent example of the sort of article I'm talking about:
Science could add decades to the average human lifespan
In a New York City laboratory, a handful of mice are poised to outlive their peers by the human equivalent of 20 years. Not only will they hang around longer, but their extended lives will be fuller. They'll recall maze patterns faster than other elderly mice. Their muscles and tendons will be stronger. Their bones will be denser, their skin more supple.
[Yet in a recent survey] more than two-thirds of Americans gave their "ideal lifespan" as between 79 and 100 years old, with just 8 per cent wanting to hit the century mark. The answers were nearly uniform across the board, with 18- to 29-year-olds being the least likely to idealize living to 100.
Dr. Gloria Gutman, who founded the Gerontology Research Centre at Simon Fraser University, suspects the tepid American response to long life was influenced by the question's lack of clarity on staying healthy. "The average person thinks in the stereotypical point of view that old means decrepit. But if you're looking at it as extending the vitality of living, then why not? If I have my mental and physical capacity, then why wouldn't I want to live to see how my kids are going to spend my money and how my grandchildren are going to turn out? ... None of us wants to be drooling in a nursing home."
At the Strategies for Engineered Negligible Senescence (SENS) Research Foundation in Mountain View, Calif., the thinking is that aging is a disease that can be controlled and "cured" through a variety of "rejuvenation biotechnologies," like a mechanic would keep a vintage car running indefinitely. The foundation spends millions of dollars a year on research to find ways to repair age-related damage to the body. An ongoing project seeks to extract "extracellular junk," malformed proteins that are no longer useful, from the brains of patients with Alzheimer's disease.
"Most people have this idea that aging is natural and sometimes desirable, and the idea that we would come along and defeat aging just doesn't compute," said the foundation's chief scientist, Dr. Aubrey de Grey, who believes aging and death are neither synonymous nor inevitable. Is he really saying immortality is possible? "Of course not, there are always trucks on the road," de Grey said to accentuate his belief that while there are many causes of death, aging does not have to be one of them.
Without aging, and with today's accident rates, we'd live for a thousand years or more. Plenty of time to figure out how to extend our healthy lives indefinitely.
REMOVING C1Q IN MICE REDUCES COGNITIVE DECLINE WITH AGING
The protein C1q is related to the processes of Wnt signaling, a name which might be more familiar to those who follow research into the molecular biochemistry and genetics of aging. Wnt shows up in all sorts of areas related to development and regeneration, and a range of research groups are investigating this area of biology. Levels of C1q increase with aging, and genetic engineering to remove C1q in mice was shown to be beneficial, producing an increase in regenerative capacity:
We here report that complement C1q activates canonical Wnt signaling and promotes aging-associated decline in tissue regeneration. Serum C1q concentration is increased with aging, and Wnt signaling activity is augmented during aging in the serum and in multiple tissues of wild-type mice, but not in those of C1qa-deficient mice. ... Skeletal muscle regeneration in young mice is inhibited by exogenous C1q treatment, whereas aging-associated impairment of muscle regeneration is restored by C1s inhibition or C1qa gene disruption.
More recent research now shows that eliminating C1q also reduces the mental decline associated with aging in mice. This might operate through similar underlying mechanisms to those that improve muscle regeneration, such as by a boost to the ability to generate new neurons and maintain neural tissue and blood vessels in the brain in better functioning condition.
A Dramatic Increase of C1q Protein in the CNS during Normal Aging
The decline of cognitive function has emerged as one of the greatest health threats of old age. Age-related cognitive decline is caused by an impacted neuronal circuitry, yet the molecular mechanisms responsible are unknown. C1q, the initiating protein of the classical complement cascade and powerful effector of the peripheral immune response, mediates synapse elimination in the developing central nervous system.
Here we show that C1q protein levels dramatically increase in the normal aging mouse and human brain, by as much as 300-fold. This increase was predominantly localized in close proximity to synapses and occurred earliest and most dramatically in certain regions of the brain, including some but not all regions known to be selectively vulnerable in neurodegenerative diseases, i.e., the hippocampus, substantia nigra, and piriform cortex.
C1q-deficient mice exhibited enhanced synaptic plasticity in the adult and reorganization of the circuitry in the aging hippocampal dentate gyrus. Moreover, aged C1q-deficient mice exhibited significantly less cognitive and memory decline in certain hippocampus-dependent behavior tests compared with their wild-type littermates.
DAMAGING THE BIOLOGY OF MICE TO MAKE THEM AGE MORE RAPIDLY OFTEN TELLS US LITTLE OF USE
Aging is damage: it is the accumulation of broken and obstructed protein machinery and nanoscale structures inside and around our cells. Living beings come with many varied repair systems, so the processes by which damage grows and eventually overwhelms those repair systems is far from straightforward. In that sense aging isn't like the wearing of stone by the weather, or the failure of a non-repairing mechanical system like a car - but it's still all about damage. At the highest level the same mathematical models of damage and component loss that work just fine as aids to understanding failure in complex non-repairing systems like electronics also work just fine for aging.
Every so often a research group feels the need to publicize work in which they damage mice or other laboratory species in ways that cause them to live shorter lives. There are many very subtle ways to alter genes, such as those involved in DNA repair, that produce what is arguably accelerated aging. (Though not everyone thinks that these forms of life span reduction are in fact accelerated aging, but that's a debate for another time and place). The point here is that I think you have to beware of taking it at face value that these research results are relevant to normal aging, or relevant to extending healthy life. You can damage mice with a hammer if you so choose, and it will certainly shorten their life spans, but examining the results won't tell you anything about aging. Similarly, it's the case that near all of the possible ways of interfering in mouse biology via genes and metabolic operation in order to reduce life span are just as irrelevant.
Here is an example of this sort of thing: researchers are producing mice with additional damage in their mitochondria, a component of cellular biology known to be important in all sorts of metabolic processes, and considered to be important in aging, and showing that these mice don't live as long. I don't think that the authors can show that they've proved much of relevance to aging with this study as constructed, however, for the reasons noted above.
Mutations of mitochondrial DNA can hasten offspring's ageing process
In ageing research, mitochondria have been scrutinized by researchers for a long time already. The mitochondria in a cell contain thousand of copies of a circular DNA genome. These encode, for instance, proteins that are important for the enzymes of the respiratory chain. Whereas the DNA within the nucleus comes from both parents, the mitochondrial DNA (mtDNA) only includes maternal genes, as mitochondria are transmitted to offspring via the oocyte and not via sperm cells. As the numerous DNA molecules within a cell's mitochondria mutate independently from each other, normal and damaged mtDNA molecules are passed to the next generation.
To examine which effects mtDNA damage exerts on offspring, researchers used a mouse model. Mice that inherited mutations of mtDNA from their mother not only died quicker compared to those without inherited defects, but also showed premature ageing effects like reduced body mass or a decrease in male's fertility. Moreover, these rodents were prone to heart muscle disease.
As the researchers discovered, mutations of mtDNA not only can accelerate ageing but also impair development: In mice that, in addition to their inherited defects, accumulated mutations of mtDNA during their lifetime, researchers found disturbances of brain development. They conclude that defects of mtDNA that are inherited and those that are acquired later in life add up and finally reach a critical number.
To show relevance, you really need to demonstrate life extension - meaning repair mechanisms for mitochondrial DNA rather than damage mechanisms should be the focus. To shorten life spans through various forms of damage is unlikely to provide anything more than hints and inference when it comes to ways to extend life.
A TWO-PART REPORT ON GLOBAL FUTURES 2045
The 2045 Initiative is a fairly young but comparatively well-backed effort to generate more support for and technological progress towards non-biological means of human life extension: artificial bodies, and ultimately artificial brains, built to be far more resilient and maintainable than our present evolved equipment. There is some debate over whether this is an efficient course in comparison to medical research, but that end of the futurist community already primarily interested in strong artificial intelligence seem to like where this is going.
There is a lot of fascinating groundwork in reverse-engineering the human brain presently under way, and it's clear that neuroscience is going to become an interesting place to be over the next few decades. However, I remain unconvinced that any of this is going to help us get over the initial hurdles to extending human longevity, meaning the frailty and short life span of the human body and physical structures that support the mind, soon enough to matter. Artificial intelligence and human minds running on machinery will certainly come to pass, and I will be surprised if the latter fails to happen in the laboratory prior to 2050 given the pace at which available processing power is growing. However, and this is important, over that time scale most of us doing the writing and the reading here and now are dead without some means of medical treatment for aging. This is one of the reasons why I pay less attention to neuroscience and mind-machine interface development than I do to repair biotechnologies for the causes of aging.
The Global Futures 2045 conference series is a part of the 2045 Initiative advocacy, and the most recent event took place a couple of months ago. I noted some of the media reports at the time. A two part report published earlier this month is quoted below and focuses more on the presentations than did past articles in the popular press, which I think is a good thing.
The world according to Itskov: Futurists convene at GF2045 (Part 1)
The development of brain-computer interfaces (BCIs) to allow paralyzed individuals to control various external prosthetic devices, such as a remote robotic arm, was another key topic at GF2045. A very recent example of the BCI research Carmena and Maharbiz discussed is Neural Dust: An Ultrasonic, Low Power Solution for Chronic Brain-Machine Interfaces. The theoretical pre-print paper proposes neural dust - thousands of ultra-miniaturized, free-floating, independent sensor nodes that detect and report local extracellular electrophysiological data - with neural dust power and communication links established through a subcranial interrogator. With the purpose being to enable "massive scaling in the number of neural recordings from the brain while providing a path towards truly chronic BMI," the researchers' goal is "an implantable neural interface system that remains viable for a lifetime."
In Making Minds Morally: the Research Ethics of Brain Emulation, Dr. Anders Sandberg - a Computational Neuroscientist, and James Martin Research Fellow at the Future of Humanity Institute at Oxford University, and Research Associate at the Oxford Neuroethics Center - addressed the social and ethical impact of cognitive enhancement and whole brain emulation. "We want to get to the future," Sandberg said in his talk, "but that implies that the future had better be a good place. Otherwise, there wouldn't be a point in getting there - but that would mean in turn that the methods we're going to use to get to the future had better be good as well."
The world according to Itskov: Futurists convene at GF2045 (Part 2)
Dr. Theodore Berger gave the most groundbreaking presentation of the Congress - one that also received a standing ovation. In Engineering Memories: A Cognitive Neural Prosthesis for Restoring and Enhancing Memory Function, Berger discussed his extraordinary research in the development of biomimetic models of hippocampus to serve as neural prostheses for restoring and enhancing memory and other cognitive functions. Berger and his colleagues have successfully replaced the hippocampus - a component of the cortex found in humans and other vertebrates that transforms short-term memory into long-term memory - with a biomimetic VLSI (Very Large-Scale Integrated circuit) device programmed with the mathematical transformations performed by the biological hippocampus.
Dr. Randal Koene, neuroscientist, neuroengineer and science director of the 2045 Initiative, has been focusing on the functional reconstruction of neural tissue since 1994. In his Whole Brain Emulation: Reverse Engineering A Mind presentation and soon-to-be published book with the same title, Koene describes the process of progressing from our current condition to a possible substrate-independent mind achieved by whole brain emulation and cites a wide range of research, including the work of fellow GF2045 presenters.
LATEST HEADLINES FROM FIGHT AGING!
A HUMAN INTEREST ARTICLE ON CANCER IMMUNOTHERAPY
Monday, August 19, 2013
This article is long on the human interest and short on scientific specifics, but is nonetheless an interesting look at the present state and potential for immunotherapies for cancer - one form of the coming generation of targeted cell destruction treatments. Therapies that can cure cancer in a fraction of even late stage patients have moved from the laboratory and into early trials in recent years, a progression that will continue and broaden:
Walt [was] in Philadelphia, where he'd come to be a guinea pig in a test of a new kind of cancer treatment. Leukemia had invaded his bone marrow and spread like a stain through his lymph nodes; the traditional options, including chemo and radiation, had failed. He was 58, and his body groaned with tumors potentially weighing as much as seven pounds. Walt needed something radically different if he was going to live. And the treatment he'd been given a few days ago was certainly that.
Over the past several years, a couple of hundred mice had received it, but Walt was only the seventh adult human. (Six men had preceded him, as well as a six-year-old girl.) The treatment wasn't a chemo drug, and it wasn't a vaccine. Instead, doctors at the University of Pennsylvania had tried to make Walt's own body the drug. In an approach known as gene therapy, they'd taken his own immune cells, modified them to give them new powers, and injected them back into his blood.
Scientists don't talk about "curing" cancer. A cure is the hope so great, so seemingly out of reach, that it must never be invoked. They've built a wall around the word. Still, the Penn researchers - as careful as they were, as professionally sober and skeptical - couldn't help but wonder: Was their small experiment the start of something that could one day affect thousands, tens of thousands, more? Was it revealing a secret about the human body that could point the way to treatments for other cancers, not just leukemia? There was no way to know until they gathered more data. They needed to show that the therapy was safe. And they needed to prove that the early patients - the men whose tumors they'd blasted away - weren't flukes.
Which is why so much now depended on Walter Keller. If Walt's condition improved and his tumors diminished, the trial would move forward, and the potential of the Penn therapy - the result of a decades-long quest of scientific passion and discovery - would continue to grow. But if he suffered harm, Penn would have to pause the trial and maybe stop it altogether.
THE STATE OF THE ART IN MISREPRESENTING LONGEVITY SCIENCE
Monday, August 19, 2013
When you read about a topic you know a great deal of in the mainstream media, you'll likely notice many errors and misrepresentations. You won't see that in topics you know less of, but those errors and misrepresentations are still there. A decent writer can make anything sound plausible and look good to someone only casually familiar with a field, even while he is omitting vital information or propagating outright falsehoods - either due to insufficient research or underlying agendas. Accuracy in media is fairly low in the list of priorities as a general rule.
Here is a good long-form example of the state of the art in misrepresentation of longevity science. All sorts of strategic omissions and outright misrepresentations are made on the work of specific scientists and the state of specific lines of research in those areas where I know enough to identify them, so I have to assume they are present elsewhere as well. Yet the piece reads as though a well-researched and constructed popular science article, and there's enough truth in there to float the falsehoods.
This is a time when we can grow human ears on the backs of mice and implant culture-grown lungs into rats. In the near future, specialists say, whenever we need replacement body parts, from blood vessels to bladders, we'll use rejection-proof artificial organs grown in laboratories using our own cells. "By putting in the parts you need, you'll be able to extend life by several decades," explains Anthony Atala, director of the Wake Forest Institute for Regenerative Medicine. "We may even push that up to 120, 130 years."
Bolstered by such promising discoveries, our understanding of aging is changing rapidly. Outside the field of organ regeneration, other genuine life-extending breakthroughs are being made in model test species. In 2011, Nature reported that dying worms yellow with a pigment called Thioflavin T (or Basic Yellow 1) makes them live 60 to 70 percent longer than the norm. There's more. Researchers are currently finding clues to longevity everywhere from Texan bat caves (where biochemists are investigating the role of misfolding proteins in long-lived bats) to the soil of Easter Island (where antifungal microbes known as rapamycin can raise the life expectancy of mice by 30 percent or more). Spermidine, a molecular compound found in human semen as well as grapefruit, has also been proven to significantly prolong the life span of worms, fruit flies, and yeast.
These strange-sounding experiments are yielding findings that could affect our lives. Will longevity research yield breakthroughs leading to immortality? Tinkering with the genes in yeast or roundworms has real effects on longevity in those species; that doesn't mean those genes will perform similarly in humans. And experiments on human cells in vitro do not guarantee similar functioning in vivo.
DAVID SINCLAIR ON THE PROSPECTS FOR LONGEVITY SCIENCE
Tuesday, August 20, 2013
David Sinclair of Sirtris leads research on a few lines of calorie restriction mimetic drug development based on sirtuins that I don't think have a hope of significantly impacting human aging. This is a part of a broader field, that of metabolic manipulation to slow aging, that I also don't think has much of a chance to significantly impact human aging within our lifetimes. Nonetheless, Sinclair is an optimist on the future of this field - which is understandable, given his choice to pursue it, but by this point, with a lot of sunk costs and little to show for it, there may be an element of talking up his position as well.
We can expect to see people live to 120 and beyond within our lifetime, a geneticist has told Insight. Harvard University's Professor David Sinclair is working on a 'cure for ageing' and believes modern medicine can significantly extend the human lifespan. "I think there will be a world where people can look forward to living at least beyond 100, and it will be not uncommon where people can live to 120. Every time we say that there's a natural limit, we develop technology to push us further."
Simple organisms, even yeast cells and fruit flies, have 'longevity genes' that can be switched on by low calorie diets and exercise, says Professor Sinclair. When these genes are 'switched on', they can protect the organism and help them live longer. "We have many of these genes in our bodies and we're just starting to learn that they do help us live longer and healthier."
Sinclair also tells Insight there are drugs already in clinical trials and, so far, they seem to be safe and showing early signs of success. "Instead of just lowering your cholesterol this pill would prevent Alzheimer's disease, lung diseases, bowel diseases, dementia, a whole list of diseases... That's what we're able to do in mice so far. The question is: can we do that in people, and how soon? No matter how much we say that it's good for you to be thin and to exercise, it doesn't seem to help for most people [to provide the motivation to actually get up and make that effort]. If we could have a simple pill that our doctor would prescribe to take with breakfast, that could help our lifestyle. I'm not saying we should just sit on the couch and get fat and take a pill, that's not the point. But we can supplement what our bodies naturally are doing to help keep us young."
ARGUING FOR RAPAMYCIN TO SLOW AGING
Tuesday, August 20, 2013
There is presently some debate over whether or not rapamycin actually slows aging - based on rigorous studies some researchers say yes, say no, it extends life in mice but only by reducing cancer risk. Rapamycin and various derivatives under development are presently the longevity enhancing drug candidates best supported by the evidence in laboratory mice, so there is probably a lesson to be learned here in regards to the soundness of the whole strategy of trying to slow aging via metabolic manipulation.
The researcher quoted here is a vocal proponent of one of the programmed theories of aging (the hyperfunction theory), so bear that in mind while reading his defense of rapamycin. His view is that it is absolutely the case that aging can be significantly impacted by intervening in genetic programs thought to be driving it, and suitable drugs are the first step on that road. This is the reverse of other side of the aging research community who see aging as caused by accumulated damage, and the accompanying metabolic changes as a reaction to that damage rather than its cause. Nonetheless there are some interesting arguments made here:
Making headlines, a thought-provocative paper by Neff, Ehninger and coworkers claims that rapamycin extends life span but has limited effects on aging. How is that possibly possible? And what is aging if not an increase of the probability of death with age. I discuss that the JCI paper actually shows that rapamycin slows aging and also extends lifespan regardless of its direct anti-cancer activities.
Found by chance on the mystical Easter island, the anti-aging drug rapamycin gave birth to numerous myths. This time, it is claimed that rapamycin prolongs lifespan and prevents aging-associated changes by aging-independent mechanisms, not by affecting aging itself. But what is then aging itself. Aging is an exponential increase of the probability of death with age. No one has died from health or without a cause. Most elderly humans die from age-related diseases, which are also called "natural causes", if a precise diagnosis is unnecessary. In mammals, death from aging means death from age-related diseases. Not only humans and other mammals but also aging worms and flies die from pathologies.
Age-related diseases are biomarkers of aging. The most common are cardiovascular diseases (associated with atherosclerosis, hypertension and cardiac hypertrophy), cancer, diabetes (and other complications of metabolic syndrome), Alzheimer and Parkinson diseases, macular degeneration and so on. Many manifestations of aging are not considered as diseases because they either develop in everyone (e.g. female menopause. The distinction is arbitrarily. For example, cancer-prone transgenic mice can exclusively die from cancer but still cancer is a disease.
Aging processes do not spring from nothing. They are continuations of normal cellular, tissue, organ and system functions in young animals. Unless miracle is possible, rapamycin must affect the same processes in old and young animals. And it does. Rapamycin extends life span independently of its anti-cancer effect and prevents cancer by slowing down aging. If rapamycin indeed prevents cancer by slowing aging (not by killing cancer cells), the prevention must be started before cancer is initiated. In other words, if rapamycin treatment is started too late in life, then its anti-cancer effect will be blunted. This was shown in cancer-prone p53+/- mice. The same was shown by Neff et al: rapamycin did not prevent cancer when the treatment was started at middle and old age. Thus, the JCI study confirms the notion that rapamycin delays cancer by slowing aging. Anti-cancer effects simply cannot be responsible for life extension by rapamycin.
THE PRICE OF COMPLEXITY IS A LOSS OF SUPERIOR REGENERATION
Wednesday, August 21, 2013
Many lower animals are capable of regenerating from near any injury, and in some species researchers struggle to find any signs that they are subject to degenerative aging. These are not complex creatures, however. Lacking a central nervous system or a brain and other complex organs implies the ability to be resilient and regrow tissues to a degree that a complex organism simply cannot match. This point was raised in comments on the possible agelessness of hydra, but there are other similar lower animals:
Hydractinia echinata has the power to regenerate any lost body part, can clone itself, does not age biologically, [and] "in theory - lives forever. Hydractinia has some stem cells which remain at an embryonic-like stage throughout its life. It sounds gruesome, but if it has its head bitten off, it simply grows another one within a few days using its embryonic or 'pluripotent' stem cells. So the potential for research is immense."
[Researchers have] discovered an unknown link between 'heat-shock' proteins and a cell-signalling pathway, known as Wnt signalling, in Hydractinia stem cells. "These two cellular signalling mechanisms are known to play important roles in development and disease, so they have been widely, though separately, studied. We have shown that they talk to each other, providing a new perspective for all scientists in this field. We found the link coincidentally - we weren't looking for it." Both the heat-shock proteins and Wnt signalling are known to be associated with cancer and cell growth. Hydractinia stem cells should be "very similar to their human counterparts and studying them may provide information on human stem cells."
"So why don't humans keep their pluripotent cells as adults? It's a good question. Keeping them in a complex body like ours is probably too dangerous, as they can easily form cancer. It's not so much a problem in simple animals - they would probably cut a cancer off. The price to become complex is to lose the ability to be immortal."
The great difference between a simple and a complex organism means that there may be little beyond knowledge to be extracted from these studies. We have evolved to lose regenerative capacity for reasons that probably have to do with the complexity of our structure - researchers can't simply port over the biology of lower animals to let our stem cells run rampant and expect positive results to follow. Improving human regeneration is something that will have to be carefully steered and controlled, as is the case in research presently taking place in the stem cell scientific community.
CONSIDERING BAT LONGEVITY
Wednesday, August 21, 2013
When investigating aging and longevity through comparing the biology of different species, one place to start is with the few species that are unusually long-lived in comparison to similarly-sized neighboring species. Hence the study of naked mole rats, which live nine times as long as other small rodents. Bats are also of interest, as they live much longer than other small active mammals. Digging into their biochemistry might tell researchers more about how the operation of mammalian metabolism determines longevity and the pace of aging. The results here, for example, may reinforce the role of growth hormone receptor (GHR) in the pace of aging:
Bats are among the most successful groups of animals. They account for ~20% of mammalian species, are the only mammals that have evolved powered flight, and are among the few animals that echolocate. Bats are also among the smallest of mammals, but are unusually long-lived, thus challenging the observed positive correlation between body mass and maximum lifespan. The Brandt's bat (Myotis brandtii) holds the record with regard to lifespan among the bats. Its reported maximal lifespan of at least 41 years also makes it the most extreme mammal with regard to disparity between body mass and longevity.
Here we report sequencing and analysis of the Brandt's bat genome and transcriptome, which suggest adaptations consistent with echolocation and hibernation, as well as altered metabolism, reproduction and visual function. Unique sequence changes in growth hormone and insulin-like growth factor 1 receptors are also observed. The data suggest that an altered growth hormone/insulin-like growth factor 1 axis, which may be common to other long-lived bat species, together with adaptations such as hibernation and low reproductive rate, contribute to the exceptional lifespan of the Brandt's bat.
It is prudent to ask whether the changes in the GHR/IGF1 axis in the Brand's bat contribute to the animal's long lifespan, its small body size or both. Although it is appreciated that other genes have been altered during the ~82 million years of bat evolution, we suggest that the changes observed in GHR and IGF1R contribute to the longevity and dwarfism-like phenotype of the Brandt's bat. Moreover, M. brandtii may mirror GHR dysfunction in mice and humans, and possibly insulin signalling in long-lived nematodes.
RESTORING AUTOPHAGY AS A BASIS TO TREAT MACULAR DEGENERATION
Thursday, August 22, 2013
The blindness of age-related macular degeneration is linked to the build up of lipofuscin in cells, a hardy collection of metabolic waste products that the body cannot effectively break down. Lipofuscin accumulates to cause progressive failure of the cellular recycling and maintenance mechanisms known as autophagy - this is due to failing lysosomes, a part of the autophagic machinery which becomes increasingly clogged and bloated by lipofuscin.
Macular degeneration is one of the better known manifestations of this process, but it happens in long-lived cells throughout the body. The SENS proposals for rejuvenation therapies include the use of bacterial enzymes to break down the components of lipofusin, so as to restore autophagy and remove this contribution to degenerative aging. The open access research into autophagy and macular degeneration quoted below supports the SENS view on how best to proceed:
A new [study] changes our understanding of the pathogenesis of age-related macular degeneration (AMD). The researchers found that degenerative changes and loss of vision are caused by impaired function of the lysosomal clean-up mechanism, or autophagy, in the fundus of the eye. The results open new avenues for the treatment of the dry form of AMD, which currently lacks an efficient treatment.
AMD is a storage disease in which harmful protein accumulations develop behind the retina. These accumulations are indicative of the severity of the disease. As the disease progresses, retinal sensory cells in the central vision area are damaged, leading to loss of central vision. The cell biological mechanisms underlying protein accumulations remain largely unknown.
For the first time ever, the present study showed that AMD is associated with impaired lysosomal autophagy, which is an important clean-up mechanism of the fundus of the eye. This renders the cells in the fundus of the eye unable to dispose of old, deformed or otherwise faulty proteins, which, in turn, leads to the development of protein accumulations and loss of vision. The study can be regarded as a breakthrough, as the results change our understanding of the pathogenesis of AMD and also open new avenues for the treatment of the dry form of AMD. Drugs inhibiting the impairment of autophagy could possibly even stop the progression of AMD.
CALORIE RESTRICTION AS A MEANS TO AUGMENT CANCER THERAPIES
Thursday, August 22, 2013
Long term calorie restriction lowers the risk of cancer in addition to extending life in laboratory animals. Here researchers show that short term calorie restriction appears to augment the effectiveness of treatments for an existing cancer:
While previous studies suggest a connection between caloric intake and the development of cancer, scientific evidence about the effect of caloric intake on the efficacy of cancer treatment has been rather limited to date. When humans and animals consume calories, the body metabolizes food to produce energy and assist in the building of proteins. When fewer calories are consumed, the amount of nutrients available to the body's cells is reduced, slowing the metabolic process and limiting the function of some proteins. These characteristics of calorie restriction have led researchers to hypothesize that reducing caloric intake could potentially help inhibit the overexpression of the protein Mcl-1, an alteration associated with several cancers.
Researchers conducted a series of experiments in mice developing lymphoma resembling Burkitt's lymphoma and diffuse large B-cell lymphoma, two human cancers of the white blood cells. The team began by separating the mice into two categories: those who would receive a regular diet and those who would receive a reduced-calorie diet (75 percent of normal intake) for the duration of the experiment. After the mice consumed either a regular or a reduced-calorie diet for one week, researchers then further divided the mice into four groups according to the treatment they would receive for the following 10 days. Of the two groups of mice that received a normal diet, one (the control group) did not receive treatment and the other received treatment with an experimental targeted therapy, ABT-737, designed to induce cancer cell death. Of the two groups of mice who received a reduced-calorie diet, one did not receive treatment and the other received ABT-737. On day 17 of the experiment, both treatment and calorie restriction ended, and mice had access to as much food as they desired.
Investigators observed that neither treatment with ABT-737 nor calorie restriction alone increased the survival of mice over that of the other mice; however, the combination of ABT-737 and calorie restriction did. Median survival was 30 days in the control group that received a regular diet and no treatment, 33 days in mice that received a regular diet and treatment with ABT-737, 30 days in mice that received a reduced-calorie diet without treatment, and 41 days in mice that received a reduced-calorie diet and treatment with ABT-737. Shortly after this experimental period, investigators also observed that the combination of calorie restriction and ABT-737 reduced the number of circulating lymphoma cells in the mice, suggesting that the combination sensitized the lymphoma cells to treatment.
A LOOK BACK AT SOME OF THE ROOTS OF MODERN THOUGHT ON RADICAL LIFE EXTENSION
Friday, August 23, 2013
The modern movements of transhumanism and support for longevity science have deep roots: you can find early expressions of the ideas of human enhancement and overcoming natural limits on our biology in a range of writings from past centuries. These ideas became more commonplace and more complex over time as the prospects for technology caught up with our desires:
Immanuel Kant (1724-1804) was an 18th century philosopher, one of the earliest philosophers belonging to the enlightenment tradition, and often considered the father of German Idealism. Kant is remembered today more for his moral philosophy than his contributions to metaphysics and epistemology (Rohlf 2010). His contributions to the field of life-extension, however, remain almost completely unexplored, despite the fact that certain claims made in his Theory of Ethics arguably qualify him as a historical antecedent of the contemporary social movement and academic discipline of life-extension.
Marquis du Condorcet (1743-1794), another historical antecedent the modern longevity movement, appears to have originated the "idea of progress" in the context of the enlightenment, which became an ideological cornerstone of the enlightenment tradition. In Sketch for a Historical Picture of the Progress of the Human Mind, Condorcet not only conceives of the idea of progress in perhaps the first form it would take within the enlightenment tradition, but also explicates its link to indefinite life-extension, which was not an existing movement or academic discipline at the time of his writing:
"Would it be absurd now to suppose that the improvement of the human race should be regarded as capable of unlimited progress? That a time will come when death would result only from extraordinary accidents or the more and more gradual wearing out of vitality, and that, finally, the duration of the average interval between birth and wearing out has itself no specific limit whatsoever? No doubt man will not become immortal, but cannot the span constantly increase between the moment he begins to live and the time when naturally, without illness or accident, he finds life a burden?"
It is this very notion of infinite progress towards endlessly-perfectible states, carried forward after Condorcet by Kant and other members of the enlightenment tradition, that also underlies Kant's own ties to the contemporary field of life-extension. Kant's claim, made in his Theory of Ethics, that to retain morality we must have comprehensively unending lives - that is, we must never, ever die - I will argue qualifies him as a historical antecedent of the contemporary life-extension movement.
THE NEXT FEW YEARS OF RESEARCH INTO ALZHEIMER'S DISEASE
Friday, August 23, 2013
A conservative view of what lies ahead for Alzheimer's disease (AD) research sees incremental progress resulting from new and better investigative biotechnologies:
In the recently published work "The Biology of Alzheimer Disease" (2012), most of what is known about AD today is described in detail. The book culminates in a chapter called Alzheimer Disease in 2020, where the editors extol "the remarkable advances in unraveling the biological underpinnings of Alzheimer disease...during the last 25 years," and yet also recognize that "we have made only the smallest of dents in the development of truly disease modifying treatments." So what can we reasonably expect over the course of the next 7 years or so? Will we bang our heads against the wall of discovery, or will there be enormous breakthroughs in identification and treatment of AD?
Though a definitive diagnosis of AD is only possible upon postmortem histopathological examination of the brain, a thorough review of the book leads me to believe that the greatest progress currently being made is in developing assays to diagnose AD at earlier stages. It is now known that neuropathological changes associated with AD may begin decades before symptoms manifest. This, coupled with the uncertainty inherent in a clinical diagnosis of AD, has driven a search for diagnostic markers. Two particular approaches have shown the most promise: brain imaging and the identification of fluid biomarkers of AD.
The authors anticipate that advances in whole-genome and exome sequencing will lead to a better understanding of all of the genes that contribute to overall genetic risk of AD. Additionally, improved ability to sense and detect the proteins that aggregate in AD and to distinguish these different assembly forms and to correlate the various conformations with cellular, synaptic, and brain network dysfunction should be forthcoming in the next few years. Lastly, we will continue to improve our understanding of the cell biology of neurodegeneration as well as cell-cell interactions and inflammation, providing new insights into what is important and what is not in AD pathogenesis and how it differs across individuals, which will lead, in turn, to improved clinical trials and treatment strategies.