FIGHT AGING! NEWSLETTER
July 9th 2012
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!
- A Lack of Biotechnology is the Only Limit on Human Longevity
- The All or Nothing Progress of Longevity Science
- Engineering Longevity in Nematodes
- Improving Cognition and Memory in Old Mice
- Latest Headlines from Fight Aging!
- Considering Mitochondrial Dynamics in the Context of Aging
- Stem Cell Transplant Explored as Alzheimer's Disease Therapy
- Nitric Oxide and Aging Blood Vessels
- Suggesting a Test of Rapamycin and Metformin Together
- Calorie Restriction Boosts Stem Cell Function
- Discussing IGF-1 and Heart Health in Mammals
- On Osteoarthritis
- AKH, Physical Activity, and Calorie Restriction Benefits
- A Different Argument for the Age-Dependence of Cancer
- Another Approach to Creating Blood Vessels in Engineered Tissue
A LACK OF BIOTECHNOLOGY IS THE ONLY LIMIT ON HUMAN LONGEVITY
As Aubrey de Grey notes, medicine is all about transcending the limits of biology. Where we have not yet transcended, such as in the matter of the maximum observed human life span, it is because the necessary biotechnology has not yet been developed:
"Are there limits on human longevity? Sure. Few people will make it past a hundred years of age in the environment of today's medical technology - but today is today, and the technology of tomorrow will be a different story. If you want to talk about longevity and mortality rates, you have to qualify your position by stating what sort of applied biotechnologies are available. Longevity is a function of the quality and type of medicine that is available across a life span.
"It so happens that most of the advances in medicine achieved over the course of human history, the vast majority of which have occurred in the past fifty years, have solved problems that killed people early in life. Infectious disease, for example, is controlled to a degree that would have been thought utopian in the squalor of Victorian England. The things that kill older people are a harder set of challenges: great progress has been made in reducing mortality from heart disease in the past few decades, for example, but that is just one late stage consequence of the complex array of biochemical processes that we call aging.
"The point of this discussion? It is that tremendous progress in medicine, including the defeat or taming of many varied causes of death and disability, has not greatly lengthened the maximum human life span as experienced in practice. The research community hasn't really started in earnest on the work on rejuvenation biotechnology that will achieve that end - the story of medicine to date has been work on other line items, or largely futile attempts to patch over the failure modes that lie at the end of aging.
"There are things that need to be fixed that currently limit human life span. Since aging is only an accumulation of damage, there is in fact a gentle trend towards extended life as a result of general improvements across the board in medicine - perhaps one year of additional life with every five years of technological progress at the present time. On average, people with access to the modern environment of technology and support are suffering biological damage at the level of cells and molecular machinery more slowly across their lives. But this incidental life extension is slow going indeed.
"Given this history of medical progress you will find many life science researchers and advocates who view the human life span as bounded - they look to past progress and extrapolate to assume that future progress can only carry on improving things within the existing human maximum life span. In other words that more and more people will live in good health closer to that maximum, but that the maximum is set in stone. There's even a name for this goal, 'compression of morbidity'.
"This is a ridiculous view when considered in the light of reliability theory and aging, but it is widely held and therefore something that advocates for rejuvenation biotechnology must work to dismiss. The future of medicine in the next few decades is not about gaining a decade of life with no hope of pushing out human life span beyond 120 years - it is about building the alpha versions of medical technologies that can provide indefinite healthy life spans through periodic repair of the known forms of cellular and molecular damage that cause aging. But unless many more people come to understand this point, there will continue to be the same lack of support for research that will lead to radical change in the relationship of medicine and aging."
THE ALL OR NOTHING PROGRESS OF LONGEVITY SCIENCE
We all win together or we all lose together - there is little middle ground in the development of new medical technologies:
"Competition drives progress, but put enough humans into any field and the successful groups will start to form cartels in order to keep their leading position without having to compete as hard for it. It is inherent in the human condition that we self-sabotage very well and very aggressively just as soon as we achieve enough success to feel somewhat elevated over our less fortunate peers. Who can even begin to guess how many opportunities have been wasted, how much potential technological progress has been lost thanks to these urges?
"The world of technology is now remarkably flat. The majority of the amenities of modern technology are available to the majority of the world: the descendants of peasants can fly for the same cost as the bloodlines of kings, cars and mobile phones are ubiquitous, and holding vast wealth doesn't in fact give a person any great and massive advantage over the middle class - or even the poor in wealthier regions - when it comes to the variety of available medical technology. Every new advance moves rapidly from being comparatively expensive, faulty, and scarce to being comparatively cheap, reliable, and widespread - whether we are talking about air conditioning or heart surgery, though the pernicious effects of regulation slow down the applications of biotechnology to a crawl in comparison to other lines of technological progress.
"One of the defining features of our age is the degree to which the very wealthy and the very connected use the same technologies as the rest of us. When new technology is developed we all win - it doesn't matter which research or development group got there first, because we will all have access soon enough. What does matter is how soon that new technology arrives, and that is a function of the size and level of competition in the research and development communities. ... The larger the community, the more healthy competition, the better the outcome and the faster the progress towards the end goal. When it comes to the biotechnology of rejuvenation we will either all win together or we all lose together - there is little in the way of middle ground in technological progress. That result is entirely determined by how fast we can create this sort of future medicine, such as that outlined in the SENS proposals."
ENGINEERING LONGEVITY IN NEMATODES
A ground of researchers roll up their sleeves and methodically build a range of genetically superior nematode worm species:
"If more life science researchers thought like engineers, we might see faster progress towards extended healthy longevity. One of the marks of pure engineering versus pure science is the willingness to pursue development of working solutions in the absence of full knowledge of the underlying principles. Both the Romans and the early British industrialists built superb bridges in the absence of a full understanding of structural and material science, not by chance but because they could deliberately and carefully use empirical knowledge to work around their ignorance of deeper scientific laws. So too there is much more room for empiricism in the development of medicine, and in longevity science in particular, than is presently practiced. In the scientific world, the favored next step following a demonstration of extended life in laboratory animals is to figure out every detail of how it works rather than explore the possibility of building a therapy - but both paths could be explored in parallel. In any case, here are results from a group of life science engineers, working with nematode worms:
"We have taken an engineering approach to extending the lifespan of Caenorhabditis elegans. Aging stands out as a complex trait, because events that occur in old animals are not under strong natural selection. As a result, lifespan can be lengthened rationally using bioengineering to modulate gene expression or to add [components from other species]. ... We overexpressed five genes that act in endogenous worm aging pathways, as well as two genes from zebrafish encoding molecular functions not normally present in worms. For example, we used zebrafish genes to alter mitochondrial function and innate immunity in ways not normally available to C. elegans and extended worm lifespan by ~40%. Next, we used a modular approach to extend lifespan by 130% by combining up to four components in the same strain. These results provide a platform to build worms having progressively longer lifespans.
"This project is conceptually similar to using engineering to increase the useful lifespan of a primitive machine (1931 Model T) using both parts from the model T as well as parts from a more advanced machine (2012 Toyota Corolla). Our results open the door to use engineering to go beyond the constraints of the C. elegans genome to extend its lifespan by adding non-native components."
IMPROVING COGNITION AND MEMORY IN OLD MICE
Separate research groups use different methods to improve brain functions in old mice:
"The researchers, appointed in the School of Medicine at The University of Texas Health Science Center San Antonio, added rapamycin to the diet of healthy mice throughout the rodents' life span. Rapamycin, a bacterial product first isolated from soil on Easter Island, enhanced learning and memory in young mice and improved these faculties in old mice, the study showed. 'We made the young ones learn, and remember what they learned, better than what is normal,' said Veronica Galvan, Ph.D., assistant professor of physiology at the Barshop Institute for Longevity and Aging Studies, part of the UT Health Science Center. 'Among the older mice, the ones fed with a diet including rapamycin actually showed an improvement, negating the normal decline that you see in these functions with age.'
"Given that rapamcyin was shown in that study to boost levels of neurotransmitters associated with neural plasticity, the first inclination would be to link the improved capabilities of the mice to increased growth and adaptability in neurons across the course of life. Further research will no doubt show whether that is a reasonable hypothesis."
"Researchers from the University of Heidelberg had injected a virus that contains extra copies of the gene responsible for creating DNA methyltransferase into the hippocampus, area of the brain responsible for memory, of elderly mice that were showing signs of diminished memory. Afterwards, the team gave the mice a series of memory tests such as showing the mice a new object to investigate for a period of time, taking it away and presenting them with the same object the next day along with another new object.
"Past studies showed that younger more able-minded mice will immediately begin investigating the newer object, while older mice will spend equal amounts of time investigating both objects, having seemingly forgotten that they'd already seen the object the day before. The research team found that once the older mice were injected with the virus, the elderly mice had spent most of their time, 70 percent of the time, investigating the new object, suggesting that an increase of the enzyme restored their faulty memories to its original capacity. However, when researchers halved the amount of DNA methyltransferase produced by younger mice, the memory abilities deteriorated to that of non-treated older mice."
The highlights and headlines from the past week follow below. Remember - if you like this newsletter, the chances are that your friends will find it useful too. Forward it on, or post a copy to your favorite online communities. Encourage the people you know to pitch in and make a difference to the future of health and longevity!
LATEST HEADLINES FROM FIGHT AGING!
CONSIDERING MITOCHONDRIAL DYNAMICS IN THE CONTEXT OF AGING
Friday, July 6, 2012
A herd of mitochondria exists in every cell, producing the ATP necessary to power that cell. Damage to mitochondria is important in aging, but how damage progresses in a cell's mitochondrial population is complicated by the fact that these are not completely discrete and static entities. They multiply like bacteria (fission), can merge with one another (fusion), and can also exchange individual components of their molecular machinery - so damage can be both passed around or mitigated depending on circumstances. Here researchers build models to better understand this dynamic: "Mitochondria are organelles that play a central role as 'cellular power plants'. The cellular organization of these organelles involves a dynamic spatial network where mitochondria constantly undergo fusion and fission associated with the mixing of their molecular content. ... Mitochondrial dynamics and mitophagy play a key role in ensuring mitochondrial quality control. Impairment thereof was proposed to be causative to neurodegenerative diseases, diabetes, and cancer. Accumulation of mitochondrial dysfunction was further linked to aging. Here we applied a probabilistic modeling approach integrating our current knowledge on mitochondrial biology allowing us to simulate mitochondrial function and quality control during aging ... We demonstrate that cycles of fusion and fission and mitophagy indeed are essential for ensuring a high average quality of mitochondria, even under conditions in which random molecular damage is present. Prompted by earlier observations that mitochondrial fission itself can cause a partial drop in mitochondrial membrane potential, we tested the consequences of mitochondrial dynamics being harmful on its own. Next to directly impairing mitochondrial function, pre-existing molecular damage may be propagated and enhanced across the mitochondrial population by content mixing. In this situation, such an infection-like phenomenon impairs mitochondrial quality control progressively. However, when imposing an age-dependent deceleration of cycles of fusion and fission, we observe a delay in the loss of average quality of mitochondria. This provides a rational why fusion and fission rates are reduced during aging and why loss of a mitochondrial fission factor can extend life span in fungi. We propose the 'mitochondrial infectious damage adaptation' (MIDA) model according to which a deceleration of fusion-fission cycles reflects a systemic adaptation increasing life span."
STEM CELL TRANSPLANT EXPLORED AS ALZHEIMER'S DISEASE THERAPY
Friday, July 6, 2012
Work on stem cell transplants in rats is outlined here: "Alzheimer's disease (AD) has been called the disease of the century with significant clinical and socioeconomic impacts. Epidemiological studies point out that AD affects 5% of the population over 65, and, parallel with increasing lifespan, the incidence of disease will rise dramatically. Clinically AD is characterized by a progressive learning capacity impairment and memory loss, especially memories of recent events ... Adult neural tissues have limited sources of stem cells, which makes neurogenesis in the brain less likely. Stem cells transplantation seems to be a promising strategy for treatment of several central nervous system (CNS) degenerative diseases such as AD, amyotrophic lateral sclerosis (ALS), and Parkinson's disease ... The present study aims to evaluate the effect of bone marrow mesenchymal stem cells (MSCs) grafts on cognition deficit in chemically and age-induced Alzheimer's models of rats. ... Two months after the treatments, cognitive recovery was assessed ... Results showed that MSCs treatment significantly increased learning ability and memory in both age- and [chemical]-induced memory impairment. Adult bone marrow mesenchymal stem cells show promise in treating cognitive decline associated with aging and [nucleus basalis magnocellularis] lesions."
NITRIC OXIDE AND AGING BLOOD VESSELS
Thursday, July 5, 2012
Nitric oxide levels are a possible target for therapies aimed at some of the signs of aging in blood vessels: "Many disorders emerge with advancing aging, and cardiovascular diseases (CVD) are a major cause of morbidity and mortality in the elderly. The term vascular aging encompasses all the structural and functional alterations in the blood vessels with progressive aging. Both smooth muscle cells and intima layers are affected. These vascular changes lead to endothelial dysfunction, arterial stiffness in consequence of intense remodeling and calcification, impaired angiogenesis, greater susceptibility to vascular injury and atherosclerotic lesions. The mechanisms underlying vascular aging are complex and involve multiple pathways and factors ... In this complex scenario, vascular function depends on the balanced production/bioavailability of nitric oxide (NO), which is maintained by the normal activity of endothelial nitric oxide synthase (eNOS). On the other hand, excessive amount of NO produced by inducible nitric oxide synthase (iNOS) up-regulation contributes to vascular dysfunction. Evidence obtained from experimental models indicates that decreased NO bioavailability as well as increased reactive nitrogen species (RNS) production contributes to aging-associated vascular dysfunction. ... Pharmacological modulation of NO generation and expression/activity of NOS isoforms may represent a therapeutic alternative to prevent the progression of cardiovascular diseases."
SUGGESTING A TEST OF RAPAMYCIN AND METFORMIN TOGETHER
Thursday, July 5, 2012
Rapamycin extends life in mice through mechanisms similar to those of calorie restriction, but has serious side-effects - though researchers are working to separate the positive mechanisms from the undesirable negative mechanisms. Metformin is also thought to be a calorie restriction mimetic drug, but the evidence for it to extend life in mice is mixed. Here, researchers suggest trying both drugs at the same time in the hopes that metformin blunts some of the side-effects of rapamycin: "Treatment with rapamycin, an inhibitor of mammalian target of rapamycin complex 1 (mTORC1) can increase mammalian life span. However, extended treatment with rapamycin results in increased hepatic gluconeogenesis concomitant with glucose and insulin insensitivity through inhibition of mTOR complex 2 (C2). Genetic studies show that increased life span associated with mTORC1 inhibition can be at least partially decoupled from increased gluconeogenesis associated with mTORC2 inhibition. Adenosine monophosphate kinase (AMPK) agonists such as metformin, which inhibits gluconeogenesis, [might] be expected to block the glucose dysmetabolism mediated by rapamycin."
CALORIE RESTRICTION BOOSTS STEM CELL FUNCTION
Wednesday, July 4, 2012
It is known that calorie restriction increases stem cell capacity in aging, thereby helping to maintain tissues for longer. From Extreme Longevity, a recent commentary on the mechanisms involved: "Like it or not food lovers, the single most effective known means of extending animal lifespan is through reducing daily caloric intake. Though not definitively proven in humans, the success of this intervention has been demonstrated in myriad species in more than 50 years of research. ... A protein called mTOR is responsible for this effect. mTOR combines with two other proteins to mediate several important cellular processes. These include translation of mRNA into protein, mitochondrial activity, and autophagy. Caloric restriction inhibits mTOR activity which leads to longer lifespan. The new studies [convincingly] demonstrate that reduction of mTOR activity causes preservation of stem cell health. They increase in abundance and proliferative potential. One study shows this occurs in intestinal cells, and the other in muscle cells. In the instestinal cell study, the authors showed that it was actually supporter cells called Paneth cells that aided the health of stem cells when they were taken from calorie restricted animals. They further showed this effect was mediated by mTOR inhibition and that it was achieved by increasing the activity of another protein called Bst1, important in cell proliferation. In the muscle study, calorie restricted animals had greater muscle stem cell proliferative capacity too. And this effect was also seen when the stem cells were transplanted into non calorically restricted animals, suggesting the microenvironment or niche around the stem cells was key. ... taken together, the two studies indicate that preserving and enhancing stem-cell function in multiple tissues is one of the ways in which calorie restriction slows the ravages of aging."
DISCUSSING IGF-1 AND HEART HEALTH IN MAMMALS
Wednesday, July 4, 2012
An open access commentary: "The mammalian heart must maintain its structural and functional integrity for decades, yet the response to damage in this vital organ is remarkably inadequate and often results in heart failure. Moreover, patients with chronic heart failure show profound metabolic changes, leading to peripheral abnormalities in addition to an initial cardiac impairment. Several evidences have suggested a relationship between the IGF-1 system and cardiovascular disease. Many cardiovascular risk factors, such as sedentary lifestyle, diabetes, smoking, oxidized low-density lipoprotein, obesity, psychological distress and reduced coronary flow reserve, have been associated with reduced IGF-1 levels. Conversely, human studies indicate that increased levels of IGF-1 are characterized by a decreased incidence of heart failure and mortality in elderly individuals. Nevertheless, the fact that IGF-1 can act either as a circulating hormone or as a local growth factor has confounded previous analyses of animal models in which transgenic IGF synthesized in extra-hepatic tissues was released into the circulation. Locally acting mIGF-1 isoform improves muscle regeneration and counters muscle wasting associated with diseases, including sarcopenia, muscular dystrophy and ALS. By contrast, circulating IGF-1 isoforms have been implicated in the restriction of lifespan and have contrasting effects on the heart when expressed as transgenes, variously promoting cell survival, or inducing prolonged hypertrophy with pathological consequences."
Tuesday, July 3, 2012
This open access review paper discusses what is known of osteoarthritis: "Half of all persons aged over 65 suffer from osteoarthritis (OA). As a matter of fact, age is the most prominent risk factor for the initiation and progression of OA. The common explanation for this is the cumulative effect of mechanical load over the years, resulting clinically in 'wear and tear' and pathologically in cartilagepathogenesis and progression of OA. Not only cartilage, but also subchondral bone, menisci, muscles as well as fat, and synovial tissues play an important role, notably in the early phase of OA. Therefore, OA has been referred to as a 'whole joint disease.' Despite a higher complexity, this concept has not only improved our understanding of the disease but also indicates potentially new treatment strategies. ... Inflammation in form of cellular infiltration of synovial tissue or subchondral bone and expression of inflammatory cytokines is more and more recognized as trigger of OA. It has been demonstrated that joint movement can exhibit anti-inflammatory mechanisms. Therefore physical activity or physiotherapy in the elderly should be encouraged, also in order to increase the muscle mass. A reduced stem cell capacity in the elderly is likely associated with a decrease of repair mechanisms of the musculoskeletal system. New treatment strategies, for example with mesenchymal stem cells (MSC) are investigated, despite clear evidence for their efficacy is lacking."
AKH, PHYSICAL ACTIVITY, AND CALORIE RESTRICTION BENEFITS
Tuesday, July 3, 2012
We know that autophagy seems to be required for calorie restriction to provide benefits to health and and longevity, and here researchers argue that exercise is also required: "Fruit flies on dietary restriction (DR) need to be physically active in order to get the lifespan extending benefits that come from their Spartan diet. ... flies on DR shift their metabolism toward increasing fatty acid synthesis and breakdown, specifically in muscle tissue. ... Dietary restriction is known to enhance spontaneous movement in a variety of species including primates, however this is the first examination of whether enhanced physical activity is necessary for its beneficial effects. This study establishes a link between DR-mediated metabolic activity in muscle, increased movement and the benefits derived from restricting nutrients. ... flies on DR who could not move or had inhibited fat metabolism in their muscle did not exhibit an extended lifespan. ... Our work argues that simply restricting nutrients without physical activity may not be beneficial in humans. ... The research also points to a potential target that could yield a drug that mimics the beneficial effects of DR. ... flies genetically engineered to overexpress the circulating peptide AKH (the fly equivalent of glucagon in mammals) showed increased fat metabolism, spontaneous activity and extended lifespan even though their diet was unrestricted. AKH plays a critical role in glucose and lipid metabolism. ... Our data suggests that DR may induce changes in muscle similar to those observed under endurance exercise and that molecules like AKH could serve as potential mimetics for DR that enhance activity and healthspan."
A DIFFERENT ARGUMENT FOR THE AGE-DEPENDENCE OF CANCER
Monday, July 2, 2012
The general view of cancer is that it occurs in the old because it depends on nuclear DNA mutations that accumulate over time - the more mutations, the greater the chance of one of them being suitable to trigger a cancer. Here a researcher argues that it has less to do with the number of mutations and more to do with the changing (and more damaged) state of tissue and systems in the body, which increases the ability of mutated cells to survive and prosper: "For evidence, DeGregori points first to the fact that by the time we stop growing in our late teens, we've already accumulated a large fraction of the mutations we will have in our lifetimes. 'There's a mismatch between the mutation curve and the cancer curve,' DeGregori says, meaning that if cancer were due to reaching a tipping point of, say, five or six mutations, we should see higher cancer rates in 20-year-olds, as this is when mutation rate is highest. Second, DeGregori points out that even healthy tissues are full of oncogenic mutations. 'These mutations are many times more common than the cancers associated with them,' DeGregori says. Simply, more mutations doesn't equal more cancer - not across the aging population and not even in specific tissues. DeGregori's final two points come from evolution. As we've evolved from one-celled, short-lived life forms into multicellular, long-lived humans, we've had to develop complicated machinery to maintain our tissues and avoid disease. 'But we're no better at preventing mutations than our yeast or bacteria cousins. You'd think if avoiding mutations was key to avoiding cancer, we'd be better at it than we are.' And finally, if these oncogenes were the evil super-villains they've been made out to be, capable of taking over surrounding tissue, then introducing oncogenes into mice stem cells should help rather than hurt these cells' survival. 'Rather, stem cells harboring the oncogenes tend to get weeded out,' says DeGregori. Instead of gathering mutations until they give us cancer, DeGregori says that as we age, the mechanisms that younger adults use to fight cancer, deteriorate. ... Our healthy cells are optimized for the conditions of our healthy, younger tissue. Change this balance, as does an oncogenic mutation, and they're no longer a perfect fit for the surroundings - healthy cells in young bodies quickly outcompete cells with cancerous mutations. But, 'when tissue is old, healthy cells are no longer a perfect fit, and mutations might help a cancer cell adapt in ways a healthy cell can't,' DeGregori says."
ANOTHER APPROACH TO CREATING BLOOD VESSELS IN ENGINEERED TISSUE
Monday, July 2, 2012
Many research groups are working on ways to overcome the challenge of generating suitable blood vessel networks for engineered tissue, as this is one of the major blocking issues in generating large tissue masses from scratch: "Researchers are hopeful that new advances in tissue engineering and regenerative medicine could one day make a replacement liver from a patient's own cells, or animal muscle tissue that could be cut into steaks without ever being inside a cow. Bioengineers can already make 2D structures out of many kinds of tissue, but one of the major roadblocks to making the jump to 3D is keeping the cells within large structures from suffocating; organs have complicated 3D blood vessel networks that are still impossible to recreate in the laboratory. Now [researchers] have developed an innovative solution to this perfusion problem: [rather] than trying to print a large volume of tissue and leave hollow channels for vasculature in a layer-by-layer approach, [they] focused on the vasculature first and designed free-standing 3D filament networks in the shape of a vascular system that sat inside a mold. As in lost-wax casting, a technique that has been used to make sculptures for thousands of years, the team's approach allowed for the mold and vascular template to be removed once the cells were added and formed a solid tissue enveloping the filaments. ... The researchers showed that human blood vessel cells injected throughout the vascular networks spontaneously generated new capillary sprouts to increase the network's reach, much in the way blood vessels in the body naturally grow. The team then created gels containing primary liver cells to test whether their technique could improve their function. ... Though these engineered tissues were not equivalent to a fully functioning liver, the researchers used cell densities that approached clinical relevance, suggesting that their printed vascular system could eventually be used to further research in lab-grown organs and organoids."