Fight Aging! Newsletter, April 28th 2014

April 28th 2014

The Fight Aging! Newsletter is a weekly email containing news, opinions, and happenings for people interested in aging science and engineered longevity: making use of diet, lifestyle choices, technology, and proven medical advances to live healthy, longer lives. This newsletter is published under the Creative Commons Attribution 3.0 license. In short, this means that you are encouraged to republish and rewrite it in any way you see fit, the only requirements being that you provide attribution and a link to Fight Aging!

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  • Working to Remove the Heaps of Unburnable Cellular Trash that Contribute to Degenerative Aging
  • Antisenescence Effects of Stem Cell Therapies
  • A Sampling of Recent Alzheimer's Research
  • The Threat of Sepsis in Old Age
  • Adult Stem Cells and the Diseases of Aging
  • Latest Headlines from Fight Aging!
    • Effective Tissue Adhesion With a Nanoparticle Solution
    • A View of the Correlation Between Individual Wealth and Adult Life Expectancy
    • An Interesting Comparison of Species Lifespan Differences
    • An Interview With Mikhail Batin
    • TFE3 Promotes Autophagy
    • How Cells Take Out the Trash
    • Altering Fat Metabolism to Inhibit Atherosclerosis
    • Data on the Aging of Stem Cells From Supercentenarian Blood
    • Blood Cells Reprogrammed into Blood Stem Cells
    • Neural Stem Cell Transplants as Stroke Treatment


Every cell in your body is a busy factory, constantly engaged in turning raw materials into complex proteins via the processes of gene expression, following the blueprints in your DNA. The source of much of the necessary supply of raw materials is the cell itself: a great deal of recycling takes place as damaged proteins and larger structures such as organelles are broken down into constituent molecules that are promptly fed back into the factory process.

This recycling isn't just a matter of obtaining parts: it is quality control for cellular machinery vital to life. Autophagy is the name given to the collection of processes by which unwanted and damaged cellular components are identified and then fed into the furnaces known as lysosomes. A lysosome is a specialized organelle packed with enzymes capable of dismantling near everything it is likely to receive in the course of its duties. It engulfs the refuse and destroys it, producing useful raw materials in the process.

With time, however, our lysosomes do in fact ingest a range of items that they cannot deal with. In our long-lived cells, many of which must last a lifetime, lysosomes become bloated and malfunctioning, packed to the gills with harmful materials collectively known as lipofusin. The ability of cells to keep themselves damage-free and functional deteriorates as a consequence, and this is one of the contributing causes of degenerative aging as a whole. It is particularly important in conditions such as macular degeneration, but a long laundry list of other age-related conditions - many of them ultimately fatal - have lysosomal dysfunction and lipofuscin accumulation noted as contributed causes.

We know that this happens, and we know that it causes great harm, but what can be done to prevent it and reverse it? To answer that question, here is the latest in a series of posts on rejuvenation research by philanthropist Jason Hope.

SENS Research Foundation Targets Lysosomal Aggregates

Cells create waste products and, left unaddressed, these byproducts disable body cells to cause serious illnesses. Scientists at SENS Research Foundation Research Center are currently developing ways to remove these waste products, known as lysosomal aggregates, from cells, in order to restore the cells to health and thereby treat these illnesses or prevent their onset. To understand the nature of the scientists' work, it helpful to create a working analogy that makes understanding lysosomal aggregates easier.

Lysosomal aggregates are like non-biodegradable plastic bags and other garbage rising over the tops of landfills to pollute nearby land. Left unaddressed, unhealthy substances from the garbage disrupt the lives of plants and animals surrounding the landfill to the point of causing disease and death to those organisms. The nature of the illness and disease depends largely on the type of waste polluting the landscape. Plastic bags might entangle a bird, for example, or antifreeze may poison a passing coyote. Each toxin causes a specific effect on a particular organism.

Each particular lysosomal aggregate tends to form in a specific type of body cell. When the amount of aggregate is large enough to interfere with normal cell function, the cell can no longer carry out its function, and as more and more cells of a given type become dysfunctional it leads to illness. Age-related macular degeneration, or AMD, is an excellent example of this action. Special cells in the retina of the eye, known as retinal pigment epithelium or RPE cells, produce the waste material A2E. Many scientists think the accumulation of A2E disables RPE cells to cause the vision loss associated with AMD.

The Lysosomal Aggregates team at SENS Research Foundation Research Center is working to identify optimal A2E-degrading enzymes, and to deliver them directly into the lysosomes in the eye. In their previous work, the team had been able to identify many enzymes capable of stopping A2E in a petri dish but was unable to deliver these enzymes into an actual lysosome in an eye. They are working to develop methods to deliver these enzymes to the lysosomes. One procedure in particular, known as SENS20, works both in vitro and in actual RPE cells, but others may work even better.

Lysosomal aggregates [are also] associated with atherosclerosis, commonly known as hardening of the arteries. Oxidation can cause breakdown of the "bad cholesterol" LDL in the bloodstream. This breakdown increases the levels of 7-ketocholesterol, or 7KC, known to cause the narrowed arteries and poor cardiac function associated with atherosclerosis. Researchers from Rice University are working to develop enzymes that reduce 7KC in hopes of reversing the processes that cause atherosclerosis.

SENS Research Foundation is making great strides in reducing the devastating health effects caused by lysosomal aggregates. With continued research, the scientists hope to someday treat or prevent widespread debilitating illnesses like age-related macular degeneration and atherosclerosis.


With advancing age ever more cells in your body enter a state of senescence. They stop dividing and emit signals that both degrade surrounding tissue structures and raise the odds of nearby cells also becoming senescent. This is an adaptation of a mechanism involved in embryonic development that lowers the odds of suffering cancer: senescent cells appear in response to cellular damage in a range of circumstances, and the types of damage that provoke cellular senescence either raise the risk of cancerous cells emerging or accompany a rising risk of cancer in normal aging. So cellular senescence is a part of the balance that evolution has come to in humans between declining ability to function on the one hand and fatal cancer on the other.

The research community, however, is going to become very good at dealing with cancer in the decades ahead. Cellular senescence isn't a great partner for a technologically sophisticated humanity, as the downside in aging very much outweighs whatever good is being done. For my money I think that the first generation of effective treatments that reverse the contribution of cellular senescence to degenerative aging will be blunt efforts that involve the targeted destruction of near-all senescent cells. This targeted destruction in fact goes on all the time in younger years, as one of the jobs of the immune system is to seek out and remove problem cells. Unfortunately like all biological systems it becomes damaged and disarrayed in later life, and alongside the damage that provokes a greater incidence of cellular senescence this is one of the reasons why the body accumulates ever more senescent cells as the years pass. We don't need these senescent cells, they can be removed, and we will benefit from their removal. The technologies used will be very similar to those already in trials for the targeted destruction of cancer cells: immune therapies, nanoparticles, engineered viruses, and so forth.

Later forms of treatment may be more sophisticated, however. Why destroy senescent cells if they can be reprogrammed into a non-senescent state? The field of cellular programming is still in its infancy at this point, and even the most impressive results are half happenstance and incompletely understood in the context of the bigger picture. Researchers throw compounds at cells to see what happens, and out of this assemble theories that inform the next set of efforts to throw compounds at cells to see what happens. Cells are enormously complex mechanisms, but from these efforts will eventually emerge a field in which any cell can be instructed to act as we want it to - even while within the body.

Stem cell treatments are leading to a greater knowledge of the mechanisms by which senescent cells might be coerced back into a more useful and functional state. Just as the delivery of stem cells causes regeneration by changing the local tissue environment and releasing signals that convince native cells to get back to work, it seems that this may also beneficially influence the balance of signals that leads to greater or lesser levels of cellular senescence. This possibility is illustrated in the following research using cell cultures. When researchers cultured and stressed their cell lines in the presence of signals emitted by stem cells, there was measurably less cellular senescence than was the case without those signals:

Rat Induced Pluripotent Stem Cells Protect H9C2 Cells from Cellular Senescence via a Paracrine Mechanism

Cellular senescence may play an important role in the pathology of heart aging. We aimed to explore whether induced pluripotent stem cells (iPSCs) could inhibit cardiac cellular senescence via a paracrine mechanism.

We collected iPSC culture supernatant as conditioned medium (CM) for the rat cardiomyocyte-derived cell line H9C2. Then we treated H9C2 cells, cultured with or without CM, with hypoxia/reoxygenation to induce cellular senescence and measured senescence-associated β-galactosidase (SA-β-gal) activity, G1 cell proportion and expressionM of the cell cycle regulators p16INK4a, p21Waf1/Cip1 and p53 at mRNA and protein levels in H9C2 cells. In addition, we [measured] concentrations of trophic factors in iPSC-derived CM.

We found that iPSC-derived CM reduced SA-β-gal activity, attenuated G1 cell cycle arrest and reduced the expression of p16INK4a, p21Waf1/Cip1 and p53 in H9C2 cells. Furthermore, the CM contained more trophic factors, e.g. tissue inhibitor of metalloproteinase-1 and vascular endothelial growth factor, than H9C2-derived CM.

[We conclude that] paracrine factors released from iPSCs prevent stress-induced senescence of H9C2 cells by inhibiting p53-p21 and p16-pRb pathways. This is the first report demonstrating that antisenescence effects of stem cell therapy may be a novel therapeutic strategy for age-related cardiovascular disease.


Alzheimer's disease is one of the few areas of research into age-related conditions that needs comparatively little assistance at this time: public awareness of the issue of dementia is growing and so is support for greater funding. The research community is already large and energetic, and at least some well-funded groups are working on technologies - such as immune therapies aimed at removal of amyloid deposits - that will probably be of use to other efforts to reverse the causes of aging. This avalanche is well underway.

All that said, it is still a very complex problem as yet comparatively poorly understood, for all that tangible progress is taking place year after year. Much like cancer research, I expect to see Alzheimer's research - already large in comparison to much of the rest of the field of aging research - grow further to consume a great deal of funding, spur the accelerating development of biotechnology, and generate much new knowledge of the intricate relationship between metabolism and aging, as well as the fine details of the operation of the human brain. Below you'll find two fairly representative samples of recent research from the Alzheimer's research community.

Loss of Memory in Alzheimer's Mice Models Reversed through Gene Therapy

[Researchers] have discovered the cellular mechanism involved in memory consolidation and were able to develop a gene therapy which reverses the loss of memory in mice models with initial stages of Alzheimer's disease. The therapy consists in injecting into the hippocampus - a region of the brain essential to memory processing - a gene which causes the production of a protein blocked in patients with Alzheimer's, the "Crtc1" (CREB regulated transcription coactivator-1). The protein restored through gene therapy gives way to the signals needed to activate the genes involved in long-term memory consolidation.

In persons with the disease, the formation of amyloid plaque aggregates, a process known to cause the onset of Alzheimer's disease, prevents the Crtc1 protein from functioning correctly. "When the Crtc1 protein is altered, the genes responsible for the synapses or connections between neurons in the hippocampus cannot be activated and the individual cannot perform memory tasks correctly this study opens up new perspectives on therapeutic prevention and treatment of Alzheimer's disease, given that we have demonstrated that a gene therapy which activates the Crtc1 protein is effective in preventing the loss of memory in lab mice".

A new approach to treating Alzheimer's disease

Cellular processes are not perfect. They, like us, make mistakes. Sometimes, the by-products of those mistakes are harmless. Other times, they can lead to disease or even death. With Alzheimer's disease, the mistake occurs when a protein called amyloid precursor protein (APP) in a neuron's membrane is cut in the wrong place, leading to a buildup of abnormal fragments called amyloid-beta. These fragments clump together to form a plaque around neurons, eventually interfering with brain function.

But the cell has systems to deal with mistakes. A protein complex called retromer acts like a cellular garbage truck, collecting faulty gene products and trafficking them to be destroyed or recycled. For years, Alzheimer's research has focused on preventing the formation of amyloid-beta with little success. But instead of trying to stop mistakes, what if researchers improved the system for dealing with them? A team of researchers [did] just that. They have devised a novel approach to the treatment of Alzheimer's disease that significantly increases retromer levels while decreasing amyloid-beta levels in neurons, without harming the cell.

Pharmacological chaperones stabilize retromer to limit APP processing

Retromer is a multiprotein complex that trafficks cargo out of endosomes. The neuronal retromer traffics the amyloid-precursor protein (APP) away from endosomes, a site where APP is cleaved into pathogenic fragments in Alzheimer's disease. Here we determined whether pharmacological chaperones can enhance retromer stability and function.

First, we relied on the crystal structures of retromer proteins to help identify the 'weak link' of the complex and to complete an in silico screen of small molecules predicted to enhance retromer stability. Among the hits, an in vitro assay identified one molecule that stabilized retromer against thermal denaturation. Second, we turned to cultured hippocampal neurons, showing that this small molecule increases the levels of retromer proteins, shifts APP away from the endosome, and decreases the pathogenic processing of APP.

These findings show that pharmacological chaperones can enhance the function of a multiprotein complex and may have potential therapeutic implications for neurodegenerative diseases.


Sepsis is a disastrous runaway failure state of the immune system and metabolism that can occur in the wake of a severe infection. It leads to organ failure and can rapidly kill you even if the infection that caused it is dealt with. Sepsis is more of a looming threat for the old than the young, those with age-damaged immune systems and other frailties. For all this, it isn't something that receives all that much attention in comparison to other common fatal age-related conditions such as heart failure and cancer. With that in mind, here is an open access paper that provides an overview of the present state of knowledge of sepsis, while introducing us to the gloomy situation that exists with regards to treatment options for sepsis in the old:

Sepsis in Old Age: Review of Human and Animal Studies

Sepsis is a serious problem among the geriatric population as its incidence and mortality rates dramatically increase with advanced age. Despite a large number of ongoing clinical and basic research studies, there is currently no effective therapeutic strategy that rescues elderly patients with severe sepsis. Recognition of this problem is relatively low as compared to other age-associated diseases.

Sepsis has been the tenth leading cause of death in patients over the age of 65 in the US since 2001. Older people make up a greater proportion (58-65%) of sepsis patients, and both incidence and mortality rates are significantly greater in the aged. Importantly, in addition to increased mortality rates for the elderly, older sepsis patients die earlier during hospitalization, and those that do survive often require additional care in long-term nursing facilities to regain functional status.

A recent study evaluated long-term mortality in elderly severe sepsis patients (only those surviving at three months post sepsis were included) and found an overall mortality rate of 55% with a 30.6% one-year morality rate and a 43% two-year mortality rate. This means that more than half of the elderly patients who survive sepsis through hospital discharge will be dead within two years.

The authors here suggest that many of the present issues in the sepsis research community - lack of progress towards more effective treatments foremost among them - stem from a poor choice of animal models used in studies.

The incidence of sepsis increases exponentially from childhood to geriatric age with a magnitude of approximately 100-times. Mortality from sepsis also increases progressively with age. The incidence of sepsis is steadily increasing as our population ages. Despite these problems, little is known about the pathophysiology of sepsis which is specific to older patients.

Sepsis patients, in addition to being a heterogeneous population, have large variations in disease course factors including severity, source of infection, comorbidities, and timing of hospital admission. While caution has to be paid for biological differences between men and rodents, the use of laboratory animals is essential for understanding the detailed pathophysiology of sepsis.

Despite the fact that there is clearly an increased precedence of elderly patients suffering from sepsis, the majority of basic research on sepsis has been conducted using young animals. This mismatch introduces a serious disconnect in interpretation of sepsis studies using mice or men because most humans with sepsis are over 50 years old, and most mice used in sepsis research are less than 3 months old, comparable to a person under 20 years of age.

For example, immune responses to infection are clearly altered by aging, thus, the use of aged animals in sepsis research would provide important information that would greatly differ from data obtained using young animals. The number of studies on sepsis using aged animals (i.e. rodents) is surprisingly small. By utilizing the PubMed journal search engine, we estimate that among all published studies using animal models of sepsis, less than 1% used appropriately aged animals.

The paper goes into greater detail as to noteworthy differences in the progression and character of sepsis between young and old individuals, and explains why these differences matter in practice. It's worth reading the whole thing.


Most of your tissues are in a constant state of flux, the cells within a mix of those destroying themselves after dividing too many times, those dividing to create new cells to make up the numbers, and a smaller flow of fresh cells with many divisions remaining that are created by a small population of stem cells. Some tissues turn over their cell populations very rapidly, such as blood or the lining of the gut. Others consist largely of cells that will last as long as you live, such as much of the central nervous system. In all these cases, however, an embedded population of stem cells supports continued maintenance and function. If stripped of stem cells you would crumble into premature death in perhaps a decade or so.

That said, aging is effectively a process of being stripped of stem cells in addition to all of its other detrimental consequences. The maintenance of tissues diminishes degree by degree with the years until organs and systems fail, eventually fatally. Modern research suggests that, for those tissues where there is good data, the stem cells are still largely present, however. They have simply relinquished their jobs, lapsing into lasting quiescence or senescence in response to rising levels of damage. This set of affairs most likely evolved as a cancer suppression mechanism, our natural life span a balance between risk of death by tissue failure versus risk of death by over-active damaged cells spawning a cancer.

Experiments in moving stem cells between young and old tissue environments suggest that most types of old stem cells examined to date are quite ready to get back to work - and even do their jobs effectively despite their age - if only the signals present in their environment instructed them to do so. It is expected that if one could wave a wand in old humans and restore stem cells in all tissues to youthful activity, the result would be a lot of cancer in addition to improved tissue maintenance, however. Still, temporarily altering specific signals to boost stem cell activity has great potential as a therapy for the near future, with raised risk of cancer compensated for by an increasing effectiveness in cancer detection and treatment. First generation stem cell transplants are in effect a way of making native cells do more than they would otherwise have done by adjusting the balance of signals in the affected tissues. In years ahead more sophisticated methods will be used to achieve better and more controlled results in the same vein.

Ultimately the goal of rejuvenation by repair of cellular and molecular damage will hopefully automatically lead to restoration of stem cell activities. If the damage goes away, so too should the signaling environment that is a response to that damage.

Here is a readable review paper on stem cells present in adult tissues and their relationship to aging. There is a lot of detail packed in there, so take a look at the whole thing:

Adult Stem Cells and Diseases of Aging

Adult stem cells serve to replenish and direct repair at sites of tissue injury throughout the body, and exhaustion of dysfunction of an adult stem cell population in vivo with age results in degenerative disease. Several finely tuned and contextually regulated pathways coordinate the activities of tissue-resident adult stem cell pools over time in response to a host of cellular stressors in an effort to maintain the balance between growth-promoting function and oncogenic resistance. Manipulation of one or more of these pathways has the potential to prevent or reverse the impact of advancing age on adult stem cell function, but is fraught with the difficulty of tipping the balance toward metabolic derangement, or more likely toward cancer formation. Harvest and manipulation of adult stem cells ex vivo for use in regenerative medicine is a piecemeal approach to addressing systemic age-related chronic illnesses, but for now may prove to be a safer approach. In this regard, it is noteworthy that the clinical safety of hematopoietic stem cells (HSCs) and mesenchymal stem cells (MSCs) has been well documented, not in the least on the basis of decades of successful clinical outcomes of heterologous bone marrow transplantation.

Given the growing evidence that many diseases of aging may reflect adult stem cell exhaustion, it is not surprising there is great interest in restoring adult stem cell function to ameliorate these conditions and regenerate aged tissues. Adoptive transfer of fetal MSCs into adult mice has been shown to extend median lifespan of the animals. Adult stem cell mobilization and transplant are two obvious strategies that have achieved moderate success for certain types of injury and disease in humans, and many types of adult stem cells have been utilized for this purpose. MSC cellular therapy has proven to be safe for a number of vascular disorders and is an attractive option for patients who are poor surgical candidates.

Despite these successes, the problem remains that adult stem cells from elderly donors, the very people who most frequently require enhanced peripheral stem cell function for tissue repair, undergo changes in their functional capacity as a result of aging. This decline in functional capacity, therefore therapeutic utility, has been combatted using some surprisingly simple interventions: Conditioning with hypoxia prior to transplant, for example, has been extensively documented as effective for reducing reactive oxygen species production by adult stem cells and improving their therapeutic efficacy in many in vivo ischemia and other disease models. This has proven sufficient to counteract the impaired oxidative stress resistance of MSCs from elderly donors.

Further development of therapeutic approaches to maintain these cells in vivo requires that the mechanistic basis of their age-related degeneration or renewal be understood. This is an area continually being informed by studies of early-onset aging syndromes and of families exhibiting extreme longevity. Transcriptional reprogramming, which effectively wipes away all signs of age from most cell types, is also yielding valuable insights into what makes a cell young or old. Rejuvenating stem cells to stave off aging safely will require highly innovative approaches, but the results of this research will have far-reaching implications for regenerative medicine.


Monday, April 21, 2014

Researchers have developed an improvement upon sutures that has a range of potential applications beyond merely sealing injuries:

The principle is simple: nanoparticles contained in a solution spread out on surfaces to be glued bind to the gel's (or tissue's) molecular network. This phenomenon is called adsorption. At the same time the gel (or tissue) binds the particles together. Accordingly, myriad connections form between the two surfaces. This adhesion process, which involves no chemical reaction, only takes a few seconds. In their latest, newly published study, the researchers used experiments performed on rats to show that this method, applied in vivo, has the potential to revolutionize clinical practice.

In a first experiment, the researchers compared two methods for skin closure in a deep wound: traditional sutures, and the application of the aqueous nanoparticle solution with a brush. The latter is easy to use and closes skin rapidly until it heals completely, without inflammation or necrosis. The resulting scar is almost invisible.

In a second experiment, still on rats, the researchers applied this solution to soft-tissue organs such as the liver, lungs or spleen that are difficult to suture because they tear when the needle passes through them. At present, no glue is sufficiently strong as well as harmless for the organism. Confronted with a deep gash in the liver with severe bleeding, the researchers closed the wound by spreading the aqueous nanoparticle solution and pressing the two edges of the wound together. The bleeding stopped. To repair a sectioned liver lobe, the researchers also used nanoparticles: they glued a film coated with nanoparticles onto the wound, and stopped the bleeding. In both situations, organ function was unaffected and the animals survived.

"Gluing a film to stop leakage" is only one example of the possibilities opened up by adhesion brought by nanoparticles. In an entirely different field, the researchers have succeeded in using nanoparticles to attach a biodegradable membrane used for cardiac cell therapy, and to achieve this despite the substantial mechanical constraints due to its beating. They thus showed that it would be possible to attach various medical devices to organs and tissues for therapeutic, repair or mechanical strengthening purposes.

Monday, April 21, 2014

A web of correlations links health, longevity, wealth, education, and intelligence. More intelligent and educated people tend to be wealthier. They also tend to live longer. All sorts of sensible causes can be proposed, such as those involving better access to medical services and a better ability to make use of that access, or the education, willpower, and peer pressure to make improved lifestyle choices. Don't get fat, keep exercising, and so forth: over the long term calorie restriction and regular exercise produce benefits to health and life expectancy in the average individual that are large in comparison to that provided by any presently available medical technology. There are less usual suggestions as well, such as the possibility of a biological connection between better health and greater intelligence.

Biology and health is very complex, and there is plenty of room to argue cause versus effect and relative impact even in deceptively simple associations such as these. The data showing these associations is robust, however, and here is another example:

[Economists] crunched the numbers and found that the richer you are, the longer you'll live. [They] parsed this data from the University of Michigan's Health and Retirement Study, a survey that tracks the health and work-life of 26,000 Americans as they age and retire. The data is especially valuable as it tracks the same individuals every two years in what's known as a longitudinal study, to see how their lives unfold.

The good news is that men of all incomes are living longer. Yet the data shows that the life expectancy of the wealthy is growing much faster than the life expectancy of the poor. Here's the sort of detail this remarkable data set can show. You can look at a man born in 1940 and see that during the 1980s, the mid-point of his career, his income was in the top 10% for his age group. If that man lives to age 55 he can expect to live an additional 34.9 years, or to the age of 89.9. That's six years longer than a man whose career followed the same arc, but who was born in 1920. For men who were in the poorest 10%, they can expect to live another 24 years, only a year and a half longer than his 1920s counterpart.

The story is rather different for women. At every income level, for both those born in 1920 and 1940, women live longer than men. But for women, the longevity and income trends are even more striking. While the wealthiest women from the 1940s are living longer, the poorest 40% are seeing life expectancy decline from the previous generation. "At the bottom of the distribution, life is not improving rapidly for women anymore. Smoking stands out as a possibility. It's much more common among women at lower income levels."

Tuesday, April 22, 2014

One branch of investigation into the mechanisms and progression of aging uses comparisons between species of differing longevity as a way to identify where to work. The ultimate aim is to narrow down the exact biological differences between short-lived and long-lived species, a process that can probably be simplified by focusing first on the exceptional cases.

Surveys and theorizing of the sort quoted below are a part of the process of deciding which of the thousands of readily available species to study are most likely to yield useful information:

Maximum lifespan in birds and mammals varies strongly with body mass such that large species tend to live longer than smaller species. However, many species live far longer than expected given their body mass. This may reflect interspecific variation in extrinsic mortality, as life-history theory predicts investment in long-term survival is under positive selection when extrinsic mortality is reduced. Here, we investigate how multiple ecological and mode-of-life traits that should reduce extrinsic mortality (including volancy (flight capability), activity period, foraging environment and fossoriality), simultaneously influence lifespan across endotherms.

Using novel phylogenetic comparative analyses and to our knowledge, the most species analysed to date (n = 1368), we show that, over and above the effect of body mass, the most important factor enabling longer lifespan is the ability to fly. Within volant species, lifespan depended upon when (day, night, dusk or dawn), but not where (in the air, in trees or on the ground), species are active. However, the opposite was true for non-volant species, where lifespan correlated positively with both arboreality and fossoriality. Our results highlight that when studying the molecular basis behind cellular processes such as those underlying lifespan, it is important to consider the ecological selection pressures that shaped them over evolutionary time.

Those of you following along over the past decade or so as researchers picked out exceptional species in order to investigate the details of their biochemistry will not be too surprised to see flight linked with longevity. Bats and birds feature prominently in the lists of species with unusual longevity for their size, and there are a range of theories as to how the metabolic demands of flight might lead to the evolution of a longer-lived species.

Tuesday, April 22, 2014

Here is a Russian-language interview with Mikhail Batin of the Science for Life Extension Foundation, following on from the recent 3rd International Conference on the Genetics of Aging and Longevity in Sochi, Russia. The state of automated translation for Russian is still very rough around the edges, so the quoted material below is tidied up somewhat from the original:

Q: But with diseases such as cancer, cardiovascular disease, and diabetes, they occur not only in the old, but also in young people. What are your arguments that old age is a disease?

A: Well, the frequency of cancer in a person of age 70 is 200 times higher than at 20 years. All age-dependent disease incidence increases with age, and grows exponentially. Aging underlies these diseases. We just tend to think that it is normal when a person goes bad, developing poor vision, poor hearing, poor thinking - and this is not normal. Aging is an illness and people die because of it.

Q: Actually, people do not want to grow old, especially women. And those who have enough willpower to lead a healthy lifestyle, eat right, play sports. And experience shows that it is, in general, it helps them to get sick less and live longer. So, maybe that's enough? Need there any special measures to combat aging?

A: It helps, but not so much. Even the person leading a healthy lifestyle does not rule out the use of antibiotics, early diagnosis of diseases, etc. Yes, you need to eat less and move more, but that does not mean you cannot also do something significant, for example, to develop the means of reversing some processes of aging not affected by exercise and diet. The idea of ​​sufficiency is bad, let's instead go ahead and set big goals.

Q: And if people don't want to live long? There was a survey of Americans in which they were asked how much they want to live. Most chose a limit of 80-90 years. And to live to 120 years old is only desired by a few. So what to do - "an iron fist pounding mankind to happiness" or work to educate the public in order to change this position?

A: You know, people often want what other people want. This is common. They do not want to stand out from the masses. So people protect the present state of their world, it's such a conquering conservatism. Yet as soon as the radical possibilities to extend life emerge and become common, people will immediately want to use them. People do not refuse technology, they just do not want to think about making it.

Wednesday, April 23, 2014

Autophagy is the name given to a collection of processes that recycle damaged cellular components and unwanted or harmful molecules. Materials flagged for recycling are engulfed by one of the cell's lysosomes and then dismantled inside it. Greater levels of autophagy are observed in a majority of the means of extending life in laboratory animals through genetic or metabolic manipulation to slow aging, including calorie restriction, in which the body reacts to low levels of nutrients, raw materials for protein manufacture in cells, by stepping up its efforts to reclaim the needed raw materials from existing structures that are past their prime.

The association of enhanced longevity and enhanced autophagy shouldn't be a surprise: aging is the accumulation of unrepaired damage, and autophagy is a process that attempts to minimize the present level of cellular damage before it can cause more harm. At some point the research community will make inroads towards creating therapies based on boosted autophagy - though this doesn't appear to be happening anywhere near as rapidly as I expected it to. Here is an example of research into the regulation of autophagy, similar to many other papers published in past years, but the expected use of this sort of knowledge to build a treatment has yet to happen:

The discovery of a gene network regulating lysosomal biogenesis and its transcriptional regulator transcription factor EB (TFEB) revealed that cells monitor lysosomal function and respond to degradation requirements and environmental cues. We report the identification of transcription factor E3 (TFE3) as another regulator of lysosomal homeostasis that induced expression of genes encoding proteins involved in autophagy and lysosomal biogenesis [in] response to starvation and lysosomal stress.

We found that in nutrient-replete cells, TFE3 was recruited to lysosomes through interaction with active Rag guanosine triphosphatases (GTPases) and exhibited mammalian (or mechanistic) target of rapamycin complex 1 (mTORC1)-dependent phosphorylation. Phosphorylated TFE3 was retained in the cytosol through its interaction with the cytosolic chaperone 14-3-3. After starvation, TFE3 rapidly translocated to the nucleus and bound to the CLEAR (Coordinated Lysosomal Expression and Regulation) elements present in the promoter region of many lysosomal genes, thereby inducing lysosomal biogenesis.

Depletion of endogenous TFE3 entirely abolished the response [of] cells to starvation, suggesting that TFE3 plays a critical role in nutrient sensing and regulation of energy metabolism. Furthermore, overexpression of TFE3 triggered lysosomal exocytosis and resulted in efficient cellular clearance in a cellular model of a lysosomal storage disorder, Pompe disease, thus identifying TFE3 as a potential therapeutic target for the treatment of lysosomal disorders.

Wednesday, April 23, 2014

Autophagy consists of a collection of cellular housecleaning processes responsible for recycling damaged cellular components. It is known to relate to longevity, as demonstrated in numerous animals studies in which aging is slowed via genetic or metabolic manipulation, and in which autophagy is seen to take place more energetically. This all seems logical, as aging is nothing more than an accumulation of unrepaired damage and the reactions to that damage, while autophagy seeks to minimize present damage before it causes more harm.

Since we've already touched on of autophagy and its relationship to longevity today, as well as the prospects for developing therapies based on increased levels of autophagy, I thought I'd point out this popular science article on the topic:

To keep themselves neat, tidy and above all healthy, cells rely on a variety of recycling and trash removal systems. If it weren't for these systems, cells could look like microscopic junkyards - and worse, they might not function properly.

One of the cell's trash processors is called the proteasome. It breaks down proteins, the building blocks and mini-machines that make up many cell parts. The barrel-shaped proteasome disassembles damaged or unwanted proteins, breaking them into bits that the cell can re-use to make new proteins. In this way, the proteasome is just as much a recycling plant as it is a garbage disposal.

Proteins aren't the only type of cellular waste. Cells also have to recycle compartments called organelles when they become old and worn out. For this task, they rely on an organelle called the lysosome, which works like a cellular stomach. Containing acid and several types of digestive enzymes, lysosomes digest unwanted organelles in a process termed autophagy.

While cells mainly use proteasomes and lysosomes, they have a couple of other options for trash disposal. Sometimes they simply hang onto their trash, performing the cellular equivalent of sweeping it under the rug. Scientists propose that the cell may pile all the unwanted proteins together in a glob called an aggregate to keep them from gumming up normal cellular machinery. If the garbage can't be digested by lysosomes, the cell can sometimes spit it out in a process called exocytosis. Once outside the cell, the trash may encounter enzymes that can take it apart, or it may simply form a garbage heap called a plaque. Unfortunately, these plaques outside the cell may be harmful, too.

Further study of the many ways cells take out the trash could lead to new approaches for keeping them healthy and preventing or treating disease.

Thursday, April 24, 2014

This is an intriguing result, though it is worth noting that - per the published paper - it was carried out in animals genetically altered to rapidly develop atherosclerosis. This is a common approach in exploratory studies: use a model in which the disease process runs more rapidly than normal, so as to bring down costs and time, but it opens the possibility for a potential treatment to only undo some of the effects of the model rather than actually working against the normal, much slower disease mechanisms. So the next step in this case is to run the experiment in unmodified laboratory animals and see what happens:

Working with mice and rabbits, [scientists] have found a way to block abnormal cholesterol production, transport and breakdown, successfully preventing the development of atherosclerosis, the main cause of heart attacks and strokes and the number-one cause of death among humans. The condition develops when fat builds inside blood vessels over time and renders them stiff, narrowed and hardened, greatly reducing their ability to feed oxygen-rich blood to the heart muscle and the brain.

[Researchers] identified and halted the action of a single molecular culprit responsible for a range of biological glitches that affect the body's ability to properly use, transport and purge itself of cholesterol - the fatty substance that accumulates inside vessels and fuels heart disease. The offender, the researchers say, is a fat-and-sugar molecule called glycosphingolipid, or GSL, which resides in the membranes of all cells, and is mostly known for regulating cell growth. Results of the experiments, the scientists say, reveal that this very same molecule also regulates the way the body handles cholesterol.

The [team] used an existing man-made compound called D-PDMP to block the synthesis of the GSL molecule, and by doing so, prevented the development of heart disease in mice and rabbits fed a high-fat, cholesterol-laden diet. The findings reveal that D-PDMP appears to work by interfering with a constellation of genetic pathways that regulate fat metabolism on multiple fronts - from the way cells derive and absorb cholesterol from food, to the way cholesterol is transported to tissues and organs and is then broken down by the liver and excreted from the body.

Thursday, April 24, 2014

Researchers may gain some insight into the aging of stem cells and the relevance (or irrelevance) of nuclear DNA damage to aging from the analysis of blood and tissue donated by a supercentenarian:

Our blood is continually replenished by hematopoietic stem cells that reside in the bone marrow and divide to generate different types of blood cells, including white blood cells. Cell division, however, is error-prone, and more frequently dividing cells, including the blood, are more likely to accumulate genetic mutations. Hundreds of mutations have been found in patients with blood cancers such as acute myeloid leukemia (AML), but it is unclear whether healthy white blood cells also harbor mutations.

In this new study, the authors used whole genome sequencing of white blood cells from a supercentenarian woman to determine if, over a long lifetime, mutations accumulate in healthy white blood cells. The scientists identified over 400 mutations in the white blood cells that were not found in her brain, which rarely undergoes cell division after birth. These mutations, known as somatic mutations because they are not passed on to offspring, appear to be tolerated by the body and do not lead to disease. The mutations reside primarily in non-coding regions of the genome not previously associated with disease, and include sites that are especially mutation-prone such as methylated cytosine DNA bases and solvent-accessible stretches of DNA.

By examining the fraction of the white blood cells containing the mutations, the authors made a major discovery that may hint at the limits of human longevity. "To our great surprise we found that, at the time of her death, the peripheral blood was derived from only two active hematopoietic stem cells (in contrast to an estimated 1,300 simultaneously active stem cells), which were related to each other. Because these blood cells had extremely short telomeres, we speculate that most hematopoietic stem cells may have died from 'stem cell exhaustion,' reaching the upper limit of stem cell divisions." Whether stem cell exhaustion is likely to be a cause of death at extreme ages needs to be determined in future studies.

Friday, April 25, 2014

As researchers continue to work on cellular reprogramming, we will see an increasing number of new research results like this one. A compelling reason for this type of work is to secure low-cost and reliable sources of large numbers patient-matched cells, grown from easily obtained tissue samples such as skin and blood:

[Scientists] have reprogrammed mature blood cells from mice into blood-forming hematopoietic stem cells (HSCs), using a cocktail of eight genetic switches called transcription factors. The reprogrammed cells, which the researchers have dubbed induced HSCs (iHSCs), have the functional hallmarks of HSCs, are able to self-renew like HSCs, and can give rise to all of the cellular components of the blood like HSCs. The findings mark a significant step toward one of the most sought-after goals of regenerative medicine: the ability to produce HSCs suitable for hematopoietic stem cell transplantation (HSCT) from other cell types, in particular more mature or differentiated cells.

The success of any individual patient's HSCT is tied to the number of HSCs available for transplant: the more cells, the more likely the transplant will take hold. However, HSCs are quite rare. "HSCs only comprise about one in every 20,000 cells in the bone marrow. If we could generate autologous HSCs from a patient's other cells, it could be transformative for transplant medicine and for our ability to model diseases of blood development."

In a series of mouse transplantation experiments, [the team found that] Hlf, Runx1t1, Pbx1, Lmo2, Zfp37 and Prdm5, Mycn, and Meis1 were sufficient to robustly reprogram two kinds of blood progenitor cells (pro/pre B cells and common myeloid progenitor cells) into iHSCs. [The] team reprogrammed their source cells by exposing them to viruses containing the genes for all eight factors and a molecular switch that turned the factor genes on in the presence of doxycycline. They then transplanted the exposed cells into recipient mice and activated the genes by giving the mice doxycycline.

The resulting iHSCs were capable of generating the entire blood cell repertoire in the transplanted mice, showing that they had gained the ability to differentiate into all blood lineages. Stem cells collected from those recipients were themselves capable of reconstituting the blood of secondary transplant recipients, proving that the eight-factor cocktail could instill the capacity for self-renewal - a hallmark property of HSCs.

Friday, April 25, 2014

Researchers here demonstrate that neural stem cells transplanted into aged rats following stroke are an effective enough treatment to be considered, and thus an old tissue environment is not a barrier to deriving benefit from such stem cell transplants:

Neural stem cells (NSCs) show therapeutic potential for ischemia in young-adult animals. However, the effect of aging on NSC therapy is largely unknown. In this work, NSCs were transplanted into aged (24-month-old) and young-adult (3-month-old) rats at 1 day after stroke. Infarct volume and neurobehavioral outcomes were examined. The number of differentiated NSCs was compared in aged and young-adult ischemic rats and angiogenesis and neurogenesis were also determined.

We found that aged rats developed larger infarcts than young-adult rats after ischemia. The neurobehavioral outcome was also worse for aged rats comparing with young-adult rats. Brain infarction and neurologic deficits were attenuated after NSC transplantation in both aged and young-adult rats. The number of survived NSCs in aged rats was similar to that of the young-adult rats and most of them were differentiated into glial fibrillary acidic protein+ (GFAP+) cells. More importantly, angiogenesis and neurogenesis were greatly enhanced in both aged and young-adult rats after transplantation compared with phosphate-buffered saline (PBS) control, accompanied by increased expression of vascular endothelial growth factor (VEGF).

Our results showed that NSC therapy reduced ischemic brain injury, along with increased angiogenesis and neurogenesis in aged rats, suggesting that aging-related microenvironment does not preclude a beneficial response to NSCs transplantation during cerebral ischemia.


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