Fight Aging! Newsletter, May 19th 2014

May 19th 2014

The Fight Aging! Newsletter is a weekly digest of news and commentary for thousands of subscribers interested in the latest longevity science: both the road to future rejuvenation and the present understanding of what works and what doesn't work when it comes to extending healthy life. Expect to see summaries of recent advances in medicine, news from the longevity science community, advocacy and fundraising initiatives to help advance rejuvenation biotechnology, links to online resources, and much more.

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  • SENS Research Foundation Newsletter for May 2014
  • Moving Beyond Stem Cells as a Basis For Regeneration
  • Working to Reverse Age-Related Loss of Elasticity in Tissues
  • The Slowly Spreading Realization that Aging Can Be Defeated
  • Genetic Determinants of Longevity Are Very Complex
  • Latest Headlines from Fight Aging!
    • Selection Effects of Human Longevity Genes are Decreasing
    • The Fear of Growing Old: Tithonus and Centenarians
    • Examining Mitochondria in Long-Lived Individuals
    • Shorter Men Have a Longer Life Expectancy
    • Reinforcing Microtubules as an Alzheimer's Treatment
    • Early Calorie Restriction Extends Life in Mice
    • Sensing Lack of Water Extends Life in Flies
    • Chronic Obstructive Pulmonary Disease is not an Age-Related Condition
    • Neural Precursor Cells Induce Repair of Myelin Loss in Mice
    • Induced Pluripotent Stem Cell Therapy Tested in Primates


The SENS Research Foundation is one of the few organizations in the world at present earnestly coordinating work on the biotechnologies needed to create treatments to halt and reverse degenerative aging. It is, like many disruptive, game-changing groups in medical research, almost entirely funded by philanthropic donations, many of which were provided by long-time readers here.

One of the ugly little secrets in life science research is that it is near impossible to obtain funding for anything other than small, incremental advances in which all of the proving work has already been accomplished on someone else's dime. New leaps in medical research are thus dependent on a mix of philanthropy and very creative budgeting. Hence when the medical community has stultified and needs to be kicked and pestered into a new era of improvement, as has been the case for aging research for at least two decades, don't look to the big established organizations to produce that change. They have suffered the fate of all establishments, ossified to the point of being incapable of revolutionary advances, or even actively resisting such change. Almost all such advances thus initially arrive from small groups that grow outside the mainstream flow of funds, making their cases incrementally, until all of a sudden there is a great shift in the tides and everyone does things the new way.

Would that there were more persistent cellular-repair-oriented initiatives like SENS aiming to upend the research community, so as to raise the odds of the great shift in aging research happening in any given year. But I think they will arrive in time. To work on repair of the causes of aging is so obvious a concept in hindsight that I don't think it can go ignored for too much longer, especially given the steadily growing interest it this field in the past few years.

The latest SENS Research Foundation newsletter arrived in my in-box today, bearing a reminder about the Rejuvenation Biotechnology Conference to be held later this year. For me, however, the best part of the newsletter is the section in which quality answers are provided to questions about the science of SENS submitted by Foundation supporters.

Question Of The Month #3: Making SENS Part Of Medicine

Q: I understand that aging specifically isn't an accepted target for therapy for regulatory purposes at present. How, then, will you get non-experimental therapies utilizing regenerative medicine techniques for the specific pathology of aging available to the common consumer?

A: That isn't nearly as big a challenge as is often portrayed. Remember, the damage-repair approach of SENS isn't an all-in-one treatment with the indication "aging," but a divide-and-conquer strategy to develop a suite of rejuvenation biotechnologies that each remove, repair, replace, or render harmless one of many specific form of cellular and molecular damage that accumulate in aging bodies. Thus, no one rejuvenation biotechnology will arrest or reverse the degenerative aging process or prevent all of its diseases and disabilities. Ironically, then, even if regulators were to develop an indication for "aging," individual rejuvenation biotechnologies wouldn't qualify!

By contrast, most forms of aging damage can be quite clearly linked with specific diseases of aging: beta-amyloid protein and malformed tau species for Alzheimer's; lysosomal aggregates in the arterial macrophage/foam cell with atherosclerosis (and through it heart attacks and stroke); cross-linked proteins with hypertension (and through it congestive heart failure, renal disease, and stroke); alpha-synuclein and Parkinson's disease; and so on.

In other cases, rejuvenation biotechnologies could initially be licensed as treatments for certain genetic disorders, even though the cause of the pathology underlying those diseases may not be related to the universal degenerative aging process. This is true, for instance, for most mitochondriopathies (inherited disorders of the mitochondria, many of which are caused by mutations in individual protein-encoding mitochondrial genes). Even though the mutations in these patients are inherited rather than acquired as a result of later metabolic mishaps, the same damage-repair approach (allotopic expression of the protein from the nucleus) can be used to replace the missing or defective protein in the mitochondrial energy-production chain and restore normal cellular function.

So the great majority of rejuvenation biotechnologies - and probably all of them - can be developed as therapies for diseases that are either already accepted as licensable indications, or in a few cases are very likely to be accepted soon (notably, sarcopenia (the loss of muscle mass and quality with aging)). Whether degenerative aging is "a disease" or not, and whether it is recognized as such by regulators, is of no consequence to the practical business of turning rejuvenation biotechnology into therapies against its associated conditions.


One can draw a timeline of stem cell research that has stem cell therapies in the modern sense emerging as an evolution of bone marrow transplantation: as biotechnology became more sophisticated researchers identified the agents producing beneficial effects in these treatments, meaning the stem cells found in bone marrow, and from there got rid of much of the baggage to create a new generation of better and more focused therapies. This sketch is a gross oversimplification of a complex period of development in medical science, but will suffice for this post.

Today, as stem cell therapies are becoming a mainstream commercial concern, entering the phase of growth and improvement that attends the heyday of every technology, researchers are already laying the groundwork for the next evolution in this series of treatments. For just as stem cells are the agents of change identified in bone marrow, so too are various signaling proteins the agents of change that might be identified in stem cells. The bone marrow was dispensed with once biotechnology was up to the task and in the next round of progress so too will be the cells.

While not true (or at least not yet proven) for all stem cell treatments, it has become increasing clear in recent years that many cell transplants produce benefits not because the transplanted cells are themselves doing much in the way of building or shoring up tissue, but rather because they are altering the local signaling environment in ways that instruct native cells to get back to work - or even to perform works of regeneration that they never would have accomplished under normal circumstances. So what prevents researchers from throwing out the cells today and just using the signals? The fact that these signaling changes are still very poorly understood. Inroads are being made, and you might recall recent work on the roles of GDF-11 or FGF-2 in this vein, but they are still just inroads.

Here is an open access example of exploration in the this direction, a task well suited to the modern tools of biotechnology, focused on the measurement and cataloging of protein levels and epigenetic patterns. The cost of these tools has dropped so precipitously this past decade that I imagine matters will progress quite rapidly towards an index of all of the regenerative signals of consequence altered by stem cell transplants.

Mechanisms of action of hESC-secreted proteins that enhance human and mouse myogenesis

Adult stem cells persist in the body as we age, but their regenerative capacity declines over time, leading to an inability of tissues and organs to maintain homeostasis and repair damage with advancing age. Old skeletal muscle loses its regenerative ability due to the failure of satellite cells (muscle stem cells) to divide and generate fusion competent myoblasts and terminally differentiated myofibers in response to muscle injury or attrition.

Previous studies have demonstrated that aging of the stem cell niche is responsible for the decline of tissue regeneration and productive homeostasis not only in skeletal muscle but also in a variety of postnatal tissues, and that old muscle can be rejuvenated to repair almost as well as young through several means. These findings may prove to be important for the development of therapies for age-related tissue degeneration and trauma. However, not all of the factors that influence the niche are known, and the various physiological molecules and balance of signaling crosstalk that modulate healthy regeneration are not well established. In addition, while numerous approaches have been utilized to reverse age-related tissue deterioration in murine models, none are suitable for clinical translation. As one example, skewing the signaling strength of one pathway (either up or down) over a long timespan is likely to be deleterious for cells and tissues, potentially leading to more cellular dysregulation or oncogenic progression. In contrast, modulation of multiple interactive signaling pathways to their "youthful" levels may have beneficial effects on tissue repair and maintenance.

Our initial study demonstrated that embryonic stem cells produce soluble proteins that robustly enhance adult muscle stem cell function even in an aged environment, and that production of such proteins is lost when these cells differentiate. Furthermore, the MAPK pathway was determined to be critical in modulating the activity of these embryonic protein(s). These findings are supported by microarray analysis conducted on cardiomyocytes subjected to hESC-conditioned medium, demonstrating that MAPK pathway signaling was among the main induced signaling cascades. Here we uncover the molecular identity of active hESC-produced proteins and demonstrate that specific FGFs are sufficient to enhance mouse and human myogenesis.

While FGFs had significant effects on cell proliferation of human and mouse myogenic progenitors, antibody neutralization of FGF-2, FGF-6 or FGF-19 did not significantly reduce the pro-myogenic properties of hESC conditioned medium, [suggesting that] many other active growth factors and MAPK ligands are secreted by the hESCs. Ultimately, the precise molecular definition of most of the pro-regenerative proteins from the hESC secretome will allow one to design optimal therapeutic applications with low off-target and side effects.


Philanthropist Jason Hope is of late writing a series of posts on SENS, the Strategies for Engineered Negligible Senescence. SENS is both a research program and an initiative for change in medical research: the aim is to produce the applications of biotechnology needed to create actual, real, working rejuvenation treatments. Which is to say forms of medicine that can bring aging under control by repairing the known causes of degeneration, the damage in and between cells that causes age-related disease and ultimately death. A sufficiently good implementation of this suite of repair treatments will prevent the young from becoming old, and restore the old to good health and vigor - but even partial treatments and early prototypes will provide sufficient benefits to merit commercial developments.

This is the vision, and at present the SENS Research Foundation works on making this a reality with a modest yearly budget of a little more than $4 million dollars and a network of allies within the advocacy and life science communities. This involves identifying those areas in which the present efforts are lacking, or the tools are absent, or no-one is making enough of an effort, and stepping in to bridge that gap using some combination of funding and persuasion.

It is sad to say, but - once you look beyond the fields of stem cell and cancer research - gaps are more or less all there is to see. Meaningful progress towards other needed forms of rejuvenation treatment is conspicuous by its absence. In comparison to stem cell research, the initiatives elsewhere in what will one day be a much broader field of regenerative medicine are sparse, a lab here and a lab there dabbling in matters like mitochondrial repair or building AGE-breakers, to pick two examples. This is far from the energetic and well funded research centers needed for a good rate of progress.

Jason Hope put in half a million dollars a few years ago to help get work underway to bridge one of these research gaps, that related to breaking down the cross-links that build up in important tissue structures with age. This form of damage has detrimental results that include a loss of tissue elasticity that contributes to a range of age-related conditions, yet the life science research community is present ill-equipped to work with the most relevant cross-link compounds in any meaningful way. Here Hope discusses some of the ongoing research that he has funded:

Extracellular Matrix Stiffening

The extracellular matrix acts as a sort of scaffolding that provides support and cushioning to the surrounding cells. The extracellular matrix, or ECM, is an interlinking mesh of fibrous proteins and a few other substances that make the matrix both strong and elastic. The extracellular matrix is very resilient and, in a perfect world, changes very little from the time you are born until you die. In this imperfect world inside the human body, however, blood sugar and other substances bathe the proteins and other compounds of the extracellular matrix. This constant exposure causes unhealthy crosslinks to develop between ECM proteins.

This crosslinking limits the flexible, independent movement of the proteins in the extracellular matrix in that area, causing stiffness and a loss of shock absorption. In time, crosslinking in the extracellular matrix causes it to lose its primary function, leading in turn to dysfunction in the cells, tissues and organs it serves.

Breaking these ECM crosslinks reverses the damage and prevents further pathology. Breaking heart and arterial ECM crosslinks, for example, can reverse stiffening in the heart and blood vessels. In 2011, SENS Research Foundation and the Cambridge University Institute of Biotechnology announced the establishment of a new SENS Research Foundation Laboratory at Cambridge. A targeted donation enabled scientists in the Cambridge SENS center and Dr. David Spiegel's Yale lab to investigate various solutions to glucosepane crosslinks.

One of the first challenges to breaking unhealthy ECM crosslinks is to detect their presence. Dr. Spiegel has developed a technique to synthesize glucosepane in a laboratory. Researchers can now use this synthesized glucosepane to develop reagents capable of detecting glucosepane crosslinking. Scientists can then use those reagents as an aide in the development and testing of new glucosepane-breaking drugs.

Progress in this area could also enable the Cambridge group to develop a method to deal with another major obstacle in breaking ECM crosslinks  -  measuring glucosepane cleavage, first in the test tube then in animal and human tissues. Researchers can use this method to determine the effect a candidate drug has on breaking glucosepane crosslinks. In the course of their research, the Cambridge researchers have already concluded that none of the commercially available methods for detecting crosslinks effectively detects glucosepane  -  and they aren't particularly good at detecting other crosslinks, either! In fact, many of the ECM antibodies currently in use do not even bind to crosslinks.

The findings of both Dr. Spiegel's group and the Cambridge group underscore the need for novel crosslink-breaking therapies. The work performed by both groups further our efforts in developing novel anti-crosslink therapies.


At some point in the next ten to twenty years the public at large, consisting of people who pay little attention to the ins and outs of progress in medicine, will start to wake up to realize that much longer healthy lives have become a possibility for the near future. The preliminaries to this grand awakening have been underway for a while, gradually, and will continue that way for a while longer. A few people every day in ordinary walks of life notice that, hey, a lot of scientists are talking about greatly extending human life spans these days, and, oh look, large sums of money are floating around to back this aim. There will be a slow dawning of realization, one floating light bulb at a time, as the concept of radical life extension is shifted in another brain from the "science fiction" bucket to the "science fact" bucket.

Some folk will then go back to what they were doing. Others will catch the fever and become advocates. A tiny few will donate funds in support of research or pressure politicians to do the same. Since we live in an age of pervasive communication, we see this process as it occurs. Many people are all to happy to share their realizations on a regular basis, and in this brave new world everyone can be a publisher in their own right.

Here is an example that I stumbled over today; a fellow with a day to day focus in a completely unrelated industry took notice and thought enough of what is going on in aging research to talk about it. He is still skeptical, but not to the point of dismissing the current state and prospects for longevity science out of hand: he can see that this is actionable, important knowledge.

What if de Grey and Kurzweil are half right?

I think these guys - and the whole movement to conquer aging - is fascinating. I am highly skeptical of the claims, however. Optimism is all well and good, and I have no off-hand holes to poke in their (very) well-articulated arguments. But at the same time, biology is fiendishly complex, the expectations beyond fantastical.

Still though, I have to wonder: What if guys like de Grey and Kurzweil are half right, or even just partially right? What if, 30 years from now, it becomes physically impossible to tell a 30-year-old from a 70-year-old by physical appearance alone? It sounds nutty. But it's a lot less nuttier, and a lot closer to the realm of possibility, than living to 1,000 - which, again, some very smart people have taken into their heads as an achievable thing.

People who don't take care of themselves are insane. Ok, not actually "insane." But seriously, given the potential rewards AND the risks, not taking care of your body and mind - not treating both with the utmost respect and care - seems absolutely nuts. At the poker table I see these young kids whose bodies are already turning to mush, and a part of me just wants to grab them by the shirt collar and say "Dudes! What the hell is WRONG with you!!!"

If it is possible - just realistically possible, mind you - that I could still be kicking ass and taking names at 125 years old, then I want to be working as hard as I can to preserve and maintain my equipment here and now. No matter what miracles medical science will achieve in future, working from the strongest, healthiest base possible will always improve the potential results, perhaps by an order of magnitude. Individuals who go into old age with fit, healthy bodies and sound minds, and longstanding habits to maintain both, may find potential for extended performance at truly high quality of life that was never before imaginable.

As the foundations of rejuvenation biotechnology are assembled and institutions like the SENS Research Foundation continue to win allies in the research community and beyond, the number of people experiencing this sort of epiphany will grow. The more the better and the sooner the better, as widespread support for the cause of defeating aging through medical science is necessary for more rapid progress: large scale funding always arrives late to the game, attracted by popular sentiment. The faster we get to that point the greater our chances of living to benefit from the first working rejuvenation treatments.


It is becoming clear that genetic contributions to natural variations in longevity are highly complex. In humans the effects discovered to date are almost always very small, and are very few indeed have been replicated between study populations. This points to the relationship between genes and longevity within a species consisting of a network of modest effects, all of which interact with one another and environmental influences. Thus any specific genetic variant might have some small positive effect in one study and no effect or some small negative effect in another, and thus might be true even if the two study populations are recruited from exactly the same city, neighborhood, or well-defined ethnicity. What this suggests to me is that it will take a long time to make any headway in deciphering this web of relationships, and the result at the end of the day, after possibly decades of work, will be no great ability to extend life through genetic alteration. Knowledge will be the primary outcome, which is good for science, but not so good for us as individuals desiring to live longer lives.

Will someone one day turn up a simple human genetic alteration that has effects as impressive as some of the single gene longevity mutations in mice or lower animals? It might still happen, but I think that the odds are tiny and fading as more is discovered of the complex morass of human genes and longevity variations. It is a swamp of thousands of small effects. Like calorie restriction, which has sizable results on mouse longevity and nowhere near the same outcome for human longevity, genetic alterations known to produce large gains in short-lived mammals just don't do the same in humans. You might look at growth hormone receptor mutants: in mice they can live 60% longer. In humans, a similar population are merely somewhat resistant to diabetes and cancer, with no great signs of longevity besides that.

Here is news of research into the relationship between calorie restriction and mitochondrial gene variants that reinforces the points I make above. It is all an intricate web of relationships, with every strand individually making only a small contribution to the whole. This is not an easy path to extending life, and should not be the dominant way forward for longevity science despite the fact that the tools for working with genes are now very cheap. That would be like searching beneath the lamp, simply because it is where it the light falls. There is a lot that can be done in medicine with genetics, but I'm dubious that a fast path to rejuvenation treatments is one of them.

Interactions may matter most for longevity

If studying a single gene or a diet that might extend longevity is like searching for a fountain of youth, then a new study calls for looking at something more like the whole watershed. [Biologists] who experimentally throttled three such factors in fruit flies found that lifespan depended more on interactions among the factors than on the factors themselves. "I think the main lesson is that these interaction effects are as significant or important as the [single] effects, such as diet effects alone or genetic effect alone. Traditionally that's what people have focused on: looking for a gene that extends longevity or a diet that extends longevity."

When researchers have looked at single or even pairs of factors in a wide variety of organisms, they've made many valuable findings about the biology of aging. But sometimes scientists have been unable to replicate each other's findings in seemingly similar experiments. Often this is attributed to mysterious "background effects," presumably other genes that were not properly accounted for. The new study chose to put such background effects into the foreground to examine dietary effects on aging in several panels of different nuclear and mitochondrial genetic pairings.

G×G×E for Lifespan in Drosophila: Mitochondrial, Nuclear, and Dietary Interactions that Modify Longevity

It is widely recognized that mitochondrial function plays an important role in longevity and healthy aging. Considerable attention has been focused on the extension of longevity by caloric or dietary restriction and mutations that alter this process, and these interventions commonly are associated with shifts in mitochondrial function. While the genetic bases of these effects are the focus of much interest, relatively little effort has been directed at understanding the role that mitochondrial DNA (mtDNA) polymorphisms play in the diet restriction response.

This work presents a comprehensive effort to quantify the effects of mtDNA variants, nuclear genetic variants and dietary manipulations on longevity in Drosophila, with a focus on testing for the importance of the interactions among these factors. We found that mitochondrial genotypes can have significant effects on longevity and the diet restriction response but these effects are highly dependent on nuclear genetic (G) background and the specific diet environment (E). For example, a mitochondrial haplotype that shortens lifespan in one nuclear background or diet regime shows no such effect when the genetic background or diet regime is changed.

Our experiments indicate that identifying individual mitochondrial, nuclear or dietary effects on longevity is unlikely to provide general results without quantifying the prevalent mitochondrial × nuclear × diet (G×G×E) interactions.


Monday, May 12, 2014

When considering survival in early old age lifestyle is more important than genetics, but genetic lineage becomes increasingly important for survival in extreme old age. This is reflected in the increased frequency of the few known genetic variants associated with longevity in older populations: those without the variants have a higher mortality rate, and so the relative proportion of those with the variants rises over time.

Researchers here demonstrate that this effect has been gently diminishing in recent decades, and thus cohorts of the oldest people born more recently include more individuals without longevity-associated genetic variants. This would be the expected outcome in an environment of consistently improving medical technology. Past improvements in medicine have only indirectly impacted the processes that drive aging, however, or provide only limited benefits to people suffering from age-related conditions because the treatments don't address the underlying causes of aging. They are essentially patches on a fast-growing hole, which is better than nothing, but not a solution.

Gene variants found to associate with human longevity in one population rarely replicate in other populations. The lack of consistent findings may partly be explained by genetic heterogeneity among long-lived individuals due to cohort differences in survival probability. In most high-income countries the probability of reaching e.g. 100 years increases by 50-100% per decade, i.e. there is far less selection in more recent cohorts. Here we investigate the cohort specificity of variants in the APOE and FOXO3A genes by comparing the frequencies of the APOE ε4 allele and the minor alleles of two variants in FOXO3A at age 95+ and 100+ in 2712 individuals from the genetically homogeneous Danish birth cohorts 1895-96, 1905, 1910-11, and 1915.

Generally, we find a decrease in the allele frequencies of the investigated APOE and FOXO3A variants in individuals from more recent birth cohorts. Assuming a recessive model, this negative trend is significant in 95+ year old individuals homozygous for the APOE ε4 allele or for the FOXO3A rs7762395 minor allele. For the APOE ε4 allele, the significance is further strengthened when restricting to women. Supportive, but non-significant, trends are found for two of the three tested variants in individuals older than 100 years.

Altogether, this indicates that cohort differences in selection pressure on survival to the highest ages are reflected in the prevalence of longevity gene variants. Although the effect seems to be moderate, our findings could have an impact on genetic studies of human longevity.

Monday, May 12, 2014

It is thought that one of the greatest hurdles to growth in public support of longevity science is the fact that most people assume increased longevity through medicine would mean being old, frail, and in pain for longer. This is very much not the case, however: the goal is always to extend or restore the period of healthy life, and given that aging is an accumulation of damage in and between cells it might not even be possible to engineer a situation in which people are older for longer rather than younger for longer. Either you repair the underlying damage that causes aging by implementing something like the SENS research program, in which case people will be all-round healthier for longer, or you don't. In the latter case you have the present situation in mainstream medicine of an expensive, only marginally beneficial, and ultimately futile process of trying to keep heavily damaged machinery running at all.

The state of present mainstream medicine is what people see and what they assume to be the case in the future, however. It is strange that we live in a time of constant change, and yet the average fellow in the street assumes that the present is a good model for what lies ahead. The relationship between aging and medicine is about to change radically, as the research community for the first time works towards directly treating the causes of aging. But to make good progress here, to raise the necessary funds, the public must be on board and supportive in the same way as they are for stem cell research or cancer research. That has yet to happen, however, and this is why we need advocacy and persuasion.

The media obsesses over the inevitable "secret" that centenarians reveal as the reason for their exceptionally long life. Scientists study centenarians and their families to isolate the causes for longevity - so that we may be able to distribute it to everyone. But centenarians are not the key to unlocking the mysteries of health and longevity - on the contrary, they epitomise our fears of growing old.

In Greek mythology, mortality was the distinguishing feature between gods and men; gods were immortal while men suffered from death (that, and the whims of the gods above them). In the story, Eos, the goddess of the dawn falls in love with a mortal man called Tithonus. Eos cannot bear the thought that Tithonus will die, so she asks Zeus to make him immortal, to which he agrees. The only problem is that she forgot to ask for eternal youth. Tithonus cannot die, but he progressively suffers from all the ill health and frailties of old age.

Centenarians are the living embodiment of Tithonus' curse. Contrary to what the media would like to portray (and some studies), many centenarians suffer ill health and frailty associated with old age, which can also affect research. Most are wheelchair or bed-bound, many suffer from dementia, muscle loss, hearing loss, eyesight loss and lack control of their orifices. When given the choice between healthy life and long life with ill health, most people choose the former. Centenarians are not a mystery of nature; they are old people who happen to suffer the damages of ageing a bit longer than others.

If we are to grow old and remain in good health, we have three options. We can try to improve our metabolism such that it generates less harmful byproducts or we can find a way to clean these up these byproducts. Or, we can deal with the consequences of this accumulation of damage over time. Medicine has mainly focused on the third option, dealing with the consequences of ageing disease such as dementia, cancer and diabetes. But though we may have added few years to our lives, we certainly haven't added life to our years.

Tuesday, May 13, 2014

A part of the genetic contribution to survival to extreme old age may have to do with adaptations allowing for better mitochondrial function despite accumulated damage. Or it could be the case that in extreme old age mitochondria are significantly different in structure to merely old age, and this is a global phenomenon for all who make it that far. Either way, this is interesting research; you might want to skip to figure 6 in the discussion section of the paper for a graphical summary of the authors' hypothesis.

Mitochondria have been considered for long time as important determinants of cell aging because of their role in the production of reactive oxygen species. In this study we investigated the impact of mitochondrial metabolism and biology as determinants of successful aging in primary cultures of fibroblasts isolated from the skin of long living individuals (LLI) (about 100 years old) compared with those from young (about 27 years old) and old (about 75 years old) subjects.

We observed that fibroblasts from LLI displayed significantly lower complex I-driven ATP synthesis and higher production of H2O2 in comparison with old subjects. Despite these changes, bioenergetics of these cells appeared to operate normally. This lack of functional consequences was likely due to a compensatory phenomenon at the level of mitochondria, which displayed a maintained supercomplexes organization and an increased mass. This appears to be due to a decreased mitophagy, induced by hyperfused, elongated mitochondria.

The overall data indicate that longevity is characterized by a preserved bioenergetic function likely attained by a successful mitochondria remodeling that can compensate for functional defects through an increase in mass, i.e. a sort of mitochondrial "hypertrophy".

Tuesday, May 13, 2014

There is plenty of evidence to show that shorter people tend to live longer. Here is more of the same:

Short height and long life have a direct connection in Japanese men, according to new research based on the Kuakini Honolulu Heart Program (HHP) and the Kuakini Honolulu-Asia Aging Study (HAAS). "We split people into two groups - those who were 5-foot-2 and shorter, and 5-4 and taller. The folks that were 5-2 and shorter lived the longest. The range was seen all the way across from being 5-foot tall to 6-foot tall. The taller you got, the shorter you lived."

The researchers showed that shorter men were more likely to have a protective form of the longevity gene, FOXO3, leading to smaller body size during early development and a longer lifespan. Shorter men were also more likely to have lower blood insulin levels and less cancer. "This study shows, for the first time, that body size is linked to this gene. We knew that in animal models of aging. We did not know that in humans. We have the same or a slightly different version in mice, roundworms, flies, even yeast has a version of this gene, and it's important in longevity across all these species."

[Researchers] noted that there is no specific height or age range that should be targeted as a cut-off in the study, in part because "no matter how tall you are, you can still live a healthy lifestyle" to offset having a typical FOXO3 genotype rather than the longevity-enhancing form of the FOXO3 gene.

Wednesday, May 14, 2014

A number of approaches to Alzheimer's disease don't seek to address the underlying causes of pathology, but rather shore up crucial mechanisms that are harmed. This approach is actually very common throughout modern medicine, and it is something that I think has to change in order to improve the effectiveness of medical research and development. This is an example of the type:

"Several years ago we discovered that NAP, a snippet of a protein essential for brain formation, which later showed efficacy in Phase 2 clinical trials in mild cognitive impairment patients, a precursor to Alzheimer's. Now, we're investigating whether there are other novel NAP-like sequences in other proteins. This is the question that led us to our discovery. NAP operates through the stabilization of microtubules - tubes within the cell which maintain cellular shape. They serve as 'train tracks' for movement of biological material. This is very important to nerve cells, because they have long processes and would otherwise collapse. In Alzheimer's disease, these microtubules break down. The newly discovered protein fragments, just like NAP before them, work to protect microtubules, thereby protecting the cell."

[The researchers] looked at the subunit of the microtubule - the tubulin - and the protein TAU (tubulin-associated unit), important for assembly and maintenance of the microtubule. Abnormal TAU proteins form the tangles that contribute to Alzheimer's; increased tangle accumulation is indicative of cognitive deterioration. [Researchers tested] both the tubulin and the TAU proteins for NAP-like sequences. After confirming NAP-like sequences in both tubulin subunits and in TAU, [they then] tested the fragments in tissue cultures for nerve-cell protecting properties against amyloid peptides, the cause of plaque build up in Alzheimer patients' brains.

"From the tissue culture, we moved to a 10-month-old transgenic mouse model with frontotemporal dementia-like characteristics, which exhibits TAU pathology and cognitive decline. We tested one compound - a tubulin fragment - and saw that it protected against cognitive deficits. When we looked at the 'dementia'-afflicted brain, there was a reduction in the NAP parent protein, but upon treatment with the tubulin fragment, the protein was restored to normal levels."

Wednesday, May 14, 2014

Reducing calorie intake for a comparatively short period of time very early in life is here shown to have life-long effects in mice. This provides more insight into the way in which metabolism in shorter-lived mammals has evolved to react to temporary famine conditions, producing more robust health and up to 40% longer life spans for life-long calorie restriction. It is interesting that even a short period of low calorie intake early in life can have the effects noted in this study.

We humans share the same evolutionary heritage of nutrient sensing mechanisms intended to alter our metabolic processes based on calorie intake, and the beneficial effects of calorie restriction on measures of health are quite similar to those in mice, but calorie restriction doesn't extend our life by anywhere near the same proportion. The consensus in the scientific community is that calorie restriction will extend human life by perhaps 5% or a little more. On the other hand, the health benefits are greater than those produced by any presently available medical technology or lifestyle choice.

The action of nutrients on early postnatal growth can influence mammalian aging and longevity. Recent work has demonstrated that limiting nutrient availability in the first three weeks of life (by increasing the number of pups, in the crowded litter (CL) model) leads to extension of mean and maximal lifespan in genetically normal mice. In this study we aimed to characterize the impact of early life nutrient intervention on glucose metabolism and energy homeostasis in CL mice. In our study we used mice from litters supplemented to 12 or 15 pups and compared those to control litters limited to 8 pups.

At weaning and then throughout adult life, CL mice are significantly leaner and consume more oxygen relative to control mice. At 6 months of age, CL mice had low fasting leptin concentrations, and low-dose leptin injections reduced body weight and food intake more in CL female mice than in controls. At 22 months, CL female mice also have smaller adipocytes compared to controls. Glucose and insulin tolerance tests show an increase in insulin sensitivity in 6 month old CL male mice, and females become more insulin sensitive later in life. Furthermore, β-cell mass was significantly reduced in the CL male mice and was associated with reduction in β-cell proliferation rate in these mice. Together, these data show that early life nutrient intervention has a significant lifelong effect on metabolic characteristics which may contribute to the increased lifespan of CL mice.

Thursday, May 15, 2014

It is well known that calorie restriction extends life in near all species in which it has been tested. In mammals much of this effect seems to operate through sensing low levels of methionine, an essential amino acid. Here researchers show that in flies in addition to mechanisms that react to the level of food intake there is a also water sensor that separately and distinctly alters metabolism so as to extend healthy life:

Sensory inputs are known to control aging. The underlying circuitry through which these cues are integrated into regulatory physiological outputs, however, remains largely unknown. Here, we use the taste sensory system of the fruit fly Drosophila melanogaster to detail one such circuit. Specifically, we find that water-sensing taste signals alter nutrient homeostasis and regulate a glucagon-like signaling pathway to govern production of internal water production. This metabolic alteration likely serves as a response to water sensory information. This control of metabolic state, in turn, determines the organism's long-term health and lifespan.

We found that loss of the critical water sensor, pickpocket 28 (ppk28), altered metabolic homeostasis to promote internal lipid and water stores and extended healthy lifespan. Additionally, loss of ppk28 increased neuronal glucagon-like adipokinetic hormone (AKH) signaling, and the AKH receptor was necessary for ppk28 mutant effects. Furthermore, activation of AKH-producing cells alone was sufficient to enhance longevity, suggesting that a perceived lack of water availability triggers a metabolic shift that promotes the production of metabolic water and increases lifespan via AKH signaling.

Thursday, May 15, 2014

There are many ways in which you can sabotage your future health, but putting on weight and smoking are the most popular choices. They even have similar harmful effects on life expectancy: a decade or more of life lost. At the level of cells and tissue structures the effects of smoking look a lot like accelerated aging in some ways - which should not be surprising if we consider aging as nothing more than accumulated damage to the biological machinery of the body. This is a theme taken up in the paper quoted here:

Chronic obstructive pulmonary disease (COPD) is a disease that usually presents clinically at an advanced age, after years of smoking cigarettes. It is usually believed that aging and its biological consequences are important mechanisms in the disease pathogenesis. This concept has maintained the focus of studies on COPD in old-age individuals.

Here we analyze the possible role of aging from a different point of view and introduce different concepts that might be considered useful additions to the understanding of the disease. Essentially, we propose and show evidence that COPD is a disease of the young susceptible smoker that progresses over time and manifests in older age because we live longer and not so much because of the effect of aging itself; we examine the concept of cell senescence, the basis of tissue aging, and how stressors like the ones produced by smoking can accelerate cell senescence with all of its untoward consequences in COPD. We thus finally suggest that COPD might accelerate aging rather than be a consequence of it.

In conclusion, we suggest that COPD could be considered a disease of the predisposed young individual that manifests clinically in old age because we live longer, with all of its consequences.

Friday, May 16, 2014

Myelin is the sheathing of nerves, and loss of myelin contributes to a number of debilitating diseases. This loss is also shown to occur to a lesser degree in aging, so just as for many types of disease it is worth keeping an eye on the progression of treatments such as the one discussed here. This paper is open access, but the full version is in PDF format only at the moment.

Using a viral model of the demyelinating disease multiple sclerosis (MS), we show that intraspinal transplantation of human embryonic stem cell-derived neural precursor cells (hNPCs) results in sustained clinical recovery, although hNPCs were not detectable beyond day 8 posttransplantation. Improved motor skills were associated with a reduction in neuroinflammation, decreased demyelination, and enhanced remyelination.

In summary, we demonstrate that transplantation of hNPCs into a mouse model of viral-induced demyelination results in prolonged clinical recovery up to at least 6 months in spite of the disappearance of transplanted hNPCs after only a week. Our findings extend the existing evidence that long-term engraftment is not important for sustained clinical and histologic recovery. Our evidence points to secreted factors produced by the hNPCs in the local environment as the regulators of T cell fate and remyelination activity by endogenous OPCs. Because they are produced by the hNPCs used in our study and have known effects on T cell development, members of the TGF-b family are strong candidates as triggers initiating clinical recovery.

As an aside, note that this is one of numerous studies in which the benefits derived from cell therapies are shown to have little to do with ongoing activities of the transplanted cells themselves. The cells change the environment and behavior of native cells even when they are only present for a comparatively short time.

Friday, May 16, 2014

Work progresses on therapies that use reprogrammed stem cells derived from easily obtained patient tissue samples, such as small pieces of skin:

Researchers have shown for the first time in an animal that is more closely related to humans that it is possible to make new bone from stem-cell-like induced pluripotent stem cells (iPSCs) made from an individual animal's own skin cells. The study in monkeys [also] shows that there is some risk that those iPSCs could seed tumors, but that unfortunate outcome appears to be less likely than studies in immune-compromised mice would suggest.

The researchers first used a standard recipe to reprogram skin cells taken from rhesus macaques. They then coaxed those cells to form first pluripotent stem cells and then cells that have the potential to act more specifically as bone progenitors. Those progenitor cells were then seeded onto ceramic scaffolds that are already in use by reconstructive surgeons attempting to fill in or rebuild bone. And, it worked; the monkeys grew new bone.

Importantly, the researchers report that no teratoma structures developed in monkeys that had received the bone "stem cells." In other experiments, undifferentiated iPSCs did form teratomas in a dose-dependent manner. The researchers say that therapies based on this approach could be particularly beneficial for people with large congenital bone defects or other traumatic injuries. Although bone replacement is an unlikely "first in human" use for stem cell therapies given that the condition it treats is not life threatening, the findings in a primate are an essential step on the path toward regenerative clinical medicine.


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