Fight Aging! Newsletter, September 2nd 2013

September 2nd 2013

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

To subscribe or unsubscribe to the Fight Aging! Newsletter, please visit the newsletter site:


  • Recent Calorie Restriction Research: Monkeys, Squirrels, Mice, and Yeast
  • Another Possible Example of Life Extension via Reduced Cancer Risk
  • Increased Expression of RbAp48 Restores Memory Capacity in Old Mice
  • Decreased mTOR Expression Provides 20% Mean Life Span Extension in Mice
  • Measuring the Impact of Cytomegalovirus in Younger People
  • Latest Headlines from Fight Aging!
    • Genomics X Prize Cancelled
    • Transplant of Bone Marrow Cells From Young Mice Modestly Extends Life in Old Mice
    • Looking for Sarcopenia Therapies in Fish
    • Hijacking Cellular Communications to Improve Regeneration
    • Engineering Life
    • An Advance in Understanding the Mechanisms of Parkinson's
    • Growing Small Amounts of Brain Tissue
    • Children of Long-Lived Parents Have Better Immune Systems
    • A Collagen Patch to Spur Heart Tissue Repair
    • Statin Use Correlates With Higher Telomerase Activity


Researchers around the world are examining the effects of calorie restriction in many different species, and have been for years. In near all species reducing calorie intake while maintaining optimal levels of vital nutrients extends life and provides numerous health benefits. Spectacular improvements in general health and lowered risk of disease are observed in human practitioners, far more than any presently available medical technology can offer a basically healthy individual, but the jury is still out on the degree to which calorie restriction can extend maximum life span in our species and other longer-lived primates. In part this is due to a lack of data: it takes a long time to run such a study when the only reliable way to measure life extension is to wait and see, and there is little in the way of large sets of historical data to mine. Researchers currently expect calorie restriction to extend human life by only a few years, and the historical absence of evidence bears this out: if calorie restriction with adequate nutrition could significantly extend human life - such as by the 40% seen in laboratory mice - then our ancestors would have found out a long time ago, and at the very least within the last few hundred years of more advanced technology and greater wealth.

Investigations into the biology of calorie restriction induced health and longevity are really only a sideshow in the grand scheme of longevity science. Radical life extension can only arrive from rejuvenation biotechnologies - therapies that can repair the low-level biological damage that causes aging. If you restrict your calories you can expect to have a much healthier life, on average, than would otherwise be the case, something that has great merit in and of itself. But don't expect it to add decades to your overall life span, because it probably won't. For that sort of result, you need to look to the Strategies for Engineered Negligible Senescence (SENS) or other similar programs aiming for new medical technologies to reverse the root causes of aging.

Nonetheless, it will be interesting to see how researchers reconcile the fact that short-term health benefits due to calorie restriction are large and similar in mice and humans, yet calorie restricted mice live for much longer, while humans probably don't. Here are a few recent papers from the breadth of ongoing research into the effects of a lower calorie intake on aging and longevity:

Long-term calorie restriction decreases metabolic cost of movement and prevents decrease of physical activity during aging in the rhesus monkeys

Short-term (less than 1 year) calorie restriction (CR) has been reported to decrease physical activity and metabolic rate in humans and non-human primate models; however, studies examining the very long-term (greater than 10 year) effect of CR on these parameters are lacking. The objective of this study was to examine metabolic and behavioral adaptations to long-term CR longitudinally in rhesus macaques.

Eighteen (10 male, 8 female) control (C) and 24 (14 male, 10 female) age matched CR rhesus monkeys between 19.6 and 31.9 years old were examined after 13 and 18 years of moderate adult-onset CR. Energy expenditure (EE) was examined by doubly labeled water (DLW; TEE) and respiratory chamber (24h EE). Physical activity was assessed both by metabolic equivalent (MET) in a respiratory chamber and by an accelerometer. Metabolic cost of movements during 24h was also calculated. Age and fat-free mass were included as covariates.

Adjusted total and 24h EE were not different between C and CR. Sleeping metabolic rate was significantly lower, and physical activity level was higher in CR than in C independent from the CR-induced changes in body composition. The duration of physical activity above 1.6 METs was significantly higher in CR than in C, and CR had significantly higher accelerometer activity counts than C. Metabolic cost of movements during 24h was significantly lower in CR than in C. The accelerometer activity counts were significantly decreased after seven years in C animals, but not in CR animals. The results suggest that long-term CR decreases basal metabolic rate, but maintains higher physical activity with lower metabolic cost of movements compared with C.

Molecular signatures of mammalian hibernation: comparisons with alternative phenotypes

Mammalian hibernators display phenotypes similar to physiological responses to calorie restriction and fasting, sleep, cold exposure, and ischemia-reperfusion in non-hibernating species. Whether biochemical changes evident during hibernation have parallels in non-hibernating systems on molecular and genetic levels is unclear.

We identified the molecular signatures of torpor and arousal episodes during hibernation using a custom-designed microarray for the Arctic ground squirrel (Urocitellus parryii) and compared them with molecular signatures of selected mouse phenotypes. Our results indicate that differential gene expression related to metabolism during hibernation is associated with that during calorie restriction and that the nuclear receptor protein PPARα is potentially crucial for metabolic remodeling in torpor. Sleep-wake cycle-related and temperature response genes follow the same expression changes as during the torpor-arousal cycle. Increased fatty acid metabolism occurs during hibernation but not during ischemia-reperfusion injury in mice and, thus, might contribute to protection against ischemia-reperfusion during hibernation.

SIRT1 but not its increased expression is essential for lifespan extension in caloric restricted mice

The SIRT1 deacetylase is one of the best-studied potential mediators of some of the anti-aging effects of calorie restriction (CR); but its role in CR-dependent lifespan extension has not been demonstrated. We previously found that mice lacking both copies of SIRT1 displayed a shorter median lifespan than wild type mice on an ad libitum diet. Here we report that median lifespan extension in CR heterozygote SIRT1+/- mice was identical (51%) to that observed in wild type mice but SIRT1+/- mice displayed a higher frequency of certain pathologies. Although larger studies in different genetic backgrounds are needed, these results provide strong initial evidence for the requirement of SIRT1 for the lifespan extension effects of CR, but suggest that its high expression is not required for CR-induced lifespan extension.

Maintenance of cellular ATP level by caloric restriction correlates chronological survival of budding yeast

The free radical theory of aging emphasizes cumulative oxidative damage in the genome and intracellular proteins due to reactive oxygen species (ROS), which is a major cause for aging. Caloric restriction (CR) has been known as a representative treatment that prevents aging; however, its mechanism of action remains elusive. Here, we show that CR extends the chronological lifespan (CLS) of budding yeast by maintaining cellular energy levels. CR reduced the generation of total ROS and mitochondrial superoxide; however, CR did not reduce the oxidative damage in proteins and DNA. Subsequently, calorie-restricted yeast had higher mitochondrial membrane potential (MMP), and it sustained consistent ATP levels during the process of chronological aging. Our results suggest that CR extends the survival of the chronologically aged cells by improving the efficiency of energy metabolism for the maintenance of the ATP level rather than reducing the global oxidative damage of proteins and DNA.


Laboratory mice are little cancer factories in comparison to humans, and so any mechanism that reduces cancer risk is going to extend life expectancy in a study group. That's one of many reasons why it is a good idea to pay more attention to research that shows a gain in maximum life extension rather than just mean life span extension. There is some debate over whether reducing cancer risk counts as an anti-aging therapy: the argument in favor suggests that since cancer is an age-related condition, risk rising to a plateau with advancing age, and since aging can be defined as increasing risk of mortality, of course reducing incidence of cancer counts as an anti-aging treatment. On the other side of the fence, there is the tendency of the research community to carve away named diseases from aging as new knowledge arises, and talk about treating those diseases rather than treating aging. See, for example, sarcopenia as the comparatively new designation for age-related loss of muscle mass and strength.

This seems to come down to how well researchers understand a given method of extending life in laboratory animals. No idea how it works, and the older individuals in the study are looking healthier? Then suggest that it is a slowing of aging. If, on the other hand, the precise mechanisms of action can be identified and have to do with cancer, then there is a reluctance to talk about the pace of aging. In this we might see some of the consequences of the remaining divisions and uncertainties over what exactly aging is, how it is caused, and how it progresses at the level of cells, cellular machinery, and biological systems.

An example of this sort of debate showed up recently in connection to rapamycin. Reputable researchers have run sizable studies on mouse life span under treatment with rapamycin: some conclude that rapamycin definitely slows aging, while others conclude that the effect on life span is due to reduced cancer risk, and yet more argue that there is no real difference in this case between life extension and reduced cancer risk as it all stems from the same underlying collection of mechanisms.

I can't say as I have a strong opinion on this topic insofar as it touches on rapamycin: research into drugs to modestly slow aging isn't the future of human longevity. Rather it is a sidebar to learning more about the operation of mammalian biology and how it adapts to various circumstances, such as calorie restriction and aging. But on this subject, I noticed a recent paper on a less well studied longevity-enhancing genetic alteration in which the authors also postulate that the mechanism is reduced cancer risk:

Reduced Malignancy as a Mechanism for Longevity in Mice with Adenylyl Cyclase Type 5 (AC5) Disruption

Disruption of adenylyl cyclase type 5 (AC5) knockout (KO) is a novel model for longevity. Since malignancy is a major cause of death and reduced lifespan in mice, the goal of this investigation was to examine the role of AC5KO in protecting against cancer. There have been numerous discoveries in genetically engineered mice over the past several decades, but few have been translated to the bedside. One major reason is that it is difficult to alter a gene in patients, but rather a pharmacological approach is more appropriate.

The current investigation employs a parallel construction to examine the extent to which inhibiting adenylyl cyclase type 5 (AC5), either in a genetic knockout (KO) or by a specific pharmacological inhibitor protects against cancer. This study is unique, not only because a combined genetic and pharmacological approach is rare, but also there are no prior studies on the extent to which AC5 affects cancer.

We found that AC5KO delayed age-related tumor incidence significantly, as well as protecting against mammary tumor development, [which] can explain why AC5KO is a model of longevity. In addition, an FDA approved anti-viral agent, adenine 9-β-D-arabinofuranoside (Vidarabine or AraAde), which specifically inhibits AC5, reduces [lung and melanoma] tumor growth. Thus, inhibition of AC5 is a previously unreported mechanism for prevention of cancers associated with aging, and which can be targeted by an available pharmacologic inhibitor, with potential consequent extension of life span.


Researchers are making strides in uncovering the low-level details of how memory operates in mammalian brains, just as they are making strides in all areas of biology. Sometimes the process of discovery comes hand in hand with a demonstration of utility, as is the case here. Putting to one side the consequences of an Alzheimer's-like build up of amyloid deposits and its associated neural dysfunction, the research quoted below demonstrates that the rest of the decline in memory function due to old age in mice can be mostly reversed by increasing the levels of one particular protein. This is very interesting, as it suggests that the processes of memory are not greatly inhibited by most of the forms of cellular damage that causes aging, at least in mice, and that this portion of mental decline occurs due to one of the epigenetic responses to that damage.

We might well ask why this came to pass in the course of evolutionary adaptation, but any sort of theorizing on my part would be very speculative at this point, following the party line on antagonistic pleiotropy in the context of aging.

A Major Cause of Age-Related Memory Loss Identified

A team of Columbia University Medical Center (CUMC) researchers [has] found that deficiency of a protein called RbAp48 in the hippocampus is a significant contributor to age-related memory loss and that this form of memory loss is reversible. The hippocampus, a brain region that consists of several interconnected subregions, each with a distinct neuron population, plays a vital role in memory. Studies have shown that Alzheimer's disease hampers memory by first acting on the entorhinal cortex (EC), a brain region that provides the major input pathways to the hippocampus. It was initially thought that age-related memory loss is an early manifestation of Alzheimer's, but mounting evidence suggests that it is a distinct process that affects the dentate gyrus (DG), a subregion of the hippocampus that receives direct input from the EC.

The researchers began by performing microarray (gene expression) analyses of postmortem brain cells from the DG of eight people, ages 33 to 88, all of whom were free of brain disease. The team also analyzed cells from their EC, which served as controls since that brain structure is unaffected by aging. The analyses identified 17 candidate genes that might be related to aging in the DG. The most significant changes occurred in a gene called RbAp48, whose expression declined steadily with aging across the study subjects. To determine whether RbAp48 plays an active role in age-related memory loss, the researchers turned to mouse studies.

When the researchers genetically inhibited RbAp48 in the brains of healthy young mice, they found the same memory loss as in aged mice, as measured by novel object recognition and water maze memory tests. When RbAp48 inhibition was turned off, the mice's memory returned to normal. The researchers also did functional MRI (fMRI) studies of the mice with inhibited RbAp48 and found a selective effect in the DG, similar to that seen in fMRI studies of aged mice, monkeys, and humans. This effect of RbAp48 inhibition on the DG was accompanied by defects in molecular mechanisms similar to those found in aged mice. The fMRI profile and mechanistic defects of the mice with inhibited RbAp48 returned to normal when the inhibition was turned off.

In another experiment, the researchers used viral gene transfer and increased RbAp48 expression in the DG of aged mice. "We were astonished that not only did this improve the mice's performance on the memory tests, but their performance was comparable to that of young mice."

It seems unlikely that what is going on under the hood is simple, even as the result of a single gene change. Researchers still can't fully and comprehensively explain any of the forms of life extension achieved through single gene manipulations, and some of those have been known for more than fifteen years. Altered levels of a single protein can trigger all sorts of sweeping changes in metabolism. I predict that much of the next decade will pass before even a rough sketch of what is going on here is assembled. Fortunately, full understanding isn't required to demonstrate the potential for therapies - it just improves the odds of producing a feasible, useful medical technology.

Here's the paper for those who like to see the original sources:

Molecular Mechanism for Age-Related Memory Loss: The Histone-Binding Protein RbAp48

To distinguish age-related memory loss more explicitly from Alzheimer's disease (AD), we have explored its molecular underpinning in the dentate gyrus (DG), a subregion of the hippocampal formation thought to be targeted by aging. We carried out a gene expression study in human postmortem tissue harvested from both DG and entorhinal cortex (EC), a neighboring subregion unaffected by aging and known to be the site of onset of AD. Using expression in the EC for normalization, we identified 17 genes that manifested reliable age-related changes in the DG. The most significant change was an age-related decline in RbAp48, a histone-binding protein that modifies histone acetylation.

To test whether the RbAp48 decline could be responsible for age-related memory loss, we turned to mice and found that, consistent with humans, RbAp48 was less abundant in the DG of old than in young mice. We next generated a transgenic mouse that expressed a dominant-negative inhibitor of RbAp48 in the adult forebrain. Inhibition of RbAp48 in young mice caused hippocampus-dependent memory deficits similar to those associated with aging, as measured by novel object recognition and Morris water maze tests. Functional magnetic resonance imaging studies showed that within the hippocampal formation, dysfunction was selectively observed in the DG, and this corresponded to a regionally selective decrease in histone acetylation.

Up-regulation of RbAp48 in the DG of aged wild-type mice ameliorated age-related hippocampus-based memory loss and age-related abnormalities in histone acetylation. Together, these findings show that the DG is a hippocampal subregion targeted by aging, and identify molecular mechanisms of cognitive aging that could serve as valid targets for therapeutic intervention.


Mammalian (or mechanistic, depending on who you ask) target of rapamycin (mTOR) is the most likely candidate for the next round of billion-dollar research funding devoted to the search for drugs that can slow aging. It will be a repeat of the overhyped and ultimately largely futile interest in sirtuin research, which generated knowledge but nothing of real practical application, except that this time there is far more compelling evidence that manipulation of mTOR actually extends life in laboratory animals. Though as always, there are those who believe that this is not in fact the case - that mTOR alteration only reduces cancer risk, rather than impacting the processes of aging per se. Just as resveratrol and resveratrol-derivatives are the compounds of choice for those investigating sirtuin biology, so rapamycin and rapamycin-derivatives are the compounds of choice for research groups focused on manipulating mTOR and its related signaling networks. I would imagine that we're in for another decade or so of overhyped claims and public and research community interest in what is in fact an inefficient, expensive, and time-consuming path towards only slightly extending healthy life.

Drugs to slow aging through alterations to metabolism are not the path to radical life extension. Slowing aging does nothing for people already old. The research community should focus instead on rejuvenation through therapies that repair and remove the cellular damage that causes aging, an approach that can actually meaningfully help the aged when realized. For all that rejuvenation is the obviously superior research strategy, however, it's taking time to convince the world of that truth. Time spent on trying to slow aging is little different in outcome to time spent investigating the details of aging but choosing to do nothing about it: a few years here and there, and nothing that is as effective as simple exercise and calorie restriction. There's no such thing as useless knowledge in the long term, but we already know enough to work effectively on human rejuvenation.

The new study quoted below will no doubt bolster the prospects of those groups presently raising funds for attempts to slow aging or further develop drug candidates derived from rapamycin. While looking at the results, however, you might compare them with plain old calorie restriction in mice, something that can produce twice the extension of healthy life shown here.

Mutant Mice Live Longer

MTOR is a kinase involved in myriad cellular processes, from autophagy to protein synthesis. Genetic studies of TOR in other organisms, such as yeast and flies, have implicated a role for the enzyme in lifespan. In mammals, however, mTOR is required for survival, making a knockout mouse model unfeasible. So the National Heart, Lung and Blood Institute's Toren Finkel and his colleagues decided to use a mouse in which transcription was only partially disrupted, reducing the levels of mTOR to about 25 percent of the normal amount.

All else being equal, the researchers found that normal mice typically lived 26 months, while those with less mTOR survived around 30 months. Finkel said the increase in lifespan was greater than other researchers have seen using the immunosuppressant rapamycin to inhibit mTOR. It's possible that having mTOR reduced beginning in the womb, rather than at middle age, could explain the disparity. Additionally, this new mutant affected the levels of both forms of mTOR - mTORC1 and mTORC2 complexes - rather than preferentially impacting one, as rapamycin would.

The paper on this research is open access, so head on over and take a look. I think you'll find it interesting. In particular note the author's cautions regarding the size of the life extension effect and the life span of the control mice in the discussion section: the number of mice used isn't large, and it's possible that the controls were just randomly a slightly short-lived group.

Increased Mammalian Lifespan and a Segmental and Tissue-Specific Slowing of Aging after Genetic Reduction of mTOR Expression

We analyzed aging parameters using a mechanistic target of rapamycin (mTOR) hypomorphic mouse model. Mice with two hypomorphic (mTORΔ/Δ) alleles are viable but express mTOR at approximately 25% of wild-type levels. These animals demonstrate reduced mTORC1 and mTORC2 activity and exhibit an approximately 20% increase in median survival. While mTORΔ/Δ mice are smaller than wild-type mice, these animals do not demonstrate any alterations in normalized food intake, glucose homeostasis, or metabolic rate. Consistent with their increased lifespan, mTORΔ/Δ mice exhibited a reduction in a number of aging tissue biomarkers. Functional assessment suggested that, as mTORΔ/Δ mice age, they exhibit a marked functional preservation in many, but not all, organ systems. Thus, in a mammalian model, while reducing mTOR expression markedly increases overall lifespan, it affects the age-dependent decline in tissue and organ function in a segmental fashion.


Cytomegalovirus (CMV) is one of the less immediately harmful members of the family of herpesviruses. It is very prevalent: most people have it in their system by the time they are old, but probably never even noticed, as the symptoms for a healthy individual are essentially nonexistent. Nonetheless like all herpesviruses CMV is very successful at remaining within the body after initial exposure, establishing a life-long infection despite the best efforts of the immune system to get rid of it. The recurring campaigns waged against CMV by your immune cells appear to have a long-term cost: we have evolved to support a given number of immune cells as adults, and as ever more of those immune cells become specialized to a specific pathogen, such as CMV, there is ever less space left in the inventory for cells that can tackle new threats or keep up with all the other jobs of the immune system, such as destroying precancerous and senescent cells.

If you eye the publications of an open access journal like Immunity and Ageing, you'll see a steady flow of papers looking at the role of CMV in age-related immune system decline, a fair-sized component of the frailty of old age. There are a range of possible approaches to this problem, but the most direct and potentially effective don't actually involve doing anything about CMV itself. Instead there are proposals to either add large numbers of new, fresh, and capable immune cells to the body or eliminate the CMV-specialized cells to free up space. Both of these approaches are quite near-term: only a a couple of years would be needed to develop a viable prototype therapy from where we are now, were a research group fully funded and tasked with the effort. Both the ability to culture immune cells and the ability to destroy specific cells in the body based on their surface markers are progressing rapidly.

Some research groups are working on a vaccine for CMV - but a successful vaccine won't do much good for those high percentage of adults in much of the world who have been infected for a long time. Their immune systems are already badly misconfigured as a result of the extended exposure. So tackling CMV isn't a good enough approach on its own, as it only stops the very slow pace of ongoing harm.

Here is a paper to suggest that the progressive disarray in the immune system caused by CMV starts early, even while young.

Rudimentary signs of immunosenescence in Cytomegalovirus-seropositive healthy young adults

Ageing is associated with a decline in immune competence termed immunosenescence. In the elderly, this process results in an accumulation of differentiated 'effector' phenotype memory T cells, predominantly driven by Cytomegalovirus (CMV) infection.

Here, we asked whether CMV also drives immunity towards a senescent profile in healthy young adults. One hundred and fifty-eight individuals (age 21 ± 3 years, body mass index 22.7 ± 2.7) were assessed for CMV serostatus, the numbers/proportions of CD4+ and CD8+ late differentiated/effector memory cells, plasma interleukin-6 (IL-6) and antibody responses to an in vivo antigen challenge (half-dose influenza vaccine). Thirty percent (48/158) of participants were CMV+.

A higher lymphocyte and CD8+ count and a lower CD4/CD8 ratio were observed in CMV+ people. Eight percent (4/58) of CMV+ individuals exhibited a CD4/CD8 ratio of less than 1.0, whereas no CMV- donor showed an inverted ratio. The numbers of late differentiated/effector memory cells were ~fourfold higher in CMV+ people. Plasma IL-6 was higher in CMV+ donors and showed a positive association with the numbers of CD8+CD28- cells. Finally, there was a significant negative correlation between [vaccine response and the levels of CMV particles present]. This reduced vaccination response was associated with greater numbers of total late differentiated/effector memory cells.

This study observed marked changes in the immune profile of young adults infected with CMV, suggesting that this virus may underlie rudimentary aspects of immunosenescence even in a chronologically young population.


Monday, August 26, 2013

The genomics X Prize had only a slight connection to aging research: the goal was to sequence the genomes of 100 centenarians at a small cost, and add that knowledge to the present state of understanding regarding the genetics of human longevity. That result would have been a side-effect of spurring work in low-cost sequencing. But sequencing is advancing rapidly regardless, there was no great public interest in the prize, and greater understanding of the genetics underlying natural variations in longevity is not the path to greatly extending human life. The research community will meaningfully extend healthy life spans through rejuvenation, by repairing the already known root causes of aging, not by altering human genes to slow down aging.

So all in all, I think that this prize was a poor choice at the outset: the goal not radical enough, and focused on an area of research and development that was already in a state of rapid progress, and with too much funding available for a research prize to be effective.

Mere weeks before its official start, the genomics X Prize - intended to spur a revolution in fast, cheap and accurate human-genome sequencing - has been abruptly cancelled. Peter Diamandis, chair of the X Prize Foundation in Playa Vista, California, says the Archon Genomics X Prize has been abandoned because it was outpaced by innovation.

Announced seven years ago, the prize asked companies to design devices that could sequence 100 human genomes in 30 days or less, with additional requirements for accuracy and cost. Today, companies are routinely sequencing human genomes for less than the $10,000 per genome the prize originally required. But the full picture is more complex. Yes, the cost of genome sequencing has plummeted, which explains why the prize had dropped its cost goal to $1000 per genome. But current technologies are still some way from meeting the revised goal for accuracy: making only one error per million DNA bases sequenced.

Genomics pioneer Craig Venter, who conceived the prize, is disappointed that companies and scientists "seem to have little or no interest in meeting the demanding goals we set up". Indeed, only two teams had entered. Given that the genome-sequencing industry has annual revenues in the billions of dollars, it is perhaps no surprise that a $10 million prize did not prove a huge incentive. In the long term, though, Venter argues that concentrating on speed and cost over accuracy is misguided. "I think for the future, it's an absolute mistake," he says.

Clifford Reid, who heads Complete Genomics of Mountain View, California, one of the leading companies in the field, agrees. But he is confident that accuracy will improve, whether or not there's an X Prize on the table. "The market forces are in the process of changing from meeting the needs of the research community to the needs of medicine," says Reid.

Monday, August 26, 2013

In past years researchers have shown that introducing young cells and cell signaling into old individuals via transplant or parabiosis improves some measures of health and reduces some measures of aging. Research here generally focuses on stem cells and the mechanisms by which stem cell activity declines with age: there appears to be a strong signaling component to this decline, presumably a part of the evolved response to accumulating damage in tissues, a way to minimize cancer risk from damaged cells at the cost of failing tissue maintenance and faster aging. So stem cells remain capable of tissue maintenance, but increasingly refrain.

Here researchers are transplanting a significant fraction of bone marrow rather than using the easier approach of blood transfusions to investigate these effects. They find a modest increase in remaining life expectancy for the old mice receiving bone marrow from young donors, but it is worth noting that this was a small group of animals, and a procedure with a high failure rate at this point - this is an early exploratory proof of concept, preliminary to a more rigorous study:

Tissue renewal is a well-known phenomenon by which old and dying-off cells of various tissues of the body are replaced by progeny of local or circulating stem cells (SCs). An interesting question is whether donor SCs are capable to prolong the lifespan of an aging organism by tissue renewal. In this work, we investigated the possible use of bone marrow (BM) SC for lifespan extension. To this purpose, chimeric C57BL/6 mice were created by transplanting BM from young 1.5-month-old donors to 21.5-month-old recipients. Transplantation was carried out by means of a recently developed method which allowed to transplant without myeloablation up to [about] 25% of the total BM cells of the mouse. As a result, the mean survival time, counting from the age of 21.5 months, the start of the experiment, was +3.6 and +5.0 (±0.1) months for the control and experimental groups, respectively, corresponding to a 39 ± 4% increase in the experimental group over the control.

The oldest transplanted animal lived 3 weeks longer than the oldest control animal. However we cannot calculate the maximal lifespan here, since it is, by definition, the mean lifespan of the most long-lived 10% of each group. In our small group, 10% would be less than one mouse. So, the investigation of an influence of BMT on maximal lifespan is the task for future work.

The obtained positive influence of BMT on the mean lifespan in our work is underestimated because of transplantation complications (including the occlusion of vessels) from which, obviously, suffered not only the two mice that died during transplantation and were excluded from the statistics, but also those that survived, though to a lesser degree. We expect a greater difference in lifespan between control and experimental groups by (i) the use of high-quality commercial filters for purification of transplanted material from cell aggregates and (ii) the use of more accurate controls injected with old BM (in this work the control animals did not get the parallel invasive treatment because of the absence of additional 20 months old animals to produce old BM for control transplantation).

Tuesday, August 27, 2013

A number of lines of research aim to find the basis for human therapies in lower animals that happen to have more favorable outcomes in aging as a result of their genetics and metabolism. Here is one example:

Sarcopenia and dynapenia pose significant problems for the aged, especially as life expectancy rises in developed countries. Current therapies are marginally efficacious at best, and barriers to breakthroughs in treatment may result from currently employed model organisms. Here, we argue that the use of indeterminate-growing teleost fish in skeletal muscle aging research may lead to therapeutic advancements not possible with current mammalian models.

Evidence from a comparative approach utilizing the subfamily Danioninae suggests that the indeterminate growth paradigm of many teleosts arises from adult muscle stem cells with greater proliferative capacity, even in spite of smaller progenitor populations. We hypothesize that paired-box transcription factors, Pax3/7, are involved with this enhanced self-renewal and that prolonged expression of these factors may allow some fish species to escape, or at least forestall, sarcopenia/dynapenia. Future research efforts should focus on the experimental validation of these genes as key factors in indeterminate growth, both in the context of muscle stem cell proliferation and in prevention of skeletal muscle senescence.

Tuesday, August 27, 2013

Researchers here spur greater regeneration following injury by broadcasting on one of the channels used for communication between cells. This is a form of cellular manipulation that will become more subtle and powerful in the years ahead as researchers gain a greater understanding of these channels and the messages they carry:

Exosomes are endosomal origin small-membrane vesicles with a size of 40 to 100 nm in diameter. They are generated by many cell types and contain functional messenger RNAs and micro RNAs (miRNAs), as well as proteins. Exosomes are well suited for small functional molecule delivery and increasing evidence indicates that they have a pivotal role in cell-to-cell communication. Recent studies indicate that exosomes and microvesicles derived from multipotent mesenchymal stromal cells (MSCs) have therapeutic promise in cardiovascular, liver, and kidney diseases. Mesenchymal stromal cells decrease neurologic deficits in rodents after stroke by increasing neurite remodeling, neurogenesis, and angiogenesis.

We have previously demonstrated that functional miRNAs are transferred between MSCs and neural cells via exosomes, and that exosome-encapsulated transfer of miRNAs promotes neurite remodeling and functional recovery of stroke in rat. These data suggest that MSC-generated exosomes enhance the stroke recovery process. Thus, it is reasonable to test the hypothesis that exosomes alone when systemically administered to an animal with stroke improve functional outcome, with therapeutic benefit reflecting that observed with systemically administered MSCs. As a proof-of-principle study, we administer cell-free exosomes generated by MSCs to rats subjected to middle cerebral artery occlusion (MCAo) and investigate functional recovery as well as the mechanisms that underlie it. Our results suggest that intravenous administration of cell-free MSC-generated exosomes post stroke improves functional recovery [and] represents a novel treatment for stroke.

Wednesday, August 28, 2013

Much of the future technology required for rejuvenation of the old involves repairing or cleaning out small-scale protein structures and components in and around cells. Given this, it is worth keeping an eye on the field of synthetic biology, wherein researchers strive to understand, alter, and recreate the low-level machinery of the cell:

Engineering began as an outgrowth of the craftwork of metallurgical artisans. In a constant quest to improve their handiwork, those craftsmen exhaustively and empirically explored the properties - alone and in combination - of natural materials. Today, there is a parallel progression unfolding in the field of synthetic biology, which encompasses the engineering of biological systems from genetically encoded molecular components. The first decade or so of synthetic biology can be viewed as an artisanal exploration of subcellular material. Much as in the early days of other engineering disciplines, the field's focus has been on identifying the building blocks that may be useful for constructing synthetic biological circuits - and determining the practical rules for connecting them into functional systems.

[One] field that now seems poised to undergo a revolution by the forward engineering of cells is biomedicine. Cells naturally perform therapeutic tasks in the body - immune cells identify and remove pathogens, for example - and unlike drugs or molecules, cells can perform complex functions, such as sensing their environments or proliferating. Indeed, patient-specific immune cells are already being genetically engineered with receptors called chimeric antigen receptors (CARs) that allow them to target and destroy tumors in the body. Synthetic circuits and approaches could be used to further enhance these cancer-fighting functions and/or make these cell-based therapies safer. Similar approaches could be envisioned for endowing cells with sense-and-response capabilities to detect and mediate a number of other dysfunctions and pathologies. Promising opportunities for cell-based therapeutics also include patient-specific stem cells for regenerative medicine and microbiome engineering to treat gastrointestinal diseases.

What's more, all of these exciting efforts are occurring simultaneously with our now unprecedented ability to make modifications to the genomes of cells. Using targeting tools, such as zinc fingers, TALEs, and CRISPR/Cas, researchers can now edit specific genes within a genome with very high precision. For example, we can - and do, in the form of gene therapy - use these tools to inactivate genes known to be involved in disease progression or in pathogen life cycles. We can also use them to introduce synthetic circuits into precise locations within a variety of genomes, including in human cells - a feat that would have been impossible less than a decade ago. We can even think about de novo designing and sculpting of genomes to have desirable properties.

Wednesday, August 28, 2013

Researchers have been making good progress in recent years on understanding the mechanisms underlying Parkinson's disease. The condition progresses due to the destruction of a vital set of dopamine-generating neurons in the brain. Like many late-onset conditions, it appears that the root causes of this cell death are an exaggerated form of the harm that falls upon all of us with advancing age. Where Parkinson's has genetic influences, those influences appear to reduce the ability of these cells to maintain themselves against the accumulated damage of aging, hence leading to a faster degeneration and an earlier appearance of the condition. So it is quite possible that one of the outcomes of Parkinson's research will be the understanding necessary to boost the ability of central nervous system cells to maintain themselves in everyone, not just those who are failing more rapidly due to a poor roll of the dice in the genetic lottery.

[Researchers] have brought new clarity to the picture of what goes awry in the brain during Parkinson's disease and identified a compound that eases the disease's symptoms in mice. One of their findings was that the function of an enzyme called parkin, which malfunctions in the disease, is to tag a bevy of other proteins for destruction by the cell's recycling machinery. This means that nonfunctional parkin leads to the buildup of its target proteins, and [researchers] are exploring what roles these proteins might play in the disease.

[Researchers created] mice whose genes for a protein called AIMP2 could be switched into high gear. AIMP2 is one of the proteins normally tagged for destruction by parkin, so the genetically modified mice enabled the research team to put aside the effects of defective parkin and excesses of other proteins and look just at the consequences of too much AIMP2. The consequences were that the mice developed symptoms similar to those of Parkinson's as they aged, the group found. As in Parkinson's patients, the brain cells that make the chemical dopamine were dying.

AIMP2 was activating a self-destruct pathway called parthanatos, [named for the] poly(ADP-ribose), or "PAR," and the Greek word thanatos, which means "messenger of death." [Researchers] had previously seen parthanatos set off after events like traumatic injuries or stroke - not by chronic disease. AIMP2 triggered parthanatos by directly interacting with a protein called PARP1, which was long thought to respond only to DNA damage - not to signals from other proteins.

[The researchers] already knew of compounds drug companies had designed to block this enzyme. Such drugs are already in the process of being tested to protect healthy cells during cancer treatment. Crucially, two of these compounds can cross over the blood-brain barrier that keeps many drugs from affecting brain cells. The research team used a compound that blocks PARP1. "Not only did the compound protect dopamine-making neurons from death, it also prevented behavioral abnormalities similar to those seen in Parkinson's disease."

Thursday, August 29, 2013

Researchers are managing to grow larger masses of tissue from stem cells of late, with more of the structure of the full organ they came from. See, for example, recent work on liver tissue engineering. This is a small step on the way towards full organ regrowth, and will probably be of greatest immediate benefit to further research, testing of therapies, and the like, as three-dimensional engineered tissues of this sort behave much more like the real thing. The brain is of course an organ just like all the others, grown from a genetic blueprint from a selection of cells - so we should expect to see the same progress here as we see for hearts and livers. It is even conceivable that less vital portions of the brain could be replaced or renewed by transplant or regrowth in the future, as not every part of the brain is essential to either storage of the data of the mind or maintenance of life.

Researchers found that immature brain cells derived from stem cells self-organize into brain-like tissues in the right culture conditions. The "cerebral organoids," as the researchers call them, grew to about four millimeters in size and could survive as long as 10 months. For decades, scientists have been able to take cells from animals including humans and grow them in a petri dish, but for the most part this has been done in two dimensions, with the cells grown in a thin layer in petri dishes. But in recent years, researchers have advanced tissue culture techniques so that three-dimensional brain tissue can grow in the lab. The new report [demonstrates] that allowing immature brain cells to self-organize yields some of the largest and most complex lab-grown brain tissue, with distinct subregions and signs of functional neurons.

[This] is the latest advance in a field focused on creating more lifelike tissue cultures of neurons and related cells for studying brain function, disease, and repair. With a cultured cell model system that mimics the brain's natural architecture, researchers would be able to look at how certain diseases occur and screen potential medications for toxicity and efficacy in a more natural setting.

Other groups are developing three-dimensional brain tissue cultures with the hopes of treating degenerative diseases or brain injury. [One set of researchers] has developed a three-dimensional neural culture to study brain injury, with the goal of identifying biomarkers that could be used to diagnose brain injury and potential drug targets for medications that can repair injured neurons. "It's important to mimic the cellular architecture of the brain as much as possible because the mechanical response of that tissue is very dependent on its 3-D structure."

Thursday, August 29, 2013

The immune system declines greatly with aging, and poor immune response is an important component of age-related frailty: old people become vulnerable to infections that the young can shrug off with ease. So we might expect to see that long-lived people have better immune systems, and that whatever underlying mechanisms cause that difference are to some degree inherited.

People may reach the upper limits of the human life span at least partly because they have maintained more appropriate immune function, avoiding changes to immunity termed "immunosenescence." Exceptionally long-lived people may be enriched for genes that contribute to their longevity, some of which may bear on immune function. Centenarian offspring would be expected to inherit some of these, which might be reflected in their resistance to immunosenescence, and contribute to their potential longevity. We have tested this hypothesis by comparing centenarian offspring with age-matched controls. We report differences in the numbers and proportions of both CD4+ and CD8+ early- and late-differentiated T cells, as well as potentially senescent CD8+ T cells, suggesting that the adaptive T-cell arm of the immune system is more "youthful" in centenarian offspring than controls. This might reflect a superior ability to mount effective responses against newly encountered antigens and thus contribute to better protection against infection and to greater longevity.

The goal of future medicine is to make inherited differences of this nature irrelevant. There are a number of promising approaches that may remove much of the age-related decline of immune function: regrow the atrophied thymus, where immune cells are cultured; create new immune cells in the clinic and infuse them regularly into older people; destroy the population of over-specialized memory cells that exist in the elderly, thus freeing up space for effective immune cells that can combat new threats.

Friday, August 30, 2013

Building patches for damaged hearts is a popular implementation in tissue engineering at the moment: it's an achievable stepping stone on the way to more complex goals, such as the creation of entire organs starting from only a patient's stem cells, something that still lies in the future. Progress towards a long-term goal in any field requires useful intermediary products, as they help pull in the greater support and funding needed for the next phase of research and development.

When heart cells die from lack of blood flow during a heart attack, replacing those dead cells is vital to the heart muscle's recovery. But muscle tissue in the adult human heart has a limited capacity to heal, which has spurred researchers to try to give the healing process a boost. Various methods of transplanting healthy cells into a damaged heart have been tried, but have yet to yield consistent success in promoting healing.

Now, [researchers] have developed a patch composed of structurally modified collagen that can be grafted onto damaged heart tissue. Their studies in mice have demonstrated that the patch not only speeds generation of new cells and blood vessels in the damaged area, it also limits the degree of tissue damage resulting from the original trauma. The key [is] that the patch doesn't seek to replace the dead heart-muscle cells. Instead, it replaces the epicardium, the outer layer of heart tissue, which is not muscle tissue, but which protects and supports the heart muscle, or myocardium.

The epicardium - or its artificial replacement - has to allow the cell migration and proliferation needed to rebuild damaged tissue, as well as be sufficiently permeable to allow nutrients and cellular waste to pass through the network of blood vessels that weaves through it. The mesh-like structure of collagen fibers in the patch has those attributes, serving to support and guide new growth. Because the patch is made of acellular collagen, meaning it contains no cells, recipient animals do not need to be immunosuppressed to avoid rejection. With time, the collagen gets absorbed into the organ.

Friday, August 30, 2013

There has been interest in extending increasing telomerase expression as a means to slow aging for some years. The available tools other than gene therapy are sparse on the ground, however. Telomerase extends telomere length, the caps of repeating DNA sequences at the ends of chromosomes that shorten with each cell division. Telomerase may have other roles that more directly impact aging, however, such as an influence on mitochondrial function.

Shorter telomeres in at least some tissues correlate with stress and ill health and aging, but this is a very dynamic system - average telomere length can change in either direction on a short time scale. It is far from clear that progressively shorter telomere length is a cause of aging rather than just a reflection of other changes and damage, and the same goes for natural variations in levels of telomerase in the body. While increasing expression of telomerase is shown to extend life in mice, that may or may not have anything to do with telomere length, and mouse telomerase biology is quite different from that of humans.

So all this said, it was only a matter of time before researchers evaluated all the existing approved drugs for treatment of age-related conditions to see if any of them altered telomerase activity. There are regulatory incentives to beware of here, however, in that it is much cheaper for research institutions to try to find marginal new uses of already approved drugs than to work on new and radically better medical technologies that would then have to go through the exceedingly and unnecessarily expensive approval process. So don't expect anything of great practical use to result from this:

Not only do statins extend lives by lowering cholesterol levels and reducing the risks of cardiovascular disease, but new research [suggests] that they may extend lifespans as well. Specifically, statins may reduce the rate at which telomeres shorten, a key factor in the natural aging process. This opens the door for using statins, or derivatives of statins, as an anti-aging therapy. "By telomerase activation, statins may represent a new molecular switch able to slow down senescent cells in our tissues and be able to lead healthy lifespan extension."

To make this discovery, Paolisso and colleagues worked with two groups of subjects. The first group was under chronic statin therapy, and the second group (control), did not use statins. When researchers measured telomerase activity in both groups, those undergoing statin treatment had higher telomerase activity in their white blood cells, which was associated with lower telomeres shortening along with aging as compared to the control group. This strongly highlights the role of telomerase activation in preventing the excessive accumulation of short telomeres.

"The great thing about statins is that they reduce risks for cardiovascular disease significantly and are generally safe for most people. The bad thing is that statins do have side effects, like muscle injury. But if it is confirmed that statins might actually slow aging itself - and not just the symptoms of aging - then statins are much more powerful drugs than we ever thought."


Post a comment; thoughtful, considered opinions are valued. New comments can be edited for a few minutes following submission. Comments incorporating ad hominem attacks, advertising, and other forms of inappropriate behavior are likely to be deleted.

Note that there is a comment feed for those who like to keep up with conversations.