Fight Aging! Newsletter, December 30th 2013

December 30th 2013

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

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  • A New Approach to Myostatin-Related Muscle Growth
  • Aubrey de Grey Explains the Role of Mitochondrial Mutations in Aging, and What to Do About It
  • Amyloid Buildup in Aging Brains is Decreasing
  • Visualizing the Global Burden of Aging
  • Fundraising Success: $60,000 Raised for Rejuvenation Science, Another $15,000 Matching Grant Announced
  • Latest Headlines from Fight Aging!
    • Examining the Opening Stages of Alzheimer's Disease
    • A Complex Relationship Between Mitochondrial Haplogroups and Natural Variations in Longevity
    • A Heart That Beats for 500 Years
    • Embrace Your Eminently Sensible Fear of Death
    • A Glance at Reflexive Opposition to Radical Life Extension
    • Data to Bolster the Usual Explanation as to Why Conscientious People Live Longer
    • Reversing Glial Scars in Brain Injuries
    • Evidence for Longer Telomeres in Women
    • A Method of Delivering Genes to Mitochondria
    • Reviewing Methods of Life Extension in Flies, From a Perspective of Maintaining Homeostasis


Blocking myostatin has been shown to boost muscle growth and regeneration in various species. There are even a few natural human myostatin mutants, but that is a rare genetic occurrence. For some years now researchers have been investigating means to manipulate myostatin levels and related signaling as a therapy for age-related loss of muscle mass and strength, as well as for various other medical conditions in which wasting of muscles plays a role. This, like many forms of modern medical research, aims to produce a form of compensatory change, potentially beneficial but in no way addressing root causes to prevent progression of the underlying condition.

Researchers here have moved on past myostatin and further down the chain of signals and molecular mechanisms to find a novel place to intervene in order to boost muscle growth in mice and humans. So far results are promising: if this treatment turns out to produce few to no side-effects, it is the sort of thing that everyone could benefit from. That said, again, it doesn't address root causes of degenerative muscle loss with aging - something that needs to be accomplished in order to reliably and most effectively extend healthy life.

New Compound Could Reverse Loss of Muscle Mass in Cancer and Other Diseases

The new compound (BYM338) acts to prevent muscle wasting by blocking a receptor that engages a cellular signaling system that exists to put the brakes on muscle development when appropriate. But sometimes those brakes are activated inappropriately, or are stuck on.

A variety of signals can activate the receptor. Prior to development of BYM338, compounds developed to block these molecules were blunt instruments, either trapping all incoming signals (which stimulated muscle growth but also caused harmful side effects) or blocking just a single receptor activator (providing only tepid growth stimulation.) BYM338 was designed to be in the Goldilocks zone (just right.)

In the study the compound boosted muscle mass 25 to 50 percent and increased strength in animal models. Those gains were significantly superior to those of compounds that blocked a single receptor activator. Clinical trials are currently underway. Preliminary data on the antibody was promising enough to have it designated a breakthrough therapy by the US Food and Drug Administration for sporadic inclusion body myositis, a rare muscle wasting disease with no approved therapies.

Here is a link to the paper - the PDF format full version is also presently available if you'd like to wade in to the details.

An Antibody Blocking Activin type II Receptors Induces Strong Skeletal Muscle Hypertrophy and Protects from Atrophy

The myostatin/Activin type II receptor (ActRII) pathway has been identified as critical in regulating skeletal muscle size. Several other ligands, including GDF11 and the Activins, signal through this pathway, suggesting that the ActRII receptors are major regulatory nodes in the regulation of muscle mass.

We have developed a novel, human anti-ActRII antibody ("Bimagrumab", aka BYM338) to prevent binding of ligands to the receptors, and thus inhibit downstream signaling. BYM338 enhances differentiation of primary human skeletal myoblasts, and counteracts the inhibition of differentiation induced by myostatin or Activin A.

BYM338 dramatically increases skeletal muscle mass in mice, beyond sole inhibition of myostatin as detected by comparing the antibody with a myostatin inhibitor. A mouse version of the antibody induces enhanced muscle hypertrophy in myostatin-mutant mice, further confirming a beneficial effect on muscle growth through blockade of ActRII ligands beyond myostatin inhibition alone.


The SENS Research Foundation (SRF), cofounded by biogerontologist and advocate Aubrey de Grey, funds work on the foundation science needed for tomorrow's rejuvenation therapies. We age and die because the operation of our metabolism generates various forms of cellular and molecular damage, some fraction of which goes unrepaired. Like rust, it accumulates and degrades the operation of organs and tissues to cause age-related disease and, ultimately, death. Work aimed at treating and repairing the root causes of aging is arguably the most important research presently taking place today: even if we combine every other cause of human suffering and death into one total, that toll is only half of the harm caused by aging.

In addition to funding research, the SENS Research Foundation staff and supporters also engage in advocacy relating to rejuvenation research: education, raising awareness, and fundraising. Too few scientists are engaged, there is far too little funding considering the gains that might be obtained comparatively soon with a suitable large-scale research program, and the public is largely ignorant and indifferent, even as they age to death, with more than hundred thousand lives lost to aging every day.

One aspect of the Foundation's outreach efforts is a growing YouTube video library of lectures and presentations by researchers in the field. A recent addition has Aubrey de Grey walking through the role of mitochondrial DNA damage, the present state of knowledge in the field, and what might be done to reverse this contribution to degenerative aging:

In this video, SRF Chief Science Officer Dr. Aubrey de Grey discusses mitochondrial mutations, their role in aging, and the SENS approach to combating their deleterious effects. Dr. de Grey opens his lecture by describing the structure of mitochondrial DNA (mtDNA) in humans. In particular, he explains that only thirteen protein-encoding mitochondrial genes actually reside in mitochondria. Throughout the course of human evolution, over a thousand other mitochondrial genes have migrated to the nuclear genome.

Next, he explains the major theories developed between the 1970 and the present that aimed to explain the role of mtDNA mutations in aging. During his discussion of the most recent theoretical ground, Dr. de Grey explains his own contribution to the field: an alternative hypothesis to explain how clonal expansion of mutant mitochondria might occur. He then turns to therapeutic strategies and discusses the three main mechanisms by which scientists might intervene in mitochondrial aging.

Dr. de Grey closes by describing the mechanism SRF finds most promising: inserting the thirteen protein-encoding mitochondrial genes into the nucleus modified in such a way that the corresponding RNA transcripts or protein-products can be imported into the mitochondria.


We are living longer than our predecessors. Much of that is due to improvements in prevention of early life mortality relating to diet, control of infectious disease, sanitation, and similar items. A person who suffers many more infections and other health challenges in younger life, while eating a poor diet, will be more frail in later life. Thus methods of reducing early life mortality have the additional effect of extending life expectancy at older ages as well.

This first phase of technological improvement in overall wealth, medicine, and sanitation is largely done, the big initial gains secured. The present trend of interest is a slow upward movement in adult life expectancy driven by (a) continued smaller gains in control of disease and other forms of medicine for young adults, and (b) improvements in the treatment and control of age-related disease. The pace is slow in the latter case because age-related diseases are late stage manifestations of spiraling damage and dysfunction in the body, well past the point at which the web of biological consequences and relationships are easy to understand or treat.

Aging is an accumulation of damage: broken DNA, damaged molecular machinery, malprogrammed cells, metabolic waste products gumming up necessary functions, and more. Our biology can and does repair some of these issues on an ongoing basis, but as the damage accumulates even normally very efficient damage repair systems start to fail, driving a downward spiral of ever-faster dysfunction. Nonetheless, we are living longer and so we must expect that at any given age we are, on balance, less damaged than our ancestors. Since we are living measurably longer than people did even half a century ago (by something like ten years of life expectancy at birth, and more like five for adult life expectancy), this decline in damage must be visible over even such a short time frame.

Below you'll fine an example of such a measure. Amyloid is a precipitation of misfolded proteins that forms in old tissues in fibrils and other structures. There are numerous different types of amyloid, not all definitively tied to specific forms of age-related degeneration at this time, but if you have heard of amyloid then it is probably in connection with Alzheimer's disease (AD), in which amyloid buildup is thought to play an important role. The presence of amyloid is a noteworthy difference between young and old tissue, and levels of amyloid tend to correlate with levels of dysfunction and disease.

Amyloid deposition is decreasing in aging brains

We compared amyloid deposition in autopsied cases aged 65 years and older who died between 1972 and 2006. We included consecutive cases for 1972-1975, 1980, 1985, 1990, 1995, and 2000-2006. We used linear regression models to assess period effects after adjustment for age, cognitive status, and neurofibrillary tangle (NFT) staging. We calculated amyloid/NFT stage ratios to account for possible changes in AD prevalence/severity over time.

Mean amyloid stage was significantly related to year of death in the total population (1,599 cases, mean age 82 ± 8 years) and decreased 24% in 1,265 individuals without dementia. This decrease was particularly marked in the oldest age groups; people 85 years and older in 2006 had less amyloid deposition compared with those aged 75 to 84 years in 1972. Recent cohorts had lower amyloid deposition. The amyloid/NFT stage ratio [decreased], confirming that more recent cases had less amyloid despite higher NFT densities.

The strong cohort effect we describe [provides] preclinical evidence supporting recently described decreases in AD incidence.


Today I was pointed to the Institute for Health Metrics and Evaluation, an organization that - among other things - provides a set of interesting visualization tools for exploring changing health and mortality data by country and cause. Part of the focus here is the traditional one on infectious disease and developing world health, but the data is global in extent, and at least two thirds of the burden of disease in the world is in fact the burden of aging: the progressive failure of the body due to damage that accumulates as a natural consequence of the operation of metabolism.

Unlike most of the presentations I've glanced at in the past, these visualizations also cover years spent in ill health, not just the bottom line of mortality. You can spent quite a lot of time walking through this data and finding things you might not have known about trends and risks.

So very much of this suffering and death due to aging - hundred of millions with disability and disease, and more than 100,000 deaths every day - is now beginning to verge on preventable. We are just a handful of years away from first generation rejuvenation therapies, were the right research strategies fully funded at this time. That full funding is minuscule in the grand scheme of things: perhaps one to two billion dollars over the next ten to twenty years. The lower end of that range is about 5% of the budget of the National Institute on Aging over the same period of time, or about what is spent on pushing a single drug to market in the Big Pharma ecosystem, or less than than the sums wasted on US politics in a presidential election year, or less than the cost per machine for some military aircraft. Priorities.


For the past month Fight Aging!, Jason Hope, and the Methuselah Foundation have been running a 3 to 1 match on up to $15,000 donated to the SENS Research Foundation before the end of the year. The Foundation is perhaps the only organization in the world presently working earnestly and seriously on the scientific foundations needed to produce actual, real, working rejuvenation therapies, piece by piece over the next few decades. The Foundation is very well connected in the research community, funds projects in labs around the world, and the scientific advisory board is made up of well-regarded names from numerous fields in the life sciences and medicine.

It is the grassroots that drives the growth of any organization: the more people that show support the easier it becomes to win large investments from conservative funding sources and philanthropists. Multi-million dollar donations for medical research only happen when thousands of people make it known that this cause is worth it by giving a little each. Thus more money raised and more supporters raising their voices at this comparatively early juncture will lead to accelerating progress over the years ahead, moving us towards the large-scale funding needed for the best practical rate of growth in this field of research. None of us are getting any younger, after all, and time is of the essence.

I'm very pleased to say that even after past months of generous donations to fund a number of projects relating to healthy life extension and research, the community still pulled together to find the full $15,000 in just a few weeks, pulling in the combined $45,000 in matching funds from Fight Aging!, Jason Hope, and the Methuselah Foundation.

But that isn't all: long-time Methuselah Foundation donor Michael Cooper has put up another $15,000 matching fund that has yet to be met. Further donations will be matched by this - so if you are still on the fence or late to the news, here is your chance. This was in the mail today from the SENS Research Foundation staff to announce present success and continued work to meet their original year-end goal of $100,000 put forward in November:

Everyone at SENS Research Foundation would like to thank you for your support of our work to change the way the world researches and treats age-related disease throughout 2013.

We are pleased to announce that your generous contributions have enabled us to fully realize our three matching grants from Jason Hope, the Methuselah Foundation and Fight Aging!.

To add to the good news, we have now received a new matching grant of $15,000 from Michael Cooper. We need your help to match this grant between now and the end of the year. Help us to meet our goal of raising $100,000 by visiting our donate page today. All donations to SENS Research Foundation are tax deductible.

Aging affects us all and the research needed to stop the suffering caused by Alzheimer's, heart disease, cancer, and other age-associated health problems remains in critical need of better funding. Please consider SRF as you choose your charitable contributions this season.

Thank you again for supporting SENS Research Foundation! Have a happy and healthy New Year.


Monday, December 23, 2013

Researchers here add data to the picture of the early stages of Alzheimer's disease:

"It has been known for years that Alzheimer's starts in a brain region known as the entorhinal cortex. But this study is the first to show in living patients that it begins specifically in the lateral entorhinal cortex, or LEC. The LEC is considered to be a gateway to the hippocampus, which plays a key role in the consolidation of long-term memory, among other functions. If the LEC is affected, other aspects of the hippocampus will also be affected."

The study also shows that, over time, Alzheimer's spreads from the LEC directly to other areas of the cerebral cortex, in particular, the parietal cortex, a brain region involved in various functions, including spatial orientation and navigation. The researchers suspect that Alzheimer's spreads "functionally," that is, by compromising the function of neurons in the LEC, which then compromises the integrity of neurons in adjoining areas.

A third major finding of the study is that LEC dysfunction occurs when changes in tau and amyloid precursor protein (APP) co-exist. "The LEC is especially vulnerable to Alzheimer's because it normally accumulates tau, which sensitizes the LEC to the accumulation of APP. Together, these two proteins damage neurons in the LEC, setting the stage for Alzheimer's."

"Now that we've pinpointed where Alzheimer's starts, and shown that those changes are observable using fMRI, we may be able to detect Alzheimer's at its earliest preclinical stage, when the disease might be more treatable and before it spreads to other brain regions." In addition, say the researchers, the new imaging method could be used to assess the efficacy of promising Alzheimer's drugs during the disease's early stages.

Monday, December 23, 2013

Mitochondria, the power plants of the cell, bear their own mitochondrial DNA (mtDNA) that is inherited from the mother. There are a range of common variants of human mitochondrial DNA known as haplogroups, and given that mitochondria are important in aging there is an expectation that some of the natural variation in human longevity can be explained via haplogroup differences. Indeed, there is evidence to suggest that some haplogroups are better than others when it comes to life expectancy, all other things being equal.

These effects are not large in the grand scheme of things, however, and as for everything involving the genetics of longevity the underlying mechanisms and relationships are complicated:

To re-examine the correlation between mtDNA variability and longevity, we examined mtDNAs from samples obtained from over 2200 ultranonagenarians (and an equal number of controls) collected within the framework of the GEHA EU project. The samples were categorized by high-resolution classification, while about 1300 mtDNA molecules (650 ultranonagenarians and an equal number of controls) were completely sequenced.

Sequences, unlike standard haplogroup analysis, made possible to evaluate for the first time the cumulative effects of specific, concomitant mtDNA mutations, including those that per se have a low, or very low, impact. In particular, the analysis of the mutations occurring in different OXPHOS complex showed a complex scenario with a different mutation burden in 90+ subjects with respect to controls.

These findings suggested that mutations in subunits of the OXPHOS complex I had a beneficial effect on longevity, while the simultaneous presence of mutations in complex I and III (which also occurs in J subhaplogroups involved in LHON) and in complex I and V seemed to be detrimental, likely explaining previous contradictory results. On the whole, our study, which goes beyond haplogroup analysis, suggests that mitochondrial DNA variation does affect human longevity, but its effect is heavily influenced by the interaction between mutations concomitantly occurring on different mtDNA genes.

Tuesday, December 24, 2013

The ocean quahog species of Arctica islandica can live for at least 500 years and individuals appear to undergo comparatively little in the way of obvious degeneration across that span. Many species of bivalve live only a couple of years, and this very large range of life spans in similar animals has attracted researchers who wish to uncover the molecular biology that determines longevity.

Study of negligibly senescent animals may provide clues that lead to better understanding of the cardiac aging process. To elucidate mechanisms of successful cardiac aging, we investigated age-related changes in proteasome activity, oxidative protein damage and expression of heat shock proteins, inflammatory factors, and mitochondrial complexes in the heart of the ocean quahog Arctica islandica, the longest-lived noncolonial animal (maximum life span potential: 508 years).

We found that in the heart of A. islandica the level of oxidatively damaged proteins did not change significantly up to 120 years of age. No significant aging-induced changes were observed in caspase-like and trypsin-like proteasome activity. Chymotrypsin-like proteasome activity showed a significant early-life decline, then it remained stable for up to 182 years. No significant relationship was observed between the extent of protein ubiquitination and age. In the heart of A. islandica, an early-life decline in expression of HSP90 and five mitochondrial electron transport chain complexes was observed. We found significant age-related increases in the expression of three cytokine-like mediators (interleukin-6, interleukin-1β, and tumor necrosis factor-α) in the heart of A. islandica.

Collectively, in extremely long-lived molluscs, maintenance of protein homeostasis likely contributes to the preservation of cardiac function. Our data also support the concept that low-grade chronic inflammation in the cardiovascular system is a universal feature of the aging process, which is also manifest in invertebrates.

Tuesday, December 24, 2013

Coming to terms with a personal future of disability, pain, and then death due to aging is very human. But coming to terms is one step removed from complacency, and the world is complacent about aging and the staggering toll of death and suffering it causes. Thus research into prevention of aging and treatments that might remove this death and suffering languish with little funding and interest, and the populace go about their days doing their best to ignore the fact that they are corroding away inside. If aging were treatable, no-one would want to go back to when it was not - that would be a nonsensical proposition, like restoring smallpox and famine. Yet all too few people today care to help us move forward into a better world.

Is there a person alive today who does not fear dying? Well yes, if they are asleep or in a coma. But most of us, while we are awake and going about our business, harbour a deep-seated fear of dying. ("Thanatophobia", in case anyone was wondering, being Greek for "fear of death".) . Now the question is what to do about it, the two opposing extremes being: try to repress it as much as possible, or embrace it with all your being. Repressing it was my first strategy. I had no idea what to do with this fear, except that I wanted it to go away. And my strategy for making it go away was essentially to not think about it. And that worked, most of the time.

One very good reason for repressing thanatophobia is that if we don't it can drive us nuts. Nobody can tolerate being scared the whole time, and the risk - even, arguably, the certainty - of dying is always there. So we must suppress it. We wouldn't have it, however, if it wasn't serving a useful purpose, and it is also thanatophobia that makes us look before we cross the road. So while there are times when we must suppress it, there are other times when we do and must embrace it.

So far this is nothing that should be particularly shocking for anyone. What is shocking for many people, however, is the possibility that we might develop technology that extends life well beyond our current life-spans. And the reason it is shocking, in my view, is that it interferes with people's delicate strategies for managing their thanatophobia. Anything that reminds people that they are not only likely (perhaps even certain) to die, but that they are terrified of this prospect, tends to horrify them. So they enter what Aubrey de Grey has described as the "pro-aging trance", in which they convince themselves that since aging (and eventual death) is inevitable it must be desirable, and that because it is desirable it must also be inevitable.

What this means, in my view, is that whatever we think of the pros and cons of radical life extension, if we are to steer ourselves as individuals and as a species through the "bottleneck" of the next few decades, we need to make greater efforts to embrace our fear of death. We need to allow ourselves to be aware of that fear, and allow it to motivate us, without completely taking over.

Wednesday, December 25, 2013

This columnist sees the signs of progress, thinks that extended longevity is plausible, but rejects radical life extension on the flimsy grounds that only death gives life meaning and removes the possibility of stasis. This seems particularly silly given that, I'm sure, this isn't someone who would advocate moving life expectancy back to where it was a century or two ago. So would he argue that life is less meaningful now, more of a "featureless expanse" as he puts it?

Death doesn't give life meaning - it strips meaning, and everything else, from us. Being alive is what allows us to inject meaning into life, and for so long as you are alive you can be a font of meaning if that's what drives you. We can draw lines and calculate totals and change careers and directions wherever we want, and then start over to work on something new and interesting. This already happens constantly throughout life, just the same as it did a century or two ago, and just the same as it will when people live far longer in good health.

The buzz around radical life extension is such that the dot-com gurus who brought us the likes of Google and PayPal now find themselves laser-focused on an Age of Longevity, as if transforming our lives was not enough whereas doubling them through moonshot thinking would be an incontrovertible contribution to human progress. Connectivity was O.K., but conjuring super-centenarians will be better. Larry Page, the chief executive of Google, and Peter Thiel, the Silicon Valley billionaire, early investor in Facebook and co-founder of PayPal, are among those who, in separate ventures, have aging in their cross hairs.

"If people think they are going to die, it is demotivating," Thiel told me. "The idea of immortality is motivational." He described his ideas as "180 degrees the opposite" of Steve Jobs's, who once said: "Remembering that you are going to die is the best way I know to avoid the trap of thinking you have something to lose. You are already naked. There is no reason not to follow your heart." It is probably wise to take Thiel's idea of an end to aging (or at least its radical postponement) seriously. Any extrapolation from technological progress over the past quarter-century makes the notion plausible. At least seriously enough to ask the question: Do we want this Shangri-La?

This year, the Pew Research Center found that in the United States, where current life expectancy is 78.7 years, 56 percent of American adults said they would not choose to undergo medical treatments to live to 120 or more. This resistance to the super-centenarian dream demonstrates good sense. Immortality - how tempting, how appalling! What a suffocating trick on the young! Death is feared, but it is death that makes time a living thing. Without it life becomes a featureless expanse. I fear death, up to a point, but would fear life without end far more: All those people to see over and over again, worse than Twitter with limitless characters.

Wednesday, December 25, 2013

In a better world, researchers who presently spend their time figuring out how and why personality traits correlate to life expectancy would instead be working on rejuvenation treatments. Alas, most of the study of aging is just that - study, with little to no interest in producing treatments. Here, scientists provide additional data to support the usual explanation as to why conscientious people live longer: they are taking better care of their health by refraining from smoking, engaging in regular exercise, not carrying excess fat tissue, and so forth. No doubt they are also making better use of available preventative and other medical services, but that isn't examined in this study.

Personality traits predict both health behaviors and mortality risk across the life course. However, there are few investigations that have examined these effects in a single study. Thus, there are limitations in assessing if health behaviors explain why personality predicts health and longevity. Utilizing 14-year mortality data from a national sample of over 6,000 adults from the Midlife in the United States Study, we tested whether alcohol use, smoking behavior, and waist circumference mediated the personality-mortality association.

After adjusting for demographic variables, higher levels of Conscientiousness predicted a 13% reduction in mortality risk over the follow-up. Structural equation models provided evidence that heavy drinking, smoking, and greater waist circumference significantly mediated the Conscientiousness-mortality association by 42%. The current study provided empirical support for the health-behavior model of personality - Conscientiousness influences the behaviors persons engage in and these behaviors affect the likelihood of poor health outcomes.

Thursday, December 26, 2013

Researchers here are working on a way to remove a type of scarring that occurs in brain injuries and forms of neurodegeneration:

When the brain is harmed by injury or disease, neurons often die or degenerate, but glial cells become more branched and numerous. These "reactive glial cells" initially build a defense system to prevent bacteria and toxins from invading healthy tissues, but this process eventually forms glial scars that limit the growth of healthy neurons. "There are more reactive glial cells and fewer functional neurons in the injury site, so we hypothesized that we might be able to convert glial cells in the scar into functional neurons at the site of injury in the brain."

[The researchers] began by studying how reactive glial cells respond to a specific protein, NeuroD1, which is known to be important in the formation of nerve cells in the hippocampus area of adult brains. They hypothesized that expressing NeuroD1 protein into the reactive glial cells at the injury site might help to generate new neurons - just as it does in the hippocampus. To test this hypothesis, his team infected reactive glial cells with a retrovirus that specifies the genetic code for the NeuroD1 protein.

In a first test, [researchers injected] NeuroD1 retrovirus into the cortex area of adult mice. The scientists found that two types of reactive glial cells - star-shaped astroglial cells and NG2 glial cells - were reprogrammed into neurons within one week after being infected with the NeuroD1 retrovirus.

In a second test, [researchers] used a transgenic-mouse model for Alzheimer's disease, and demonstrated that reactive glial cells in the mouse's diseased brain also can be converted into functional neurons. Furthermore, the team demonstrated that even in 14-month-old mice with Alzheimer's disease - an age roughly equivalent to 60 years old for humans - injection of the NeuroD1 retrovirus into a mouse cortex can still induce a large number of newborn neurons reprogrammed from reactive glial cells.

Thursday, December 26, 2013

Women tend to live longer than men for reasons that remain much debated, an example of the way in which identifying cause and effect for natural variations in longevity can be very challenging. Telomeres, the caps of repeating DNA sequences at the end of chromosomes, tend to become shorter on average with age and illness. Some forms of telomere length measurement in some tissues may be useful as a biomarker of aging, but so far this hasn't proven to be straightforward. Given these two line items we might expect to find that women have longer telomeres than men, once the details are sorted out:

It is widely believed that females have longer telomeres than males, although results from studies have been contradictory. We carried out a systematic review and meta-analyses to test the hypothesis that in humans, females have longer telomeres than males and that this association becomes stronger with increasing age. Searches were conducted in EMBASE and MEDLINE and additional datasets were obtained from study investigators. Eligible observational studies measured telomeres for both females and males of any age, had a minimum sample size of 100 and included participants not part of a diseased group. We calculated summary estimates using random-effects meta-analyses. Heterogeneity between studies was investigated using sub-group analysis and meta-regression.

Meta-analyses from 36 cohorts (36,230 participants) showed that on average females had longer telomeres than males. There was little evidence that these associations varied by age group or cell type. However, the size of this difference did vary by measurement methods, with only Southern blot but neither real-time PCR nor FlowFISH showing a significant difference. This difference was not associated with random measurement error. Further research on explanations for the methodological differences is required.

Friday, December 27, 2013

One of the causes of aging is mitochondrial DNA damage. The mitochondria, the cell's herd of bacteria-like power plants, contain their own DNA, separate from that in the cell nucleus. It is more vulnerable to damage: mitochondrial DNA repair mechanisms are not as good as those operating in the nucleus, and mitochondria generate reactive free radical molecules in the course of their operation.

DNA provides the blueprints for protein machinery, and some forms of damage to mitochondrial DNA can lead to crippled mitochondria that can nonetheless out-compete their undamaged brethren. Cells become taken over by broken mitochondria and themselves begin to malfunction and harm surrounding tissue: by the time you are old this is a very significant issue that contributes to a range of fatal age-related conditions. Yet this can all be reversed provided that the necessary proteins are provided to the mitochondria. There are numerous strategies, some more permanent than others: the SENS Research Foundation favors a one-time life-long fix that puts copies of mitochondrial genes into the cell nucleus, for example. But more temporary solutions include delivering the proteins directly, or delivering extra copies of undamaged mitochondrial DNA to swamp out the damaged copies and provide the necessary protein blueprints.

A number of ways are either proposed or demonstrated to deliver new DNA to mitochondria, and here is another of them. As is usually the case, the focus here is on comparatively rare genetic disorders rather than the ubiquitous problem of aging, however:

Mitochondrial genetic disorders are a major cause of mitochondrial diseases. It is therefore likely that mitochondrial gene therapy will be useful for the treatment of such diseases. Here, we report on the possibility of mitochondrial gene delivery in skeletal muscle using hydrodynamic limb vein (HLV) injection. The HLV injection procedure, a useful method for transgene expression in skeletal muscle, involves the rapid injection of a large volume of naked plasmid DNA (pDNA) into the distal vein of a limb.

We hypothesized that the technique could be used to deliver pDNA not only to nuclei but also to mitochondria, since cytosolic pDNA that is internalized by the method may be able to overcome mitochondrial membrane. We determined if pDNA could be delivered to myofibrillar mitochondria by HLV injection by PCR analysis. These findings indicate that HLV injection promises to be a useful technique for in vivo mitochondrial gene delivery.

Friday, December 27, 2013

If you consider aging to be an accumulation of cellular and molecular damage, then loss of homeostasis in tissues - a progressive failure of stability and maintenance - is a consequence of that damage, and epigenetic changes shown to occur with aging are reactions to damage or driven by damage. The way to reverse the issue is to repair the damage. If, on the other hand, you consider aging to be a genetic program, then loss of homeostasis and damage are both consequences of these epigenetic changes. The way to reverse the issue is to restore epigenetic patterns to a youthful level.

Interestingly, while the majority of the research community holds the view that aging is damage accumulation, they also tend to work on projects that better fit the programmed aging hypothesis - aiming to use drugs to alter the operation of metabolism in order to slow aging, for example. This is most likely because these projects look more like past drug development and exploration of the molecular basis for disease, and are thus more palatable to conservative funding sources and regulatory bodies. This is just one of numerous ways in which the research community proceeds in a less than rational manner, following short term incentives at the expense of longer term goals.

Aging is characterized by a widespread loss of homeostasis in biological systems. An important part of this decline is caused by age-related deregulation of regulatory processes that coordinate cellular responses to changing environmental conditions, maintaining cell and tissue function. Studies in genetically accessible model organisms have made significant progress in elucidating the function of such regulatory processes and the consequences of their deregulation for tissue function and longevity. Here, we review such studies, focusing on the characterization of processes that maintain metabolic and proliferative homeostasis in the fruitfly Drosophila melanogaster.

The primary regulatory axis addressed in these studies is the interaction between signaling pathways that govern the response to oxidative stress, and signaling pathways that regulate cellular metabolism and growth. The interaction between these pathways has important consequences for animal physiology, and its deregulation in the aging organism is a major cause for increased mortality.

Importantly, protocols to tune such interactions genetically to improve homeostasis and extend lifespan have been established by work in flies. This includes modulation of signaling pathway activity in specific tissues, including adipose tissue and insulin-producing tissues, as well as in specific cell types, such as stem cells of the fly intestine.


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