Via ScienceDaily: researchers "have identified two key regulatory proteins critical to clearing away misfolded proteins that accumulate and cause the progressive, deadly neurodegeneration of Huntington's disease (HD). ... It's a lead we can vigorously pursue, not just for Huntington's disease, but also for similar neurodegenerative conditions like Parkinson's disease and maybe even Alzheimer's disease. ... In HD, an inherited mutation in the huntingtin (htt) gene results in misfolded htt proteins accumulating in certain central nervous system cells. ... [Researchers] focused on a protein called PGC-1alpha, which helps regulate the creation and operation of mitochondria, the tiny organelles that generate the fuel required for every cell to function. ... It's all about energy. Neurons have a constant, high demand for it. They're always on the edge for maintaining adequate levels of energy production. PGC-1alpha regulates the function of transcription factors that promote the creation of mitochondria and allow them to run at full capacity. ... the mutant form of the htt gene interfered with normal levels and functioning of PGC-1alpha, [and] elevated levels of PGC-1alpha in a mouse model of HD virtually eliminated the problematic misfolded proteins. ... PGC-1alpha influenced expression of another protein vital to autophagy - the process in which healthy cells degrade and recycle old, unneeded or dangerous parts and products, including oxidative, damaging molecules generated by metabolism. For neurons, which must last a lifetime, the self-renewal is essential to survival. ... Mitochondria get beat up and need to be recycled. PGC-1alpha drives this pathway through another protein called transcription factor EB or TFEB. ... If you can induce the bioenergetics and protein quality control pathways of nervous system cells to function properly, by activating the PGC-1alpha pathway and promoting greater TFEB function, you stand a good chance of maintaining neural function for an extended period of time."

Link: http://www.sciencedaily.com/releases/2012/07/120711141853.htm

Source:
http://www.longevitymeme.org/newsletter/latest_rss_feed.cfm

Via ScienceDaily: researchers "have identified two key regulatory proteins critical to clearing away misfolded proteins that accumulate and cause the progressive, deadly neurodegeneration of Huntington's disease (HD). ... It's a lead we can vigorously pursue, not just for Huntington's disease, but also for similar neurodegenerative conditions like Parkinson's disease and maybe even Alzheimer's disease. ... In HD, an inherited mutation in the huntingtin (htt) gene results in misfolded htt proteins accumulating in certain central nervous system cells. ... [Researchers] focused on a protein called PGC-1alpha, which helps regulate the creation and operation of mitochondria, the tiny organelles that generate the fuel required for every cell to function. ... It's all about energy. Neurons have a constant, high demand for it. They're always on the edge for maintaining adequate levels of energy production. PGC-1alpha regulates the function of transcription factors that promote the creation of mitochondria and allow them to run at full capacity. ... the mutant form of the htt gene interfered with normal levels and functioning of PGC-1alpha, [and] elevated levels of PGC-1alpha in a mouse model of HD virtually eliminated the problematic misfolded proteins. ... PGC-1alpha influenced expression of another protein vital to autophagy - the process in which healthy cells degrade and recycle old, unneeded or dangerous parts and products, including oxidative, damaging molecules generated by metabolism. For neurons, which must last a lifetime, the self-renewal is essential to survival. ... Mitochondria get beat up and need to be recycled. PGC-1alpha drives this pathway through another protein called transcription factor EB or TFEB. ... If you can induce the bioenergetics and protein quality control pathways of nervous system cells to function properly, by activating the PGC-1alpha pathway and promoting greater TFEB function, you stand a good chance of maintaining neural function for an extended period of time."

Link: http://www.sciencedaily.com/releases/2012/07/120711141853.htm

Source:
http://www.longevitymeme.org/newsletter/latest_rss_feed.cfm

It is unfortunate that popular culture, that ongoing conversation of countless threads that lies at the center of our diverse society, is so focused on drugs and pills as the sum of all medicine - anything that is consumed, and so especially when it comes to influencing the pace of aging. It is a terribly wrong, horribly damaging viewpoint, but one that is relentless propagated by the loudest voices, coincidentally also those who gain the most in the short term by creating a culture of customers for their products. When the world thinks of medicine for aging in terms of pills and potions, it shuts the door on support for real rejuvenation biotechnology, such as the detailed plans for development advocated by the SENS Foundation and others.

Part of the process of building the true medicine of rejuvenation - which will look like gene therapies, tailored cell alterations, engineered enzymes to strip away harmful metabolic side-products, and so on - is obtaining the support and at least superficial understanding of the public at large. That is still very much lacking, and some fraction of the blame for that can be pinned on the short-sighted idiots of the "anti-aging" marketplace who propagate lies and myths about aging and what can be done about it in order to sell products that do next to nothing. They have spent so much time and effort on this over the past decades that they have shaped the visions of popular culture to follow their message - and that harms us all by stripping away possible support for meaningful research and development, and making it harder to create that support.

The vast majority of commentary on aging, science, longevity, and what can be done about it is garbage at worst, and interesting but ultimately irrelevant to the future of our lives at best. Into the latter half falls work on calorie restriction mimetics such as metformin and rapamycin. They simply don't do enough to worth sinking billions of dollars into further research and development - though of course that research and development will happen anyway, regardless of my opinions on the matter. There are far better paths ahead than tinkering with compounds and genes that have modest effects, on a par with calorie restriction, and potentially serious side-effects to go along with that.

If results are what matter - and I think they are the only measure worth considering given the pace of death caused by aging - then world of aging and longevity research should focus on the SENS vision of targeted, deliberate repair of specific forms of damage, and move on from the tired old model of patching the end results of damage by trying a lot of compounds to find some that sort of do something beneficial. Nor should research spend their time on the comparatively new approach of trying to slow down the pace at which damage accumulates - again by trying a bunch of compounds to find some that sort of do something beneficial.

There are now far more effective paths forward for the treatment of aging than the approaches undertaken in past decades when biotechnology and the state of knowledge was too poor to do better. The world of aging science must up-end, change, become quite different. The SENS Foundation and the network of research groups working on related matters are doing the right thing. Big Pharma, the calorie restriction mimetic developers, the people searching for longevity genes or gene therapies to slow aging - they are heading down a side-path that will do little beyond generating new knowledge. Our lives will not be greatly lengthened by their efforts, as we will be old by the time that they produce therapies with modest effects on human life span by slowing down the pace at which damage accumulates. Ways to slow aging are of little value to those already aged. Our healthy lives will be significantly extended only by the successful development of methods of rejuvenation - of damage repair, ways to actually reverse the toll of aging on cells and systems.

Which, conveniently, are planned out and proposed in some detail.

Source:
http://www.longevitymeme.org/newsletter/latest_rss_feed.cfm

From Maria Konovalenko: "I met Dr. Bredesen during the Buck Advisory Council meeting at the Buck Institute for Research on Aging in Novato, California on May 21. [The] Advisory Council consists of influential individuals who can contribute to Buck Institute's mission of advancing aging research. A very interesting crowd. ... Dale Bredesen opened the mini conference with his report on Alzheimer's research. The majority of scientists envision this horrible degenerative process as accumulation of toxic molecules, namely amyloid beta and tau proteins. Amyloid beta forms plaques between the cells and tau protein tangles inside the cells. These toxic proteins disrupt the functions of our neurons. ... So, Dr. Bredesen views Alzheimer's disease differently - as an imbalance between synaptic maintenance and synaptic reorganization. The thing is that for our brain to function properly we need to form connections between our neurons, and also we need to break down those connections that we no longer need. According to Dale Bredesen, this balance disrupts, it shifts towards synaptic reorganization, we loose our memory, face the horrors of loosing our consciousness and eventually we die. ... So how can we preserve this balance? Dr. Bredesen's lab studies the underlying mechanisms of neurodegeneration. There were able to find out that one of the things that contributes to the balance shift is the change in APP cleavage. APP is amyloid precursor protein. It is concentrated in synapses of our neurons. APP can break down into either two, or four parts. When it breaks down into 2 parts those proteins are sAPP alfa and CTF alfa. This is a 'good' combination. However, during aging amyloid precursor protein cleavage shifts towards the 'bad' combination, which is sAPP beta, Amyloid beta, Jcasp and C31. This is the shift in balance that leads to the onset of disease. The shift can be restored. The mouse strain that has one mutation that leads to not having APP to break down to Jcasp and C31 proteins leads to restoring memory in mice. But the most exciting thing is that Dr. Bredesen is testing a drug that shifts the APP cleavage balance back to normal."

Link: http://mariakonovalenko.wordpress.com/2012/07/03/dale-bredesen-alzheimers-is-a-problem-of-imbalance-not-toxicity/

Source:
http://www.longevitymeme.org/newsletter/latest_rss_feed.cfm

From Maria Konovalenko: "I met Dr. Bredesen during the Buck Advisory Council meeting at the Buck Institute for Research on Aging in Novato, California on May 21. [The] Advisory Council consists of influential individuals who can contribute to Buck Institute's mission of advancing aging research. A very interesting crowd. ... Dale Bredesen opened the mini conference with his report on Alzheimer's research. The majority of scientists envision this horrible degenerative process as accumulation of toxic molecules, namely amyloid beta and tau proteins. Amyloid beta forms plaques between the cells and tau protein tangles inside the cells. These toxic proteins disrupt the functions of our neurons. ... So, Dr. Bredesen views Alzheimer's disease differently - as an imbalance between synaptic maintenance and synaptic reorganization. The thing is that for our brain to function properly we need to form connections between our neurons, and also we need to break down those connections that we no longer need. According to Dale Bredesen, this balance disrupts, it shifts towards synaptic reorganization, we loose our memory, face the horrors of loosing our consciousness and eventually we die. ... So how can we preserve this balance? Dr. Bredesen's lab studies the underlying mechanisms of neurodegeneration. There were able to find out that one of the things that contributes to the balance shift is the change in APP cleavage. APP is amyloid precursor protein. It is concentrated in synapses of our neurons. APP can break down into either two, or four parts. When it breaks down into 2 parts those proteins are sAPP alfa and CTF alfa. This is a 'good' combination. However, during aging amyloid precursor protein cleavage shifts towards the 'bad' combination, which is sAPP beta, Amyloid beta, Jcasp and C31. This is the shift in balance that leads to the onset of disease. The shift can be restored. The mouse strain that has one mutation that leads to not having APP to break down to Jcasp and C31 proteins leads to restoring memory in mice. But the most exciting thing is that Dr. Bredesen is testing a drug that shifts the APP cleavage balance back to normal."

Link: http://mariakonovalenko.wordpress.com/2012/07/03/dale-bredesen-alzheimers-is-a-problem-of-imbalance-not-toxicity/

Source:
http://www.longevitymeme.org/newsletter/latest_rss_feed.cfm

Researchers examine possible molecular mechanisms for rheumatoid arthritis in a paper published earlier in the year: "Rheumatoid arthritis (RA) is a systemic autoimmune inflammatory and destructive joint disorder that affects tens of millions of people worldwide. Normal healthy joints maintain a balance between the synthesis of extracellular matrix (ECM) molecules and the proteolytic degradation of damaged ones. In the case of RA, this balance is shifted toward matrix destruction due to increased production of cleavage enzymes and the presence of (autoimmune) immunoglobulins resulting from an inflammation induced immune response. Herein we demonstrate that a polyclonal antibody against the proteoglycan biglycan (BG) causes tissue destruction that may be analogous to that of RA affected tissues. The effect of the antibody is more potent than harsh chemical and/or enzymatic treatments designed to mimic arthritis-like fibril de-polymerization. ... The specific antigen that causes the RA immune response has not yet been identified, although possible candidates have been proposed, including collagen types I and II, and proteoglycans (PG's) such as biglycan. We speculate that the initiation of RA associated tissue destruction in vivo may involve a similar non-enzymatic decomposition of collagen fibrils via the immunoglobulins themselves that we observe here ex vivo."

Link: http://dx.doi.org/10.1371/journal.pone.0032241

Source:
http://www.longevitymeme.org/newsletter/latest_rss_feed.cfm

As noted numerous times in the past here at Fight Aging!, chronic inflammation is a bad thing. Aging is the accumulation of damage, and the evidence strongly suggests inflammation to be a mechanism by which many different medical conditions cause damage and reduce life expectancy - such as autoimmune diseases, for example. Even the presence of excess visceral fat tissue appears to raise the risk of age-related disease and lower life span through boosting levels of inflammation. Furthermore, as you get older, and even in the best of circumstances and health, the immune system itself starts to fall into a malfunctioning state in which it causes ever greater levels of inflammation - thus producing ever more damage while at the same time failing to do its job.

Markers of inflammation correlate well with mortality rates, which is well worth keeping in mind given just how easy it is to slip into a lifestyle that greatly raises levels of inflammation.

So avoid inflammation as best you can. The easiest and some of the best tools are calorie restriction and exercise, both of which do far more for a generally healthy individual than any presently available medical technology. But not everyone has the luxury of being able to be a generally healthy individual: those suffering auto-immune disorders like rheumatoid arthritis are going suffer increasing inflammation and a lowered life expectancy until a cure arrives. So the future of health has to be as much about technological progress as it is about better using the tools that are to hand today.

Here are a couple of open access papers as a reminder of the bad things that inflammation does to you - and, for most of the younger members of the audience, via the agency of that surplus visceral fat tissue you happen to be carrying around.

Inflammation in Aging: Cause, Effect, or Both?

Aging is a progressive degenerative process tightly integrated with inflammation. Cause and effect are not clear. A number of theories have been developed that attempt to define the role of chronic inflammation in aging ... However, no single theory explains all aspects of aging; instead, it is likely that multiple processes contribute and that all are intertwined with inflammatory responses.

...

While there does not appear to be a "cure" for the complex process of aging, it should be possible to facilitate successful aging, namely, aging without significant loss of cognitive or physical function and relatively free of disease. There are lifestyle factors and potential interventions that can slow specific processes primarily through reduction or prevention of chronic inflammation and therefore forestall aging itself.

Systemic immune challenges trigger and drive Alzheimer-like neuropathology in mice

Alzheimer's disease (AD) is the most prevalent form of age-related dementia, and its effect on society increases exponentially as the population ages. Accumulating evidence suggests that neuroinflammation, mediated by the brain's innate immune system, contributes to AD neuropathology and exacerbates the course of the disease.

...

We found that a systemic immune challenge during late gestation predisposes [mice] to develop AD-like neuropathology during the course of aging. They display chronic elevation of inflammatory cytokines [and] significant impairments in working memory in old age. If this prenatal infection is followed by a second immune challenge in adulthood, the phenotype is strongly exacerbated, and mimics AD-like neuropathologic changes. ... Based on the similarity between the changes in immune-challenged mice and the development of AD in humans, we suggest that systemic infections represent a major risk factor for the development of AD.

Infections mean inflammation, of course - one of the many reasons that people exposed to a large burden of infectious disease tend not to live as long as their peers. They become more burdened by damage, from the disease process and from the inflammation that attends it, with each infection. One of the reasons that we live longer than our ancestors is that we are better at controlling and evading infectious disease: not just the diseases that kill people in youth, but the diseases that are survived.

Source:
http://www.longevitymeme.org/newsletter/latest_rss_feed.cfm

Competition drives progress, but put enough humans into any field and the successful groups will start to form cartels in order to keep their leading position without having to compete as hard for it. It is inherent in the human condition that we self-sabotage very well and very aggressively just as soon as we achieve enough success to feel somewhat elevated over our less fortunate peers. Who can even begin to guess how many opportunities have been wasted, how much potential technological progress has been lost thanks to these urges?

The world of technology is now remarkably flat. The majority of the amenities of modern technology are available to the majority of the world: the descendants of peasants can fly for the same cost as the bloodlines of kings, cars and mobile phones are ubiquitous, and holding vast wealth doesn't in fact give a person any great and massive advantage over the middle class - or even the poor in wealthier regions - when it comes to the variety of available medical technology. Every new advance moves rapidly from being comparatively expensive, faulty, and scarce to being comparatively cheap, reliable, and widespread - whether we are talking about air conditioning or heart surgery, though the pernicious effects of regulation slow down the applications of biotechnology to a crawl in comparison to other lines of technological progress.

One of the defining features of our age is the degree to which the very wealthy and the very connected use the same technologies as the rest of us. When new technology is developed we all win - it doesn't matter which research or development group got there first, because we will all have access soon enough. What does matter is how soon that new technology arrives, and that is a function of the size and level of competition in the research and development communities. Michael Batin has this to say, machine translated from the Russian:

In most types of social interactions, people want to be the first. In sport, business, politics, the most coveted, the most honorable place - this place is number 1. This behavior is due to our neurophysiology, our genetics. Often, the winner takes all. During the war, or fight a duel to win - means to survive.

But, in the fight against aging is a totally different situation. We will survive, if any other scientist, institution or fund wins [in the fight against] aging. Yes, these [strangers get] the glory, money and women. At the same time everyone else interested in the victory over the aging gets a chance to live. No amount of money can [be] compared with the value of life. When you're alive, you have the opportunity to achieve whatever you want. When a person is dead, for him [nothing] is possible.

When we see someone [doing better than us to] extend the life of an animal model [and struggle] with aging, [he benefits us] because he can give us life. The more people who are trying to find a cure for old age, the greater our chances of survival, [and] for the return of youth to radical life extension.

The larger the community, the more healthy competition, the better the outcome and the faster the progress towards the end goal. When it comes to the biotechnology of rejuvenation we will either all win together or we all lose together - there is little in the way of middle ground in technological progress. That result is entirely determined by how fast we can create this sort of future medicine, such as that outlined in the SENS proposals.

Source:
http://www.longevitymeme.org/newsletter/latest_rss_feed.cfm

A herd of mitochondria exists in every cell, producing the ATP necessary to power that cell. Damage to mitochondria is important in aging, but how damage progresses in a cell's mitochondrial population is complicated by the fact that these are not completely discrete and static entities. They multiply like bacteria (fission), can merge with one another (fusion), and can also exchange individual components of their molecular machinery - so damage can be both passed around or mitigated depending on circumstances. Here researchers build models to better understand this dynamic: "Mitochondria are organelles that play a central role as 'cellular power plants'. The cellular organization of these organelles involves a dynamic spatial network where mitochondria constantly undergo fusion and fission associated with the mixing of their molecular content. ... Mitochondrial dynamics and mitophagy play a key role in ensuring mitochondrial quality control. Impairment thereof was proposed to be causative to neurodegenerative diseases, diabetes, and cancer. Accumulation of mitochondrial dysfunction was further linked to aging. Here we applied a probabilistic modeling approach integrating our current knowledge on mitochondrial biology allowing us to simulate mitochondrial function and quality control during aging ... We demonstrate that cycles of fusion and fission and mitophagy indeed are essential for ensuring a high average quality of mitochondria, even under conditions in which random molecular damage is present. Prompted by earlier observations that mitochondrial fission itself can cause a partial drop in mitochondrial membrane potential, we tested the consequences of mitochondrial dynamics being harmful on its own. Next to directly impairing mitochondrial function, pre-existing molecular damage may be propagated and enhanced across the mitochondrial population by content mixing. In this situation, such an infection-like phenomenon impairs mitochondrial quality control progressively. However, when imposing an age-dependent deceleration of cycles of fusion and fission, we observe a delay in the loss of average quality of mitochondria. This provides a rational why fusion and fission rates are reduced during aging and why loss of a mitochondrial fission factor can extend life span in fungi. We propose the 'mitochondrial infectious damage adaptation' (MIDA) model according to which a deceleration of fusion-fission cycles reflects a systemic adaptation increasing life span."

Link: http://dx.doi.org/10.1371/journal.pcbi.1002576

Source:
http://www.longevitymeme.org/newsletter/latest_rss_feed.cfm