Parkinson's disease involves a greatly accelerated loss of vital dopamine-generating neurons in the brain, leading to the characteristic symptoms in earlier stages of the condition. In recent years, scientists have focused on the role of ?-synuclein in the processes that cause this cell death:

The discovery of ?-synuclein has had profound implications concerning our understanding of Parkinson's disease (PD) and other neurodegenerative disorders characterized by ?-synuclein accumulation. In fact, as compared with pre-?-synuclein times, a "new" PD can now be described as a whole-body disease in which a progressive spreading of ?-synuclein pathology underlies a wide spectrum of motor as well as nonmotor clinical manifestations.

At this point ?-synuclein is taking on a similar role to beta-amyloid in Alzheimer's disease - a magnet for interest and research funds, while potential clinical intervention involves removing or other otherwise nullifying the buildup of this unwanted compound. Fairly compelling research results were recently published on this topic, wherein researchers managed to convincingly replicate the effects of Parkinson's in mice:

Misfolded protein transmits Parkinson's from cell to cell

A [team] injected a misfolded synthetic version of the protein ?-synuclein into the brains of normal mice and saw the key characteristics of Parkinson's disease develop and progressively worsen. The study [suggests] that the disease is spread from one nerve cell to another by the malformed protein, rather than arising spontaneously in the cells.

Parkinson's disease has two distinct features: clumps of protein called Lewy bodies and a dramatic loss of nerve cells that produce the chemical messenger dopamine. When [the] team injected the misfolded ?-synuclein into a part of the mouse brain rich in dopamine-producing cells, Lewy bodies began to form. This was followed by the death of dopamine neurons. Nerve cells that linked to those near the injection site also developed Lewy bodies, a sign that cell-to-cell transmission was taking place.

The study lends theoretical support to the handful of biotechnology companies that are sponsoring clinical trials of ?-synuclein antibodies for Parkinson's ... At least one mystery still remains: why do the Lewy bodies appear in the first place? ... Parkinson's disease is not a disorder in which somebody injects synuclein into your brain. So what sets it in motion?

As is also the case for Alzheimer's it remains much debated as to how and why some people exhibit Parkinson's disease while others do not - which is not to say that there is any shortage of theories on how the condition progresses from its earliest stages. Just as for many other age-related conditions the commonplace correlations apply: being overweight and sedentary increases your risk, exercise and calorie restriction reduce it.

On the subject of Lewy bodies in Parkinson's disease, I noticed a couple of recently published papers suggesting that their appearance is symptomatic of a later stage of the condition, or less relevant to Parkinson's disease specifically - meaning that investigating their biochemistry may be less important than work on ?-synuclein at this juncture:

• Neurodegeneration in Parkinson disease: Moving Lewy bodies out of focus
• Lewy pathology is not the first sign of degeneration in vulnerable neurons in Parkinson disease

Source:
http://www.fightaging.org/archives/2012/11/evidence-for--synucleins-central-role-in-parkinsons-disease.php

By way of following on from yesterday's thoughts on progress in longevity science, I'll point out that the August 2012 issue of Rejuvenation Research is available online. The leading editorial by Aubrey de Grey of the SENS Foundation covers much the same set of topics and is presently open access - so head on over and read it while that lasts.

What's Really Delaying the Defeat of Aging?

In the mid-1990s, when I decided to switch from computer science to gerontology, I recognized that the creation of a credible assault on aging would require solving three basic problems: (1) Creating a credible plan; (2) getting the people best placed to implement it to be interested in doing so; and (3) giving them the financial resources to get on with the job.

I broke the back of the first problem in mid-2000, when I realized that regenerative medicine - repairing the accumulating damage of aging - will probably be far simpler and easier to implement than the alternative followed by most biogerontologists, namely slowing the creation of that damage. By that time, I had also done most of the heavy lifting of item 2 (as I continued to do thereafter), by connecting with leading researchers worldwide, mostly face to face at conferences, and improving their understanding of how their expertise could be productively applied to aging. By way of illustration, quite a few of the most prestigious such people are named on the front cover of this journal as associate editors, and they accepted such a position for that reason. But what about item 3?

Unfortunately, I cannot tell so positive a story with respect to financial resources. Nearly a decade ago, I began to make public predictions of how soon we would achieve success in our crusade. I did so, as I still do, in the manner that (for better or worse) preoccupies the general public, namely in terms of longevity, but I have always been careful to incorporate two key caveats: (1) The level of uncertainty of the time frames, even if only scientific uncertainty is considered, and (2) the reliance of such estimates on adequate funding.

The first of these caveats is often elided, but it is simple: I estimate that we have a 50% chance of achieving the milestone of "robust human rejuvenation" (essentially, the rejuvenation of 60 year olds comprehensively enough that they won't be biologically 60 again until they're chronologically 90) within 25 years, but I also estimate that we have at least a 10% chance of not getting there in 100 years. But...that is all subject to the second caveat, namely funding.

Tragically, the level of funding that has been forthcoming during the past decade is only a few percent (at most) of what is necessary. The rate of progress in research to defeat aging has been quite amazing in view of that, but nonetheless, I estimate that it has been only about one-third of what could have been achieved with 10-20 times more money.

Which is much as I said yesterday: there are now plenty of researchers and research groups who would work on building real rejuvenation biotechnology as described in the SENS vision if they were given a budget to do so. That budget is, however, sadly lacking at this time. Millions of dollars are going to SENS and SENS-like research programs these days (which is a big improvement over their non-existence ten years ago) - but a hundred times that flow of resources would be needed to achieve earnest progress at the best possible rate.

One of the logical conclusions emerging from this point of view is that longevity science remains in that stage of growth wherein advocacy and education are the primary drivers of progress. There is sufficient buy-in from the scientific community to make institutional investment in research the bottleneck to progress, and obtaining that funding is a matter of persuasion.

In one sense this is encouraging: it is a characteristic state of affairs during a rapid shift in priorities for any field of human endeavor. Organizations with large sums to place into research tend to be the most conservative portions of their community, and thus among the last to heed the changing winds of knowledge and priority. This present stage, in which researchers are now interested and supportive but lacking in sources of funding that will allow them to actually work on the problem at hand, is a natural, albeit frustrating, part of the process. It is a considerable step up from the previous era in which few researchers had any interest in working on the biotechnologies of engineered human longevity, and even talking about it in public was discouraged.

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

A few days back, I pointed out research that indicates brain cells increasingly become senescent with age. This is a challenge: we want to get rid of senescent cells and prevent their buildup because the harm they cause contributes to degenerative aging, but the obvious way to do that is through targeted destruction via one of the many types of cell-targeting and cell-killing technologies presently under development. This is fine and well for tissues like skin and muscle, in which cells turn over and are replaced - but in the brain and nervous system there are many small but vital populations of cells that are never replaced across the normal human life span. The cells you are born with last a lifetime, and some fraction of those cells contain the data that makes up the mind.

Thus it begins to seem likely that we can't just rampage through and destroy everything that looks like a senescent cell: possible therapies to address cell senescence as a contribution to aging will have to be more discriminating, and so more complex and costly to develop.

Following on in this topic, I noticed an open access paper today that examines the role of cellular senescence of astrocyte, the support cells of the brain, in Alzheimer's disease (AD). Unlike the research I noted above, the biochemical signatures of senescence examined here are the same as those used in last year's mouse study showing benefits resulting from a (necessarily) convoluted way of destroying senescent cells as they emerge - which of course starts the mind wandering on what might be going on in the brain of these mice. Astrocytes can perhaps be replaced without harming the mind or important nervous cells, but what about other cells in the brain?

In any case, here is the paper:

Astrocyte Senescence as a Component of Alzheimer's Disease

A recent development in the basic biology of aging, with possible implications for AD, is the recognition that senescent cells accumulate in vivo. Although senescent cells increase with age in several tissues, little is known about the potential appearance of senescent cells in the brain. The senescence process is an irreversible growth arrest that can be triggered by various events including telomere dysfunction, DNA damage, oxidative stress, and oncogene activation. Although it was once thought that senescent cells simply lack function, it is now known that senescent cells are functionally altered. They secrete cytokines and proteases that profoundly affect neighboring cells, and may contribute to age-related declines in organ function.

...

Astrocytes comprise a highly abundant population of glial cells, the function of which is critical for the support of neuronal homeostasis. ... Impairment of these functions through any disturbance in astrocyte integrity is likely to impact multiple aspects of brain physiology. Interestingly, astrocytes undergo a functional decline with age in vivo that parallels functional declines in vitro. We demonstrated that in response to oxidative stress and exhaustive replication, human astrocytes activate a senescence program.

...

The importance of senescent astrocytes in age-related dementia has been the subject of recent discussion, but to date, there is little evidence to suggest that senescent astrocytes accumulate in the brain. In this study, we examined brain tissue from aged individuals and patients with AD to determine whether senescent astrocytes are present in these individuals. Our results demonstrate that senescent astrocytes accumulate in aged brain, and further, in brain from patients with AD.

Furthermore, since A? peptides induce mitochondrial dysfunction, oxidative stress, and alterations in the metabolic phenotype of astrocytes; we examined whether A? peptides initiate the senescence response in these cells. In vitro, we found that exposure of astrocytes to A?1-42 triggers senescence and that senescent astrocytes produce high quantities of interleukin-6 (IL-6), a cytokine known to be increased in the [central nervous system] of AD patients. Based on this evidence, we propose that accumulation of senescent astrocytes may be one age-related risk factor for sporadic AD.

As I mentioned in the last post on this subject, this all seems to point to the likely need for ways to reverse cellular senescence, not just selectively destroy senescent cells - at least for some populations of nerve cells. One open question here is whether fixing all the known fundamental forms of cellular damage (as described in the Strategies for Engineered Negligible Senescence) would be sufficient to achieve this end.

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

From the MIT Technology Review: "Alzheimer's patients given a drug that is already used to treat immune disorders saw their condition stabilize in a small study presented at a conference this week. Study participants were given the compound - known as intravenous Ig, or IVIg - for three years. During this period, they showed no signs of further cognitive decline or memory loss. ... All participants in the study had mild to moderate Alzheimer's disease. Only four received the optimal dose of IVIg over three years. These patients showed no decline from their baseline state in cognition, memory, daily functioning, or mood - all expected effects of the disease. Patients who initially received a placebo but were later switched to IVIg treatment declined more slowly while receiving the drug. IVIg [contains] a mixture of antibodies isolated from the pooled plasma of blood donated by healthy people. The assumption is that this blood by-product contains antibodies from the healthy donors that attack the damaged proteins in Alzheimer's patients. ... such results [should] inspire a large number of scientific studies aimed at identifying the functional ingredients in the immune mixture, so that others could potentially develop a synthetic form. ... I really do hope that it turns out to work, because then it gives a good platform to start finding out what components are in there, What is it in the IVIg - is it selective antibodies against beta-amyloid, against tau, or something else?"

Link: http://www.technologyreview.com/news/428546/study-suggests-alzheimers-disease-can-be/

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

Progress towards a non-invasive test for Alzheimer's disease: "Reliability and failure to replicate initial results have been the biggest challenge in this field. We demonstrate here that it is possible to show consistent findings. ... [Researchers] measured the levels of 190 proteins in the blood of 600 study participants [including] healthy volunteers and those who had been diagnosed with Alzheimer's disease or mild cognitive impairment (MCI). MCI, often considered a harbinger for Alzheimer's disease, causes a slight but measurable decline in cognitive abilities. A subset of the 190 protein levels (17) were significantly different in people with MCI or Alzheimer's. When those markers were checked against data from 566 people participating in the multicenter Alzheimer's Disease Neuroimaging Initiative, only four markers remained: apolipoprotein E, B-type natriuretic peptide, C-reactive protein and pancreatic polypeptide. Changes in levels of these four proteins in blood also correlated with measurements from the same patients of the levels of proteins [beta-amyloid] in cerebrospinal fluid that previously have been connected with Alzheimer's. The analysis grouped together people with MCI, who are at high risk of developing Alzheimer's, and full Alzheimer's. ... Though a blood test to identify underlying Alzheimer's disease is not quite ready for prime time given today's technology, we now have identified ways to make sure that a test will be reliable."

Link: http://www.eurekalert.org/pub_releases/2012-08/eu-btf080912.php

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

Work on stem cell transplants in rats is outlined here: "Alzheimer's disease (AD) has been called the disease of the century with significant clinical and socioeconomic impacts. Epidemiological studies point out that AD affects 5% of the population over 65, and, parallel with increasing lifespan, the incidence of disease will rise dramatically. Clinically AD is characterized by a progressive learning capacity impairment and memory loss, especially memories of recent events ... Adult neural tissues have limited sources of stem cells, which makes neurogenesis in the brain less likely. Stem cells transplantation seems to be a promising strategy for treatment of several central nervous system (CNS) degenerative diseases such as AD, amyotrophic lateral sclerosis (ALS), and Parkinson's disease ... The present study aims to evaluate the effect of bone marrow mesenchymal stem cells (MSCs) grafts on cognition deficit in chemically and age-induced Alzheimer's models of rats. ... Two months after the treatments, cognitive recovery was assessed ... Results showed that MSCs treatment significantly increased learning ability and memory in both age- and [chemical]-induced memory impairment. Adult bone marrow mesenchymal stem cells show promise in treating cognitive decline associated with aging and [nucleus basalis magnocellularis] lesions."

Link: http://dx.doi.org/10.1155/2012/369417

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

It is taken as a tenet around here that involuntary death is a bad thing, and the process of getting to be dead despite your own wishes on the matter is arguably worse - it involves a great deal of ongoing suffering and pain as the body progressively fails. Greatly diminishing the incidence of death is one aim of the longevity science movement, achieved through the elimination of degenerative aging, the greatest cause of death. Can we say why being dead is bad, however? That is supposedly a harder job than declaring suffering to be bad and worthy of amelioration - though most philosophers fail to consider the economic costs of destruction, and in the end it should all come down to "I've decided I don't like it, and so I'll work towards doing something about it through progress in medical science." Reasons beyond personal choice are unnecessary, but here is a brief tour of some of the philosophy of death and nonexistence: "We all believe that death is bad. But why is death bad? In thinking about this question, I am simply going to assume that the death of my body is the end of my existence as a person. But if death is my end, how can it be bad for me to die? After all, once I'm dead, I don't exist. If I don't exist, how can being dead be bad for me? ... there's a puzzle raised by the Roman philosopher Lucretius, who thought it a mistake to find the prospect of my death upsetting. Yes, as the deprivation account points out, after death we can't enjoy life's pleasures. But wait a minute, says Lucretius. The time after I die isn't the only period during which I won't exist. What about the period before my birth? If nonexistence is so bad, shouldn't I be upset by the eternity of nonexistence before I was born? But that's silly, right? Nobody is upset about that. So, he concludes, it doesn't make any sense to be upset about the eternity of nonexistence after you die, either. It isn't clear how best to reply to Lucretius. One option, presumably, is to agree that we really do need to treat those two eternities of nonexistence on a par, but to insist that our prebirth nonexistence was worse than we thought. Alternatively, we might insist that there's an asymmetry that explains why we should care about the one period but not the other. But what is that difference? Perhaps this: When I die, I have lost my life. In contrast, during the eternity before my birth, although I'm not alive, I have not lost anything. You can't lose what you never had. So what's worse about death is the loss."

Link: http://chronicle.com/article/Is-Death-Bad-for-You-/131818/

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

Researchers "have collaborated on a project to restore neuron function to parts of the brain damaged by Huntington's disease (HD) by successfully transplanting HD-induced pluripotent stem cells into animal models. ... Induced pluripotent stem cells (iPSCs) can be genetically engineered from human somatic cells such as skin, and can be used to model numerous human diseases. They may also serve as sources of transplantable cells that can be used in novel cell therapies. In the latter case, the patient provides a sample of his or her own skin to the laboratory. In the current study, experimental animals with damage to a deep brain structure called the striatum (an experimental model of HD) exhibited significant behavioral recovery after receiving transplanted iPS cells. The researchers hope that this approach eventually could be tested in patients for the treatment of HD. ... the transplanted cells will be genetically identical to the patient and therefore no medications that dampen the immune system to prevent graft rejection will be needed. ... transplanted iPSCs initially formed neurons producing GABA, the chief inhibitory neurotransmitter in the mammalian central nervous system, which plays a critical role in regulating neuronal excitability and acts at inhibitory synapses in the brain. GABAergic neurons, located in the striatum, are the cell type most susceptible to degeneration in HD."

Link: http://www.vai.org/News/News/2012/05_29_Huntingtons.aspx

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

Crowdfunding of commercial products is having a lengthy day in the sun at the moment. It has emerged from years of great success in small markets, such as the pen and paper gaming and indie publishing industries, and people are now applying the same models to fields where much more money is involved. Quite successfully too, some raising millions in what amount to well-run and timely preorder campaigns for products yet to be built. The range of endeavors open to crowdfunding of course includes scientific research, which is why it is a topic that shows up here every now and again:

If you can raise money for books, art projects, and widgets, why not for discrete life science research projects with determined goals? The LongeCity (previously the Immortality Institute) crowd have been trying this for some years, with a great deal of success considering the limited audience of this community in comparison to the audience available through Kickstarter. It is sad but true that far more people are brought to a state of excitedly opening their wallets for the development of an iPhone widget than for any sort of biotechnology project, even one that will contribute to the reversal of aging.

If you have a dedicated community, then you want to turn that dedication into professional organizations and the funds to run them. This is always going to be a messy, organic process of development, but which perhaps may be open to improvement through the spread of a more formalized crowdfunding culture. But in any case, I wanted to expand on the point made in the quote above - that crowdfunding for scientific research is a radically different undertaking from crowdfunding for development of a commercial product. This seems worth emphasizing, given that a whole range of startups and new ventures seem to be trying to port over crowdfunding into the sciences pretty much as-is, or with just a few embellishments. Like these, for example:

• EurekaFund
• FundaGeek
• GeekFunder
• Microryza
• Petridish
• Rockethub
• Sciflies

What we can hope for from this wealth of effort is that some groups figure out the magic formula that will make science funding work in this environment - and make it work with the same degree of liquidity and interest as in commercial projects. Experimentation is clearly needed, however.

The basic point of divergence between crowdfunding a product versus crowdfunding research is that in the former case the funders are definitively buying something concrete: that is their motivation and incentive. They are putting down money in expectation that what they are doing is submitting a preorder. Variations on the preorder theme are legion, but they all boil down to paying for a definitive item, a which will usually have fairly solid delivery date. Scientific research is notoriously bad when it comes to delivering on both those points, however. The work that is most amenable to crowdfunding consists of small projects that only incrementally add value to their fields - and which may not even do that, given the necessarily high failure rate for research.

The challenge facing science crowdfunding is the same challenge faced by scientific advocates at all times: they do their part to grow communities of supporters and encourage those supporters to pay for research work. That work will give no immediate result, the eventual result may be hard for supporters to understand, it will likely not benefit them for some time, if ever, and in addition to all of that the undertaking will quite likely fail. Science is a high risk endeavor, with few short-term payoffs that people find rewarding - and thus it is a hard sell when held up against the allure of immediate gratification, candy, and shiny objects.

But technological progress is the only thing that matters, not today's pretty baubles that are made possible by past successes in science. Funding of science has to be made to work if we want to continue on this upward curve to longevity, wealth, and expansion of what it means to be human.

Despite all of the challenges, the old messy, organic way of funneling money into scientific projects does in fact make progress. People who care about the end result, something decades away, do step up to fund science. You might look at our little community of longevity science enthusiasts for example, making noise and raising somewhere north of $14 million over the past eight years for organizations and initiatives like the Methuselah Foundation, the New Organ Prize, and the SENS Foundation. Knowing that this is possible, and regardless of the fact that it is hard, very hard, to convince people to open their wallets for science, you have to look at what's happening in the crowdfunding space right now and think that fundraising for science could all be made easier - if someone just goes about it in the right way, builds the right tools, hits the right business model, pulls together the right sort of seed community.

And maybe so. I've watched most of a decade of a small community funding research, and the cryonics advocates have watched much the same thing for far longer, but I don't have any good answers - and I'm not sure that they do either. So it is a good thing that a number of venture funded and bootstrapped groups are working on this; they'll have a few years of runway to work on finding the key to the problem, and we'll all benefit should one of them come up with a good way forward.

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

The choroid plexus is, amongst other things, a filter for cerebrospinal fluid - you might think of this role as analogous to that of the kidney as a filter for blood, though the two organs are very different in structure at every level, and the choroid plexus also produces the fluid it filters. Like all of the systems in the body and brain, the choroid plexus progressively fails in its function with age, and researchers have reason to believe that this failure contributes to conditions such as Alzheimer's disease:

An organ in the brain called the choroid plexus apparently plays a critical role in preventing the accumulation of a protein associated with Alzheimer's disease. The researchers found that the choroid plexus acts as a sort of 'fishnet' that captures the protein, called beta-amyloid, and prevents it from building up in the cerebrospinal fluid, which surrounds and bathes the brain and spinal cord. Moreover, tissue in the organ is able to soak up large amounts of the protein and may contain enzymes capable of digesting beta-amyloid.

Levels of beta-amyloid in the brain are more dynamic than their slow buildup over the years implies. You might think of the condition - and indeed the increase in amyloid levels in aging in general - as a slowly progressing imbalance of amyloid creation and clearance mechanisms rather than a slow and irrevocable deposition of amyloid. That in turn implies that a working therapy could quickly reverse all but the latest stages of the disease, when neurons are dying in large numbers.

Do rising brain levels of a plaque-forming substance mean patients are making more of it or that they can no longer clear it from their brains as effectively? ... Clearance is impaired in Alzheimer's disease. We compared a group of 12 patients with early Alzheimer's disease to 12 age-matched and cognitively normal subjects. Both groups produced amyloid-beta (a-beta) at the same average rate, but there's an average drop of about 30 percent in the clearance rates of the group with Alzheimer's. ... Scientists calculate this week [that] it would take 10 years for this decrease in clearance to cause a build-up of a-beta equal to those seen in the brains of Alzheimer's patients. The results have important implications for both diagnosis and treatment.

Here is a more recent paper that reviews what is known of the role of the choroid plexus:

Pathological Alteration in the Choroid Plexus of Alzheimer's Disease: Implication for New Therapy Approaches

In the recent years, much attention has been directed to the roles of the choroid plexus in the central nervous system (CNS) under both normal and pathological conditions. This specialized ventricular structure has recently emerged as a key player in a variety of processes that monitor and maintain the biochemical and cellular homeostasis of the CNS.

The main role of the choroid plexus is to produce cerebrospinal fluid (CSF) and to maintain the extracellular environment of the brain by monitoring the chemical exchange between the CSF and the brain tissue. This involves the surveying of the chemical and immunological status of the extracellular fluid and the removal of toxic substances as well as important roles in the regenerative processes following traumatic events. In addition to CSF, the plexus produces various peptides which can have nourishing and neuroprotective properties.

...

Morphological alterations of choroid plexus in Alzheimer's disease (AD) have been extensively investigated. These changes include epithelial atrophy, thickening of the basement membrane, and stroma fibrosis. As a result, synthesis, secretory, and transportation functions are significantly altered resulting in decreased cerebrospinal fluid (CSF) turnover. Recent studies discuss the potential impacts of these changes, including the possibility of reduced resistance to stress insults and slow clearance of toxic compounds from CSF with specific reference to the amyloid peptide.

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

Researchers continue to investigate why the ApoE4 gene variant is associated with Alzheimer's disease: "A well-known genetic risk factor for Alzheimer's disease triggers a cascade of signaling that ultimately results in leaky blood vessels in the brain, allowing toxic substances to pour into brain tissue in large amounts, scientists report ... a gene called ApoE4 makes people more prone to developing Alzheimer's. People who carry two copies of the gene have roughly eight to 10 times the risk of getting Alzheimer's disease than people who do not. [Scientists] found that ApoE4 works through cyclophilin A, a well-known bad actor in the cardiovascular system, causing inflammation in atherosclerosis and other conditions. The team found that cyclophilin A opens the gates to the brain assault seen in Alzheimer's. ... In the presence of ApoE4, increased cyclophilin A causes a breakdown of the cells lining the blood vessels in Alzheimer's disease in the same way it does in cardiovascular disease or abdominal aneurysm ... In studies of mice, the team found that mice carrying the ApoE4 gene had five times as much cyclophilin A compared to other mice in cells known as pericytes, which are crucial to maintaining the integrity of the blood-brain barrier. Blood vessels died, blood did not flow as completely through the brain as it did in other mice, and harmful substances like thrombin, fibrin, and hemosiderin, entered the brain tissue. When the team blocked the action of cyclophilin A, either by knocking out its gene or by using the drug cyclosporine A to inhibit it, the damage in the mice was reversed. Blood flow resumed to normal, and unhealthy leakage of toxic substances from the blood vessels into the brain was slashed by 80 percent."

Link: http://www.urmc.rochester.edu/news/story/index.cfm?id=3512

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

An Australian program featuring researchers Aubrey de Grey and David Sinclair: "It feels like science fiction, but it's actually true. And we're really at the cutting edge, it's a really exciting time in the field right now. ... There's no such thing as ageing gracefully. I don't meet people who want to get Alzheimer's disease, or who want to get cancer or arthritis or any of the other things that afflict the elderly. Ageing is bad for you, and we better just actually accept that. As far as I'm concerned, ageing is humanity's worst problem, by some serious distance. ... Now if you think that's an overstatement, consider this: world-wide, a hundred and fifty thousand people die each day, two-thirds of them from ageing. That means potentially one hundred thousand people could be saved every day with therapies that combat ageing. ... Ageing is simply and clearly, the accumulation of damage in the body. That's all that ageing is. What it's going to take is development of thoroughly comprehensive regenerative medicine for ageing. That means medicine which can repair the molecular and cellular damage that accumulates in our bodies throughout life, as side effects of our normal metabolic processes. ... We do not know what humanity of the future is going to want to do. If thirty or fifty years from now people don't have the problems that we thought they might have, but we didn't develop those therapies, so those people have to die anyway, after a long period of decrepitude and disease, then they're not going to be terribly happy are they? That's why we have a moral obligation to develop these technologies as soon as possible."

Link: http://www.abc.net.au/catalyst/stories/3465499.htm

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

Via EurekAlert!: "Daily physical exercise may reduce the risk of Alzheimer's disease, even in people over the age of 80 ... The study showed that not only exercise but also activities such as cooking, washing the dishes and cleaning are associated with a reduced risk of Alzheimer's disease. These results provide support for efforts to encourage physical activity in even very old people who might not be able to participate in formal exercise but can still benefit from a more active lifestyle. ... For the study, a group of 716 people with an average age of 82 wore an actigraph, a device that monitors activity, on their non-dominant wrist continuously for 10 days. All exercise and non-exercise was recorded. They also were given annual tests during the four-year study that measured memory and thinking abilities. During the study, 71 people developed Alzheimer's disease. ... The research found that people in the bottom 10 percent of daily physical activity were more than twice as likely to develop Alzheimer's disease as people in the top 10 percent of daily activity. The study also showed that those people in the bottom 10 percent of intensity of physical activity were almost three times as likely to develop Alzheimer's disease as people in the top 10 percent of intensity of physical activity."

Link: http://www.eurekalert.org/pub_releases/2012-04/aaon-gmd041012.php

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

It has been a number of years since researchers started to investigate the role of DJ-1 in Parkinson's disease. Here, the work has made it to the stage of a possible therapy: "As we age, we naturally lose dopamine-producing neurons. Parkinson's patients experience a rapid loss of these neurons from the onset of the disease, leading to much more drastic deficiencies in dopamine than the average person. ... Mutations in the gene known as DJ-1 lead to accelerated loss of dopaminergic neurons and result in the onset of Parkinson's symptoms at a young age. The ability to modify the activity of DJ-1 could change the progress of the disease. [Researchers have] now developed a peptide which mimics DJ-1's normal function, thereby protecting dopamine- producing neurons. What's more, the peptide can be easily delivered by daily injections or absorbed into the skin through an adhesive patch. Based on a short protein derived from DJ-1 itself, the peptide has been shown to freeze neurodegeneration in its tracks, reducing problems with mobility and leading to greater protection of neurons and higher dopamine levels in the brain. ... We attached the DJ-1-related peptide to another peptide that would allow it to enter the cells, and be carried to the brain. ... In pre-clinical trials, the treatment was tested on mice ... From both a behavioral and biochemical standpoint, the mice that received the peptide treatment showed remarkable improvement. Symptoms such as mobility dysfunctions were reduced significantly, and researchers noted the preservation of dopamine-producing neurons and higher dopamine levels in the brain. Preliminary tests indicate that the peptide is a viable treatment option. Though many peptides have a short life span and degrade quickly, this peptide does not."

Link: http://www.aftau.org/site/News2?page=NewsArticle&id=16503

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

A few years ago, researchers demonstrated a way to reverse some of the effects of Alzheimer's disease - a method that, interestingly, didn't involve targeting buildup of beta amyloid, presently the mainstream focus of the Alzheimer's research community.

HDAC2 regulates the expression of a plethora of genes implicated in plasticity - the brain's ability to change in response to experience - and memory formation. ... Several HDAC inhibitors are currently in clinical trials as novel anticancer agents and may enter the pipeline for other diseases in the coming two to four years. ... The researchers conducted learning and memory tasks using transgenic mice that were induced to lose a significant number of brain cells. ... after taking HDAC inhibitors, the mice regained their long-term memories and ability to learn new tasks. In addition, mice genetically engineered to produce no HDAC2 at all exhibited enhanced memory formation.

There are a few other studies out there to place question marks next to the primacy of amyloid in Alzheimer's disease - but you have to weigh them against the huge number of studies suggesting that it is important. But it's certainly the case that, given the ability, we would want to remove all such buildups of metabolic byproducts that appear with age. Young people don't have them, old people have them, ergo they may be part of the problem - and given limited information and large resources, why not work toward reversing all changes?

Here's a recent update on HDAC2 research. To my eyes, the most promising aspect of this work is not that it will necessarily lead to a viable therapy - the odds are always low for every research program - but that it shows Alzheimer's to be a reversible disease until quite late in the game.

The researchers found that in mice with Alzheimer's symptoms, HDAC2 (but not other HDACs) is overly abundant in the hippocampus, where new memories are formed. HDAC2 was most commonly found clinging to genes involved in synaptic plasticity - the brain's ability to strengthen and weaken connections between neurons in response to new information, which is critical to forming memories. In the affected mice, those genes also had much lower levels of acetylation and expression. .. The researchers then shut off HDAC2 in the hippocampi of mice with Alzheimer's symptoms, using a molecule called short hairpin RNA, which can be designed to bind to messenger RNA - the molecule that carries genetic instructions from DNA to the rest of the cell. With HDAC2 activity reduced [genes] required for synaptic plasticity and other learning and memory processes [were] expressed. In treated mice, synaptic density was greatly increased and the mice regained normal cognitive function.

...

The researchers also analyzed postmortem brains of Alzheimer's patients and found elevated levels of HDAC2 in the hippocampus and entorhinal cortex, which play important roles in memory storage.

...

The findings may explain why drugs that clear beta-amyloid proteins from the brains of Alzheimer's patients have offered only modest, if any, improvements in clinical trials ... The new study shows that beta amyloid also stimulates production of HDAC2, possibly initiating the blockade of learning and memory genes. ... We think that once this epigenetic blockade of gene expression is in place, clearing beta amyloid may not be sufficient to restore the active configuration of the chromatin.

Which all sounds to me very much like real progress in understanding the mechanics of Alzheimer's, if it's all validated by the research community - incremental, true, but progress nonetheless.

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

Via EurekAlert!: "Alzheimer's disease is characterized by abnormal deposits in the brain of the protein Amyloid-ß, which induces the loss of connections between neurons, called synapses. Now, scientists [have] discovered that specific antibodies that block the function of a related protein, called Dkk1, are able to completely suppress the toxic effect of Amyloid-ß on synapses. ... Dkk1 is elevated in the brain biopsies of people with Alzheimer's disease but the significance of these findings was previously unknown. Scientists [have] found that Amyloid-ß causes the production of Dkk1, which in turn induces the dismantling of synapses (the connections between neurons) in the hippocampus, an area of the brain implicated in learning and memory. ... scientists conducted experiments to look at the progression of synapse disintegration of the hippocampus after exposure to Amyloid-ß, using brain slices from mice. They were able to monitor how many synapses survived in the presence of a specific antibody which targets Dkk1, compared to how many synapses were viable without the antibody. The results show that the neurons that were exposed to the antibody remained healthy, with no synaptic disintegration."

Link: http://www.eurekalert.org/pub_releases/2012-03/ucl-sdt030512.php

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

The second part of an article in CMAJ that shows off some of the subtle prejudices against cryonics that exist in the medical scientific community (such as in the choice of title) while attempting objectivity: "Although death and taxes are said to be the only two certainties in life, a small but vocal community takes issue with the inclusion of the former. There is, they say, the alternative of cryonics, in which a legally dead person is preserved at -196C in hopes that he will ultimately be revived and rejuvenated, once a cure for his ailment is found. And it's entirely consistent with the basic tenets of medicine, providers argue. ... Although it seems like an unusual and radical idea to many people, I think in the very truest sense of the term, this is conservative medicine. This is literally conserving a patient rather than giving up on them by today's standards of medicine. It's true a doctor can't do anything more for these people, but that doesn't mean the future cannot. ... Those interested in cryonics tend be optimistic, hopeful about technological developments and dissatisfied with an ordinary life span, says Ben Best, president of the Cryonics Institute. ... a miniscule chance is better than none, enthusiasts say. ... Nobody has come up with a better idea yet, so therefore myself, as well as some others, believe that cryonics is simply the second worst thing that can happen. You're going to die. You're going to stop breathing. Whether you be buried or cremated or cryopreserved, it's going to happen. There's nothing we can do about this now, but I know that if I'm cremated or buried, even if technology vastly increased, I'm never coming back. ... Enthusiasts are mystified that only a small segment of the general population has investigated the cryonic option. ... I don't know why there are far more people who don't sign up for cryonics arrangements. It's true that what we do is unorthodox and different, at least in 2012. But there are so many bizarre ideas out there which have no evidence to support them and get many, many people fascinated ... Yet we only have less than 1000 members after 40 years. ... People tend in my experience to kind of rely on this naturalistic [fallacy] that because people have always gotten older and died, therefore they should get older and die as a result of simply living longer."

Link: http://www.cmaj.ca/site/earlyreleases/20mar12_the-church-of-cryopreservation.xhtml

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

Here is an open access PDF format mini-review on what is known of growth hormone and aging - that less of it is generally better: "A recent report of virtually complete protection from diabetes and cancer in a population of people with hereditary dwarfism revived interest in elucidating the relationships between growth, adult body size, age-related disease and longevity. In many species, smaller individuals outlive those that are larger and a similar relationship was shown in studies of various human populations. Adult body size is strongly dependent on the actions of growth hormone (GH) and the absence of GH or GH receptor in mice leads to a remarkable extension of longevity. Many mechanisms that may account for, or contribute to, this association have been identified. It is suggested that modest modifications of the diet at different ages may extend human healthspan and lifespan by reducing levels of hormones that stimulate growth."

Link: http://www.ncbi.nlm.nih.gov/pubmed/22261798

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