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

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

The developing technology of bioprinting, producing tissue structures using inkjet or other print technologies, has a promising future:

Desktop 3-D printers can already pump out a toy trinket, gear set or even parts to make another printer. Medical researchers are also taking advantage of this accelerating technology to expand their options for regenerative medicine.

Researchers have made great strides in coaxing cells to grow over artificial, porous scaffolds that can then be implanted in the body to replace hard tissue, such as bone. ... But now, instead of relying on poured molds, foam designs or donated biological materials, researchers can print custom scaffold structures with biocompatible, biodegradable polymers. ... These methods have allowed us to develop very complex scaffolds which better mimic the conditions inside the body. ... Engineers can carefully control the minute, internal structures of these porous scaffolds to best promote cellular growth. And these new printing methods also allow quick and cheap experiments that test various one-off designs.

Advancing bio-printing technologies can also be used for the biological material itself. Like color printing, biomaterial printing can switch among different organic materials as well as produce gradients and blending. Inkjet printing is preferred for depositing cells themselves, and as a demonstration of this in the 1980s an unmodified HP desktop printer was used to print out collagen as well as tissuelike structures. Printing, however, is tough on cells. Some studies have successfully kept more than 95 percent of cells intact through the process, but others have not done as well - losing more than half from damaged membranes.

The future of bio-printing may be the combination of these approaches - printing both highly specific scaffolds and cell structures. Recent research has shown that stem cell fate can be controlled by the surfaces onto which the cells are printed.

Link: http://blogs.scientificamerican.com/observations/2012/11/15/print-it-3-d-bio-printing-makes-better-regenerative-implants/

Source:
http://www.fightaging.org/archives/2012/11/the-state-of-bioprinting.php

A range of age-related conditions are characterized by a buildup or clumping of harmful proteins, and research tends to focus first on ways to safely break down these compounds. Here researchers are testing a new candidate method of breaking down the beta amyloid and tau associated with Alzheimer's disease:

Last March, researchers at UCLA reported the development of a molecular compound called CLR01 that prevented toxic proteins associated with Parkinson's disease from binding together and killing the brain's neurons. Building on those findings, they have now turned their attention to Alzheimer's disease, which is thought to be caused by a similar toxic aggregation or clumping, but with different proteins, especially amyloid-beta and tau.

And what they've found is encouraging. Using the same compound, which they've dubbed a "molecular tweezer," in a living mouse model of Alzheimer's, the researchers demonstrated for the first time that the compound safely crossed the blood-brain barrier, cleared the existing amyloid-beta and tau aggregates, and also proved to be protective to the neurons' synapses - another target of the disease - which allow cells to communicate with one another.

Even though synapses in transgenic mice with Alzheimer's may shut down and the mice may lose their memory, upon treatment, they form new synapses and regain their learning and memory abilities. ... For humans, unfortunately, the situation is more problematic because the neurons gradually die in Alzheimer's disease. That's why we must start treating as early as possible. The good news is that the molecular tweezers appear to have a high safety margin, so they may be suitable for prophylactic treatment starting long before the onset of the disease.

Link: http://www.eurekalert.org/pub_releases/2012-11/uoc--rrp111512.php

Source:
http://www.fightaging.org/archives/2012/11/molecular-tweezers-versus-alzheimers-disease.php

A range of age-related conditions are characterized by a buildup or clumping of harmful proteins, and research tends to focus first on ways to safely break down these compounds. Here researchers are testing a new candidate method of breaking down the beta amyloid and tau associated with Alzheimer's disease:

Last March, researchers at UCLA reported the development of a molecular compound called CLR01 that prevented toxic proteins associated with Parkinson's disease from binding together and killing the brain's neurons. Building on those findings, they have now turned their attention to Alzheimer's disease, which is thought to be caused by a similar toxic aggregation or clumping, but with different proteins, especially amyloid-beta and tau.

And what they've found is encouraging. Using the same compound, which they've dubbed a "molecular tweezer," in a living mouse model of Alzheimer's, the researchers demonstrated for the first time that the compound safely crossed the blood-brain barrier, cleared the existing amyloid-beta and tau aggregates, and also proved to be protective to the neurons' synapses - another target of the disease - which allow cells to communicate with one another.

Even though synapses in transgenic mice with Alzheimer's may shut down and the mice may lose their memory, upon treatment, they form new synapses and regain their learning and memory abilities. ... For humans, unfortunately, the situation is more problematic because the neurons gradually die in Alzheimer's disease. That's why we must start treating as early as possible. The good news is that the molecular tweezers appear to have a high safety margin, so they may be suitable for prophylactic treatment starting long before the onset of the disease.

Link: http://www.eurekalert.org/pub_releases/2012-11/uoc--rrp111512.php

Source:
http://www.fightaging.org/archives/2012/11/molecular-tweezers-versus-alzheimers-disease.php

In this modern age people tend to grow increasingly fat with advancing age. Near any given individual can choose not to do so, but considered in aggregate the masses tend to follow the available incentives more often than not: cheap food; cheap ways to get around without walking; lots of interesting activities that don't require you to move from your chair; and so forth. For your typical fellow in a developed country advancing age means more wealth, more calories, and less exercise, and this has the inevitable effect on waistline, metabolism, long-term health, and life expectancy. With more fat and more years spent fat, the costs pile up: more money spent on medical services, more disability, frailty, and age-related disease, and more years cut from your life expectancy.

So don't get fat, don't stay fat. The weight of evidence tells us that being fat isn't good for you - and for everyone in a developed region, excepting a tiny handful of people with profound genetic disorders, whether or not you are in fact fat is absolutely a choice.

Given the ready way in which we can alter the amount of fat in our bodies through diligence - or lack of same - and the way in which lifestyle choices change with age for most people, there is no desperate need for other explanations as to why people gather more fat with advancing years. Nonetheless, I'll point out a recent open access paper (the full text is PDF only): if I'm reading it right, the researchers here argue that one of the unfortunate low-level biochemical effects of the presence of advanced glycation endproducts (AGEs) in our tissues is that it encourages the growth of fat tissue, or adipose tissue to give it the more formal name - to be fat is to have adiposity, and growth of fat tissue is adipogenesis.

Since AGE levels rise with age, even if an individual doesn't increase their ingested levels of AGEs, this mechanism for AGEs to spur fat tissue growth leaves the door open for some interesting speculation. The researchers don't put any useful numbers to the putative effect, however, and thus I'm inclined to think it small in comparison to, say, how much a person eats or exercises:

An advanced glycation end products (AGEs)-the receptor for AGEs axis restores adipogenic potential of senescent preadipocytes through modulation of p53 function

Impaired adipogenic potential of senescent preadipocytes is a hallmark of adipose aging and aging-related adipose dysfunction. ... We show a novel pro-adipogenic function of AGEs in replicative senescent preadipocytes.

While our study is largely based on in vitro and ex vivo studies, we would predict that a chronic dietary intake of AGEs would positively contribute to adipose development during aging. ... To our knowledge, our study is the first report that AGEs are able to restore senescence-impaired adipogenic potential of aged preadipocytes. These findings implicate that AGEs-induced adipogenesis in senescent preadipocytes is likely to contribute to exacerbating aging-related adiposity.

If you look back in the Fight Aging! archives, you'll find much more information on AGEs and their role in degenerative aging - the established discussion of past years, rather than the new thoughts on fat tissue quoted above. The characteristic buildup of AGEs and similar compounds that occurs with age harms the integrity of tissue and biological systems in a number of ways:

• SENS5 Video: Talking About AGEs and Aging
• AGE Breakers Beyond Alagebrium
• A Raft of Papers on AGEs, ALEs, RAGE
• Commenting on the Utility of AGE-Breakers

Advanced glycation endproducts (AGEs) are a class of undesirable metabolic byproduct. The level of AGEs in the body rises with age and causes harm through a variety of mechanisms, such as by excessively triggering certain cellular receptors or gluing together pieces of protein machinery by forming crosslinks, thus preventing them from carrying out their proper function.

In past years a number of efforts were undertaken to develop drugs that can safely break down at least some forms of AGE. Early promising candidates in laboratory animals failed in humans because the most harmful forms of AGE are different for short-lived versus long-lived mammals - so what benefits a rat isn't of much utility for we humans. So far little progress has been made towards a therapy for the dominant type of AGE in humans, glucosepane, sad to say, as there is comparatively little interest in this field of research.

Source:
http://www.fightaging.org/archives/2012/11/arguing-that-ages-contribute-to-increased-fat-tissue-with-age.php

Arguably metastasis is what makes cancer so dangerous: that a single malignant tumor of any size can seed further tumors throughout the body; that a diaspora of metastasized cells is exceedingly hard to eliminate once let lose. If metastasis could be blocked many forms of cancer would become tractable and far less threatening, which is a fair-sized step towards a robust cure for cancer - very much needed as a part of any package of biotechnologies aimed at greatly extending healthy human life. Thus it is promising to see signs of early progress along these lines:

In laboratory experiments, scientists have eliminated metastasis, the spread of cancer from the original tumor to other parts of the body, in melanoma by inhibiting a protein known as melanoma differentiation associated gene-9 (mda-9)/syntenin. ... With further research, the approach used by the scientists could lead to targeted therapies that stop metastasis in melanoma and potentially a broad range of additional cancers.

[Researchers] found that Raf kinase inhibitor protein (RKIP) interacted with and suppressed mda-9/syntenin. Mda-9/syntenin [was] shown in previous studies to interact with another protein, c-Src, to start a series of chemical reactions that lead to increased metastasis. ... Prior research suggests that RKIP plays a seminal role in inhibiting cancer metastasis, but, until now, the mechanisms underlying this activity were not clear.

Now that the researchers have demonstrated the ability of RKIP to inhibit mda-9/syntenin-mediated metastasis, they are focusing their attention on developing small molecules imitating RKIP that could be used as new treatments for melanoma.

Link: http://www.eurekalert.org/pub_releases/2012-11/vcu-rbc111412.php

Source:
http://www.fightaging.org/archives/2012/11/eliminating-metastasis-in-melanoma.php