Longevity Meme Newsletter, July 27 2009

July 27 2009

The Longevity Meme Newsletter is a weekly e-mail containing news, opinions, and happenings for people interested in healthy life extension: making use of diet, lifestyle choices, technology, and proven medical advances to live healthy, longer lives.



- On Progress and Attitudes to Longevity
- Attacking TTR Amyloidosis
- Welcome Stem Cell Advances
- Discussion
- Latest Healthy Life Extension Headlines


Human longevity is increasing by a few years every decade, but attitudes towards aging and the potential to increase longevity further are stuck in the era of our parents and grandparents:


"Fundamentally the issue is that most people live in the world of their parents and grandparents, their views on aging shaped by what has happened to people who did not have access to the technologies that will exist in 20 or 40 or 60 years time. When you're young, being old doesn't look all that great - and whatever self-protective rationalizations occur later in life, you were right. The experience and insight that comes with years of life is good, but degenerative aging is horrible, truly horrible.

"People expect the course of life they have seen happen already to those they know best, not the course of life that is possible with biotechnology that will be developed over the next couple of decades. The trend in life expectancy is presently upward, a few months every year thanks new medical technologies that are but a tiny hint of what will come in years ahead. Extending those trends through a time of revolution in biotechnology is naive - pins stuck in the map because someone somewhere (such as the life insurance industry) needs an answer. If bloated regulatory powers win out and slow medical advances to a crawl, then yes, Japan will likely have only 600,000 centenarians in 2050. But for that to be the case, rather than a world in which people routinely undergo rejuvenation therapies and few die before reaching 100 years of age, we must collectively fail to achieve progress in biotechnologies aimed at repairing damaged human tissues."


Many of the underlying mechanisms that cause age-related degeneration have a corresponding fatal disease in which that mechanism is greatly accelerated or exaggerated. The cellular malfunction at the heart of progeria, for example, accumulates in old people at much lower levels than exhibited by those who suffer the condition. Given that the FDA forbids the application of medical technology to treat aging, these conditions (or, alternatively, a revolution) are the best hope for driving some form of general progress into biotechnologies that can later be applied to reverse or slow aging.


"Why should those of us interested in engineered longevity pay attention to research and drug development for a type of amyloidosis called TTR amyloid polyneuropathy (ATTR-PN) or Familial Amyloid Polyneuropathy (FAP), a condition that likely has only around 10,000 sufferers worldwide? The answer is that forms of TTR amyloidosis have a much broader relevance to degeneration and death in the oldest old, those centenarians who have survived or avoided all other forms of age-related disease. ... What kills most of them [is] a condition, extremely rare among younger people, called senile cardiac TTR Amyloidosis. TTR is a protein that cradles the thyroid hormone thyroxine and whisks it around the body. In TTR Amyloidosis, the protein amasses in and clogs blood vessels, forcing the heart to work harder and eventually fail."


These news items from the stem cell research community are worth noting and sharing:


"You'll recall that stem cells transplanted into the heart spur regeneration of damage, such as that caused by a stroke, through releasing growth factors and other signaling chemicals. Researchers have now demonstrated that a similar process can be made to happen in the brain. Mice genetically engineered to have Alzheimer's performed markedly better on memory tests a month after mouse neural stem cells were injected into their brains. The stem cells secreted a protein that created more neural connections, improving cognitive function.

"This work is, obviously, performed in the context of trying to do something about Alzheimer's - if only by spurring the body to greater feats of ongoing repair rather than by altering the conditions that are causing damage - but I'm sure you can see the potential for more general application. Memory declines in everyone with age, and some fraction of that process is caused by damage to the same synaptic connections as are devastated by Alzheimer's. The memories are still encoded in there somewhere, but the brain has lost the connections needed to retrieve them, and in its default state of operation will not fix this situation."


"The research community is rapidly reproducing the past ten years of stem cell technology demonstrations, using induced pluripotent stem (iPS) cells this time around. You'll recall that iPS cells are normal cells - usually skin cells - reprogrammed to act as though they are stem cells. The methodology is well within reach of any laboratory previously working on stem cells, and many research groups have dived into the fray since the first publication of the reprogramming method. Rapid progress has been made in a very short time, a characteristic state of affairs for biotechnology these days.

"As a recent paper shows, iPS researchers have reached the point of demonstrating regeneration of damaged hearts in mice. At this rate, I'd guess at it being no more than another few years before the first clinical trials in humans are getting started. They will mirror the trials that have taken place for heart disease in recent years, using much the same methods, but replacing stem cells cultured from the patient's existing stem cell populations with stem cells created from scratch using a skin sample."


The highlights and headlines from the past week follow below.

Remember - if you like this newsletter, the chances are that your friends will find it useful too. Forward it on, or post a copy to your favorite online communities. Encourage the people you know to pitch in and make a difference to the future of health and longevity!




Controlling Cells to Regenerate the Heart (July 24 2009)
If you know exactly how to order cells around, you don't need stem cells to spur healing that would not normally take place: reaearchers "have devised a method to coax heart muscle cells into reentering the cell cycle, allowing the differentiated adult cells to divide and regenerate healthy heart tissue after a heart attack ...The key ingredient is a growth factor known as neuregulin1 (NRG1 for short) ... To my knowledge, this is the first regenerative therapy that may be applicable in a systemic way ... For instance, he added, people might one day go to the clinic for daily infusions of NRG1 over a period of weeks. ... In principle, there is nothing to preclude this going into the clinic. Based on the all the information we have, this is a promising candidate ... The heart had long been considered an organ largely incapable of repairing itself. Heart muscle cells, also known as cardiomyocytes, do proliferate during prenatal development. ... recent evidence has shown that adult heart muscle cells can replace themselves at some low level, with perhaps half of the cells in the heart turning over in the course of a lifetime ... The new study provides multiple lines of evidence for this turnover ability - including video of the cells in action - and shows that neuregulin1 can ramp up the process."

An Important Proof for iPS Cells (July 24 2009)
Researchers have demonstrated an important proof of the capabilities of induced pluripotent stem (iPS) cells: "Since Shinya Yamanaka of Kyoto University in Japan created the first iPS cells in 2006, researchers have wondered whether they could generate an entire mammalian body from iPS cells, as they have from true embryonic stem cells. ... the team reports 27 live births. With their best cell line and optimal recipe, they were able to get 22 live births from 624 injected embryos, a success rate of 3.5%. ... the mice seem to have a high death rate, with some dying after just two days, and others displaying physical abnormalities, details of which the team would not reveal. But some of their mice passed one of the most fundamental tests of health: all 12 mice that were mated produced offspring, and the offspring showed no abnormalities. The team says it now has hundreds of second-generation, and more than 100 third-generation, mice. The team found no tumours in the mice, although they have not systematically looked for them." You might look at this as analogous to early cloning attempts - high failure rates and abnormalities in early efforts are beside the point. The point is that the process works, will be rapidly improved, and some form of induced pluripotent stem cells can eventually be substituted for embryonic stem cells for every application.

Bold Predictions on Artificial Brains (July 23 2009)
You should watch with interest progress towards emulating the human brain in hardware; this is the (long) path to ensuring we can live a lot, lot longer than our biology allows for. The claims in this BBC article are bold, conditional on massive funding and a large research community, but probably not completely out of line: "A detailed, functional [simulated] artificial human brain can be built within the next 10 years, a leading scientist has claimed. Henry Markram, director of the Blue Brain Project, has already simulated elements of a rat brain. He told the TED Global conference in Oxford that a synthetic human brain would be of particular use finding treatments for mental illnesses. ... It is not impossible to build a human brain and we can do it in 10 years. ... Over the last 15 years, Professor Markram and his team have picked apart the structure of the neocortical column. ... The project now has a software model of 'tens of thousands' of neurons - each one of which is different - which has allowed them to digitally construct an artificial neocortical column."

Puzzled by MCLK1 (July 23 2009)
MCLK1 has been known as a mouse longevity gene for some years; reducing its activity extends life by 30% or so, apparently through the common method of reducing mitochondrial free radical generation and consequent damage. Closer inspection is producing more questions than are answered, however: "they found was that in young (3 month old) MCLK1-defective mice, mitochondria were quite energy inefficient and produced a lot of harmful oxygen radicals; yet surprisingly, when these mice were 23 months old, their mitochondria were working better than normal mice. So, despite the oxidative stress, these mice experienced less deterioration than normal. To confirm whether MCLK1-defiency could be somehow protective, the researchers crossed MCLK1-defective mice with those lacking SOD2, a major protein antioxidant. Normally, SOD2-defective mice accumulate cellular damage quickly, yet when combined with MCLK1-defiency, they exhibited less damage and oxidative stress. ... In explaining this seeming paradox, [researchers] suggest that while MCLK1-defective mice produce more oxygen radicals from their mitochondria, their overall inefficiency results in less energy and fewer oxygen radicals being produced in other parts of a cell."

More Potential Mouse Longevity Genes (July 22 2009)
The advance of biotechnology means that there are more ways than life span studies to identify potential longevity genes. Researchers can also look at specific forms of damage or level of cellular function in tissues, as is done here: "the p38MAPK protein, already known for its role in inflammation, also promotes aging when it activates another protein p16, which has long been linked to aging. In addition, they found that reducing the levels of p38MAPK delayed the aging of multiple tissues. Through their experiments, the scientists found that partial inactivation of p38MAPK was sufficient to prevent age-induced cellular changes in multiple tissues, as well as improve the proliferation and regeneration of islet cells, without affecting the tumour suppressor function of p16 in mice. ... several organs, including the pancreas, in the mice that had a reduced amount of p38MAPK protein exhibited a delayed degeneration as the mice grew older. ... Due to the previously established involvement of p38MAPK in inflammatory diseases, small molecule inhibitors of p38MAPK signalling have already entered clinical trials for the treatment of other medical conditions such as rheumatoid arthritis. Our latest discovery offers the possibility that a novel, pharmacological approach could be developed to combat age-related disorders."

The Mechanisms by Which Excess Fat Harms You (July 22 2009)
Excess fat leads to chronic inflammation and damage over time. From ScienceDaily: "Fat tissue is no longer considered simply a storage place for excess calories, but in fact is an active tissue that secretes multiple compounds, thereby communicating with other tissues, including the liver, muscles, pancreas and the brain. Normal communication is necessary for optimal metabolism and weight regulation. However, in obesity, fat (adipose) tissue becomes dysfunctional, and mis-communicates with the other tissues. This places fat tissue at a central junction in mechanisms leading to common diseases attributed to obesity, like type 2 diabetes and cardiovascular diseases. ... Fat tissue dysfunction is believed to be caused by obesity-induced fat tissue stress: Cells over-grow as they store increasing amounts of fat. This excessive cell growth may cause decreased oxygen delivery into the tissue; individual cells may die (at least in mouse models), and fat tissue inflammation ensues. Also, excess nutrients (glucose, fatty acids) can also result in increased metabolic demands, and this in itself can cause cellular stress." You might also look at the role of macrophages in fat-induced inflammation.

Seeking to Understand Flatworm Regeneration (July 21 2009)
From EurekAlert!: "Planarian flatworms are only a few millimeters up to a few centimeters in length, live in freshwater and are the object of intense research, because they possess the extraordinary ability to regenerate lost tissue with the help of their stem cells (neoblasts) and even grow an entirely new worm out of minute amputated body parts. ... Many planaria genes resemble those of humans, and also many genes specifically linked to planarian stem cell biology and regeneration are conserved in humans. Understanding planarian regeneration therefore promises to yield important insights into human regeneration and stem cell biology, the researchers are convinced. The researchers looked for small RNAs in stem cells as well as in the whole planarian organism. They discovered 60 new microRNA genes and could demonstrate that ten microRNAs are specifically linked to stem cell biology and may therefore play a role in regeneration. A few of these microRNAs also exist in humans." You might also look at similar research in salamanders, seeking the mechanisms of limb regeneration.

Building Nerves in the Lab (July 21 2009)
Via EurekAlert!, researchers "report on the first lab-grown motor nerves that are insulated and organized just like they are in the human body. The model system will drastically improve understanding of the causes of myelin-related conditions, such as diabetic neuropathy and later, possibly multiple sclerosis (MS). In addition, the model system will enable the discovery and testing of new drug therapies for these conditions. MS, diabetic neuropathy, and many conditions that are caused by a loss of myelin, which forms protective insulation around our nerves, can be debilitating and even deadly. ... The [team] plans to use their new model system to explore the origins of diabetic neuropathy. Once the causes of myelin degradation are identified, targets for new drug therapies can be tested with the model. Other planned experiments will focus on how electrical signals travel through myelinated and unmyelinated nerves to reveal how nerves malfunction as well as for spinal cord injury studies." Loss of myelin appears to be important in general degenerative aging as well, so advances in understanding here will probably have wider application in the repair of the aging nervous system.

Tissue Elasticity in Aging (July 20 2009)
A look at the role of elastin and its degeneration in aging: "The ability of elastic tissues to deform under physiological forces and to subsequently release stored energy to drive passive recoil is vital to the function of many dynamic tissues. ... elastic fibres allow arteries and lungs to expand and contract, thus controlling variations in blood pressure and returning the pulmonary system to a resting state. Elastic fibres are composite structures composed of a cross-linked elastin core and an outer layer of fibrillin microfibrils. These two components perform distinct roles; elastin stores energy and drives passive recoil, whilst fibrillin microfibrils direct [creation of elastin], mediate cell signalling, maintain tissue homeostasis [and] potentially act to reinforce the elastic fibre. In many tissues reduced elasticity, as a result of compromised elastic fibre function, becomes increasingly prevalent with age and contributes significantly to the burden of human morbidity and mortality. ... As compromised elasticity is a common feature of ageing dynamic tissues, the development of strategies to prevent, limit or reverse this loss of function will play a key role in reducing age-related morbidity and mortality."

Calorie Restriction Provides Benefits Even Started Late (July 20 2009)
Here is another example of research showing benefits from late adoption of calorie restriction in mice: "Numerous reports implicate increased oxidative stress in the functional and structural changes occurring in the brain and other organs as a part of the normal aging process. Dietary restriction (DR) has long been shown to be life-prolonging intervention in several species. This study was aimed to assess the potential efficacy of late-onset short term DR when initiated in 21 months old male wistar rats for 3 months on the antioxidant defense system and lipid peroxidation, cellular stress response protein HSP 70 and synaptic marker protein synapsin 1 in discrete brain regions such as cortex, hypothalamus, and hippocampus as well as liver, kidney and heart from 24 month old rats. Age-associated decline in activities of superoxide dismutase, catalase, glutathione peroxidase, glutathione, and elevated levels of lipid peroxidation was observed in brain and peripheral organ as well as increased expression of HSP 70 and reduction in synapsin 1 was observed in brain studied. Late-onset short term DR was effective in partially restoring the antioxidant status and in decreasing lipid peroxidation level as well as enhancing the expression of HSP 70 and synapsin 1 in aged rats. Late onset short term DR also prevented age-related neurodegeneration [in] hippocampus and cortex regions of rat brain. Thus our current results suggest that DR initiated even in old age has the potential to improve age related decline in body functions."



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