Longevity Meme Newsletter, September 06 2010

September 06 2010

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



- Spurring Efforts to Remove Glucosepane
- A Future of Bioartificial Kidneys
- Fundraising Success for Mitochondrial Uncoupling
- Thyroid Function and Human Longevity
- Discussion
- Latest Healthy Life Extension Headlines


As we age, a class of chemical gunk called advanced glycation end-products (AGEs) accumulates in our body, gluing together important proteins and generally making a mess of things. This is one contribution to degenerative aging, causing damage and disarray in biochemical processes. In humans, glucosepane is the dominant AGE, and therefore the target to focus on. With this in mind, the SENS Foundation has recently undertaken a more active initiative to spur research into safely breaking down glucosepane:


"Sadly, very few scientists are working in any way on an AGE-breaker for glucosepane. The only group I know of is Legendary Pharmaceuticals, which is a very small outfit indeed. This is a state of affairs very familiar to anyone who spends much time looking into the science of human aging and the potential for engineered longevity: a great deal is known about what needs to be done, but, aside from the field of regenerative medicine, next to nothing is being done.

"This is where non-profits like the SENS Foundation or Methuselah Foundation enter the picture: working to raise awareness, spur interest, persuade scientists, and generate research funding. In the case of glucosepane, the SENS Foundation has branched out to work with InnoCentive, a company with an interesting business model: they are a marketplace for people in search of cost-effective solutions to specific problems in life science development, biotechnology, and engineering. ... The SENS Foundation has dipped into this marketplace in search of the development path to an AGE-breaker for glucosepane, and a kick in the pants for the research and development community who should already be working on the problem."

This lack of research is particularly frustrating because breaking down glucosepane is one of the aspects of aging that could be very effectively and profitably targeted by the mainstream drug discovery and development industry as it exists today. Yet nothing is happening.


Artificial organs are in our future: researchers are presently in the early stages of using a mix of materials science, mechanical engineering, and cultured cells to build replacements for natural organs. This line of research will give tissue engineering a run for its money for decades to come, as advances in miniaturization result in bioartifical organs that can be implanted. Here is the latest news on progress towards bioartificial kidneys:


"UCSF researchers today unveiled a prototype model of the first implantable artificial kidney, in a development that one day could eliminate the need for dialysis. The device, which would include thousands of microscopic filters as well as a bioreactor to mimic the metabolic and water-balancing roles of a real kidney, is being developed in a collaborative effort by engineers, biologists and physicians nationwide. ... [The] goal is to apply silicon fabrication technology, along with specially engineered compartments for live kidney cells, to shrink that large-scale technology into a device the size of a coffee cup. The device would then be implanted in the body without the need for immune suppressant medications, allowing the patient to live a more normal life."


Good news from the Immortality Institute:


"A little while back, I pointed out the Immortality Institute's present fundraising program for modestly sized research projects. The Institute volunteers solicit proposals from life science researchers, showcase the most worthy, and match donations with funds from from the Institute coffers. The latest project will run in a Singaporean research laboratory and investigate mitochondrial uncoupling. ... I donated to the Institute to help fund this research project, and encouraged everyone else to do likewise. ... I'm pleased to note that a number of folk followed through, and the fundraising target has been met. Thank you all. You can follow the research as it takes place and ask questions of the researchers over in the Immortality Institute forums - take advantage of the opportunity. This is the way in which research will progress in the future, with a great deal more dialog and openness."


Levels of circulating thyroid hormones are associated with human longevity, with the hormones T3 and T4 being of most interest:


"These are amongst a number of hormones in the human body that touch on almost everything you would expect to influence life span over time: metabolic rate, cell growth, use and processing of food, and so forth. ... Eight hundred fifty-nine nonagenarian siblings (median age 92.9 yr) from 421 long-lived families participated in the study. Families were recruited from the entire Dutch population if at least two long-lived siblings were alive and fulfilled the age criterion of age of 89 yr or older for males and 91 yr or older for females. We found that a lower family mortality history score (less mortality) of the parents of nonagenarian siblings was associated with higher serum TSH levels and lower free T4 levels as well as lower free T3 levels in the nonagenarian siblings."

The practice of calorie restriction has been shown to lower T3 levels, so while some of your thyroid function is a matter of inherited genes and thus presently beyond your control, there is something you can do to even the odds.



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!




Via EurekAlert!: "Scientists have devised a method for coaxing mouse embryonic stem cells into forming a highly specific motor neuron subtype. The research [provides] new insight into motor neuron differentiation and may prove useful for devising and testing future therapies for motor neuron diseases. ... The existence of dozens of muscle groups in the limbs of most mammals demands an equivalent diversity of motor neuron pool subtypes ... During normal development, motor neurons settle into specific sections of the spinal cord (called columns), which correspond to the muscles that they will innervate. For example, cells in one area link up with muscles in the limbs, while cells residing in another region innervate muscles in the body wall. Although previous studies have shown that mouse and human embryonic stem cells can be converted into motor neurons, it was not clear whether these were 'generic' neurons or whether they could acquire characteristics of the specific specialized subtypes. In the current study, [researchers] showed that removing a key differentiation factor allowed cultured embryonic stem cells to form motor neurons with molecular characteristics corresponding to a limb innervating subtype, without the need for genetic manipulation or added factors. Importantly, when this stem cell-derived subtype was transplanted into embryonic chick spinal cords, the motor neurons settled in the expected columnar position within the cord and had projections that mimicked the trajectory of limb innervating motor neurons."

Ray Kurzweil in h+ Magazine: "There has been recent disappointment expressed in the progress in the field of genomics. In my view, this results from an overly narrow view of the science of genes and biological information processing in general. ... To reverse-engineer biology we need to examine phenomena at different levels, especially looking at the role that proteins (which are coded for in the genome) play in biological processes. In understanding the brain, for example, there is indeed exponential progress being made in simulating neurons, neural clusters, and entire regions. This work includes understanding the 'wiring' of the brain (which incidentally includes massive redundancy) and how the modules in the brain (which involve multiple neuron types) process information. Then we can link these processes to biochemical pathways, which ultimately links back to genetic information. But in the process of reverse-engineering the brain, genetic information is only one source and not the most important one at that. So genes are one level of understanding biology as an information process, but there are other levels as well, and some of these other levels (such as actual biochemical pathways, or mechanisms in organs including the brain) are more accessible than genetic information. In any event, just examining individual genes, let alone SNPs, is like looking through a very tiny keyhole."

Excess fat tissue in your body actively works to change your metabolism, and largely for the worse. Here's a reminder of that fact: "Scientists are reporting new evidence that the fat tissue - far from being a dormant storage depot for surplus calories - is an active organ that sends chemical signals to other parts of the body, perhaps increasing the risk of heart attacks, cancer, and other diseases. They are reporting discovery of 20 new hormones and other substances not previously known to be secreted into the blood by human fat cells and verification that fat secretes dozens of hormones and other chemical messengers. ... [Researchers] note that excess body fat can contribute to heart disease, diabetes, cancer and other diseases. Many people once thought that fat cells were inert storage depots for surplus calories. But studies have established that fat cells can secrete certain hormones and other substances much like other organs in the body. Among those hormones is leptin, which controls appetite, and adiponectin, which makes the body more sensitive to insulin and controls blood sugar levels. However, little is known about most of the proteins produced by the billions of fat cells in the adult body."

The mainstream press notices sarcopenia: "Bears emerge from months of hibernation with their muscles largely intact. Not so for people, who, if bedridden that long, would lose so much muscle they would have trouble standing. Why muscles wither with age is captivating a growing number of scientists, drug and food companies ... Comparisons between age groups underline the muscle disparity: An 80-year-old might have 30 percent less muscle mass than a 20-year-old. And strength declines even more than mass. Weight-lifting records for 60-year-old men are 30 percent lower than for 30-year-olds; for women the drop-off is 50 percent. With interest high among the aging, the market potential for maintaining and rebuilding muscle mass seems boundless. Drug companies already are trying to develop drugs that can build muscles or forestall their weakening ... In addition, geriatric specialists, in particular, are now trying to establish the age-related loss of muscles as a medical condition under the name sarcopenia. ... But with sarcopenia still not established as a treatable condition, 'there is no real defined regulatory path as to how one would get approved in this area.'" When you live under a regime in which all that is not permitted is forbidden, it should be no surprise that progress is slow and expensive. One of the best things that could be done for medicine in this modern age is to tear down the FDA and other similar regulatory bodies.

The mainstream view of aging in the adaptive immune system is that too many memory T cells exist, uselessly specialized and using up limited resources that should be devoted to the naive T cells needed to tackle new threats. An alternative (and not mutually exclusive) theory is presented in this paper: that memory cell populations are failing in old age, meaning that acquired immunity vanishes. "Evidence is accumulating that old individuals are more susceptible to infection with organisms to which they were previously immune, indicating that there might be a limit to the persistence of immune memory. The prevailing concept is that defects in memory T-cell populations result from inexorable end-stage differentiation as a result of repeated lifelong antigenic challenge. We discuss here mechanisms that might constrain the persistence of memory T cells and consider whether humans will suffer from memory T-cell exhaustion as life expectancy increases." Whether or not this in fact occurs, the proposed therapies would look much the same as for other immune system issues known to occur with aging: destroy the old, misconfigured, damaged immune cells and replace them with new cells grown from the patient's stem cells.

As researchers peer more deeply, the accelerated aging condition progeria continues to look very much like one aspect of "normal" aging run amok: "Children with Hutchinson-Gilford progeria syndrome (HGPS) exhibit dramatically accelerated cardiovascular disease (CVD), causing death from myocardial infarction or stroke between the ages of 7 and 20 years. We undertook the first histological comparative evaluation between genetically confirmed HGPS and the CVD of aging. ... We present structural and immunohistological analysis of cardiovascular tissues from 2 children with HGPS who died of myocardial infarction. Both had features classically associated with the atherosclerosis of aging, as well as arteriolosclerosis of small vessels. In addition, vessels exhibited prominent adventitial fibrosis, a previously undescribed feature of HGPS. Importantly, although progerin was detected at higher rates in the HGPS coronary arteries, it was also present in non-HGPS individuals. Between the ages of 1 month and 97 years, progerin staining increased an average of 3.34% per year in coronary arteries. ... Vascular progerin generation in young non-HGPS individuals, which significantly increases throughout life, strongly suggests that progerin has a role in the cardiovascular aging of the general population."

One consequence of the success of calorie restriction research is that scientists are now more closely investigating the biochemistry of exercise - and its potential to slow aging. For example: "Brain aging is a period of decreasing functional capacity and increasing vulnerability, which reflect a reduction in morphological organization and perhaps degeneration. Since life is ultimately dependent upon the ability to maintain cellular organization through metabolism, this review explores evidence for a decline in neural metabolic support during aging, which includes a reduction in whole brain cerebral blood flow, and cellular metabolic capacity. Capillary density may also decrease with age, although the results are less clear. Exercise may be a highly effective intervention for brain aging, because it improves the cardiovascular system as a whole, and increases regional capillary density and neuronal metabolic capacity. Although the evidence is strongest for motor regions, more work may yield additional evidence for exercise-related improvement in metabolic support in non-motor regions. The protective effects of exercise may be specific to brain region and the type of insult. For example, exercise protects striatal cells from ischemia, but it produces mixed results after hippocampal seizures. Exercise can improve metabolic support and bioenergetic capacity in adult animals, but it remains to be determined whether it has similar effects in aging animals. What is clear is that exercise can influence the multiple levels of support necessary for maintaining optimal neuronal function."

An example of the next generation of targeted cancer therapies: "Since last April, 19 cancer patients whose liver tumors hadn't responded to chemotherapy have taken an experimental drug. Within weeks of the first dose, it appeared to work, by preventing tumors from making proteins they need to survive. The results are preliminary yet encouraging. With a slight redesign, the drug might work for hundreds of diseases, fulfilling the promise that wonder cures like stem cells and gene therapy have failed to deliver. ... We can turn off any one of 20,000 genes with RNAi. The challenge has been to get a drug into only the desired cells and not harm others. ... Researchers have worried that a drug might disrupt normal protein production in a healthy cell, or that the immune system will destroy the drug before it reaches its target. [Scientists] overcame both concerns by packaging the drug in a fatty envelope that is absorbed primarily by the liver. This allowed doctors to administer the drug through the blood, rather than by an injection to one spot, which improves results by ensuring that the entire liver receives an even dose. The technique's ability to attack single genes could lead to drugs for the 75 percent of cancer genes that lack any specific treatment, as well as for other illnesses. [Researchers are] already testing RNAi therapy for Huntington's disease and high cholesterol in cell cultures; other researchers are tackling macular degeneration, muscular dystrophy and HIV. The potential has driven nearly every major pharmaceutical company to start an RNAi program."

From The Week: "In 20 years, we will have stem cell banks like pharmacies. You will get a specific diagnosis and take a specific type of stem cell. ... Meantime, scientists are using cells to produce pig hearts, rat livers, and mice teeth that grow independently in a lab. Anthony Atala, director of the Wake Forest Institute for Regenerative Medicine, grows human bladders, and has implanted more than two dozen of them in human patients since 2006. ... Hollow organs are easier to create than solid ones, but researchers have recently made strides with livers, hearts, and even lungs. Major challenges remain. But sometime in the future, scientists hope, humans will be able to mimic the processes that enable other animals to regenerate body parts. When a salamander loses a leg, it sprouts a new one. A zebra fish can even regenerate a portion of its heart. Humans can regenerate bones and skin, but like other higher species, lost the capacity to regrow limbs and organs during the process of evolution. By manipulating specific genes, scientists may turn this miraculous power back on. ... In a world in which aging or diseased people can swap a damaged heart, liver, or other organ for a new one created from their own DNA, a majority of children alive today might live to 100 or beyond. It's hard to know how far-reaching the effects might be because we're still only at the dawning of the biological revolution. But true believers have seen enough to predict changes of historical import. ... We're beginning to understand how life is coded and how life makes things. How we make things, where we make things, is going to change on a scale similar to that of the Industrial Revolution. It's already happening."

Broadly, we might think that there are two types of degeneration that accompany aging: the forms that are largely preventable via lifestyle choices, and the forms that you can only slow down, even with the best tools presently available. Insulin resistance is an example of the former, and mitochondrial damage is an example of the latter. From a recent review paper: "This review addresses the question whether insulin sensitivity and mitochondrial oxidative capacity are independently affected during aging and type 2 diabetes. ... Humans with or at risk of type 2 diabetes frequently exhibit insulin resistance along with structural and functional abnormalities of muscular mitochondria. Low mitochondrial oxidative capacity causes muscular fat accumulation, which impedes insulin signaling via lipid intermediates, in turn affecting oxidative capacity. However, insulin sensitivity is not generally reduced with age, when groups are carefully matched for physical activity and body fatness. Moreover, lifestyle intervention studies revealed discordant responses of mitochondrial oxidative capacity and insulin sensitivity. ... In the elderly, low mitochondrial oxidative capacity likely results from age-related effects acquired during life span. Insulin resistance occurs independently of age mostly due to unhealthy lifestyle on top of genetic predisposition. Thus, insulin sensitivity and mitochondrial function may not be causally related, but mutually amplify each other during aging."



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