Longevity Meme Newsletter, September 20 2010

September 20 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.



- Attitudes and Regulations that Hold Back Progress
- Developing Mitochondrial Antioxidants
- Recent Research into Klotho and Aging
- Discussion
- Latest Healthy Life Extension Headlines


Sadly a great many people involved in both life science research and in the regulatory bodies that prevent the immediate application of that research actually have little interest in progress - they work without any sense of urgency, or are far more interested in their own fiefdoms than new medicines.


"A recent interview with James Watson, for example, is on the topic of cancer research, but his comments could equally well be applied to all of medicine and biotechnology: [the] Nobel Laureate bemoaned some pessimistic cancer researchers who he said were more interested in merely researching cancer and didn't realise that they had an obligation to cure people and save lives. 'I got real annoyed with someone ... at the end of his talk he said, 'we're going to get somewhere over the next ten to twenty years'. He could have said twenty to forty or why didn't he say five to ten? We should try and cure cancer now, not ten to twenty years from now. It would be sort of irresponsible to all those people who would die of cancer if we don't try and do it now.'

"Watson told journalists that he was in favour of less regulation for clinical trials as this could speed up the process of finding a cure for cancer: 'We're terribly held back on clinical tests by regulations which say that no one should die unnecessarily during trials; but they are going to die anyway unless we do something radical. I think the ethics committees are out of control and that it should be put back in the hands of the doctors. There is an extraordinary amount of red tape which is slowing us down. We could go five times faster without these committees.'"


Several research groups are presently demonstrating designed antioxidant compounds that, unlike every other antioxidant presently available, target mitochondria and extend life span. This is presumably a result of soaking up the free radicals produced by mitochondria and that normally cause damage that contributes to aging.


"Unfortunately, raising funds to develop any sort of longevity enhancing therapy for humans - even one with a probably small effect, and which looks exactly like run of the mill drug discovery and evaluation - runs right into the roadblock of the FDA. Since the FDA bureaucrats don't recognize aging as a medical condition, they will not approve any commercial application sold to that end. Since there can be no selling, and hence no potential for profit, no-one will fund the research and development. All potential approaches to extending longevity are instead sidelined into becoming just another therapy for the late stages of an age-related condition like diabetes. Wasted time, wasted effort.

"From where I stand, the preferable ways forward are to tear down the FDA (for all that this once grand country seems very lacking in revolutionary spirit these days), or take the commercial development overseas, which may force much the same end result in the fullness of time. But many groups choose to stay within the US regulatory straitjacket.

"For the targeted antioxidant development, two potential lines of within-the-system development spring to mind. Firstly, as a therapy for sepsis, [and secondly] it appears that wound healing, and especially in the old, may benefit from mitochondrially targeted antioxidants. ... Either of these uses is probably sufficiently large to support a fair-sized research and development effort in the US, should the present lines of research continue to show promise and benefit. But it won't be work on slowing aging any more - which is perhaps the most pernicious effect of the FDA roadblock on applied longevity science."


Klotho is a gene that can be manipulated to either shorten or lengthen life spans in mice and nematode worms. Researchers are still working to understand how it operates:


"Here are some examples of more recent studies involving klotho, starting with evidence that klotho extends life in nematodes by acting through two known longevity mechanisms. We would expect to see a lot of this sort of thing - that a new longevity-associated gene works by indirectly manipulating one of the known processes that can affect life span. ... In comparison to this, there is the oxidative stress viewpoint: that klotho confers resistance to the damage caused by free radicals such as reactive oxygen species, and therefore we would expect extended life to result under the free radical theory of aging. ... This view is not incompatible with the first - they are looking at different layers or areas of biochemistry. Metabolism is ferociously complex, which is one of the challenges facing those who want to safely alter its operation in humans to slow aging.

"Klotho doesn't exist in a vacuum of course. Like all parts of our biochemistry, its level of expression may be altered by circumstances and other changes taking place in our biological machinery - which in turn means that it is causing further alterations. All of which has made it historically challenging to figure out where the end of the string lies. What is cause, what is contributor, and what is irrelevant - answers which may turn out to be very different for the same process when conducted under only slightly different circumstances. The study of metabolism is not for the faint of heart."


The highlights and headlines from the past week follow below.

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These researchers suggest that heat shock proteins might be used as a biomarker of aging, a way to determine biological age rather than chronological age, and hence predict life span or evaluate the effectiveness of potentially longevity-inducing therapies: "Since their discovery in Drosophila, the heat shock proteins (Hsps) have been shown to regulate both stress resistance and life span. Aging is characterized by increased oxidative stress and the accumulation of abnormal (malfolded) proteins, and these stresses induce Hsp gene expression through the transcription factor HSF. In addition, a subset of Hsps is induced by oxidative stress through the JNK signaling pathway and the transcription factor Foxo. The Hsps counteract the toxicity of abnormal proteins by facilitating protein refolding and turnover, and through other mechanisms including inhibition of apoptosis. The Hsps are up-regulated in tissue-specific patterns during aging, and their expression correlates with, and sometimes predicts, life span, making them ideal biomarkers of aging. The tools available for experimentally manipulating gene function and assaying healthspan in Drosophila provides an unparalleled opportunity to further study the role of Hsps in aging."

Researchers uncover details of the mechanism for the link between germline cells and longevity in lower animals, connecting it to known longevity genes: "In Caenorhabditis elegans and Drosophila melanogaster, removing the germline precursor cells increases lifespan. In worms, and possibly also in flies, this lifespan extension requires the presence of somatic reproductive tissues. How the somatic gonad signals other tissues to increase lifespan is not known. The lifespan increase triggered by loss of the germ cells is known to require sterol hormone signaling, as reducing the activity of the nuclear hormone receptor DAF-12 [prevents] germline loss from extending lifespan. In addition to sterol signaling, the FOXO transcription factor DAF-16 is required to extend lifespan in animals that lack germ cells. ... In this study, we show that the DAF-12-sterol signaling pathway has a second function to activate a distinct set of genes and extend lifespan in response to the somatic reproductive tissues. When germline-deficient animals lacking somatic reproductive tissues are given dafachronic acid, their expression of DAF-12/NHR-dependent target genes is restored and their lifespan is increased. Together, our findings indicate that in C. elegans lacking germ cells, the somatic reproductive tissues promote longevity via steroid hormone signaling to DAF-12."

A great many research groups continue to investigate the biochemistry of calorie restriction, and this paper is a good illustration as to why this is the case: "It is well known that calorie restriction (CR) can retard the aging process in organisms ranging from yeast to non-human primates, and delay the onset of numerous age-related diseases including neurodegenerative disorders. Translation of the knowledge gained from CR research in animal models to disease prevention strategies in humans should provide therapeutic approaches for these diseases. Signaling pathways induced by CR are therefore potentially new therapeutic targets for neurodegenerative diseases. This review summarizes the evidence on key biological mechanisms underlying the beneficial effects of CR based on our current understanding, with particular emphasis on the recent impact of CR on neuroprotection, and on the emerging development of pharmacological agents that target signaling pathways induced by CR. We focus in particular on recent findings on sirtuins for prevention of neurodegenerative diseases." Even outside the context of aging, there is potentially much to learn about human biochemistry by following the effects of calorie restriction.

The process of declaring parts of aging as a disease is driven by regulation: the FDA does not permit treatments for aging, only for named diseases. Since there is little funding for research that cannot be legally commercialized, the incentive is to carve off chunks of the process of aging and go through the process of having government employees add it to the list of diseases - which can take years and millions of dollars. Sarcopenia, for example, is still not recognized by the FDA, meaning that no potential treatment can be commercially developed in the US. Here is an example of this process at work for memory loss: "Simply getting older is not the cause of mild memory lapses often called senior moments, according to a new study ... even the very early mild changes in memory that are much more common in old age than dementia are caused by the same brain lesions associated with Alzheimer's disease and other dementias. ... The very early mild cognitive changes once thought to be normal aging are really the first signs of progressive dementia, in particular Alzheimer's disease. The pathology in the brain related to Alzheimer's and other dementias has a much greater impact on memory function in old age than we previously recognized. ... dementias are the root cause of virtually all loss of cognition and memory in old age. They aren't the only contributing factors; other factors affect how vulnerable we are to the pathology and to its effects. But the pathology does appear to be the main force that is driving cognitive decline in old age."

Calorie restriction has been shown to slow down almost every measure of degenerative aging examined to date. Here is another such open access study: "Dietary restriction (DR) extends the lifespan of a wide variety of species and reduces the incidence of major age-related diseases. Cell senescence has been proposed as one causal mechanism for tissue and organism ageing. We show for the first time that adult-onset, short-term DR reduced frequencies of senescent cells in the small intestinal epithelium and liver of mice, which are tissues known to accumulate increased numbers of senescent cells with advancing age. This reduction was associated with improved telomere maintenance without increased telomerase activity. We also found a decrease in cumulative oxidative stress markers in the same compartments despite absence of significant changes in steady-state oxidative stress markers at the whole tissue level. The data suggest the possibility that reduction of cell senescence may be a primary consequence of DR which in turn may explain known effects of DR such as improved mitochondrial function and reduced production of reactive oxygen species." The telomere maintenance line item above might suggest that the shortest-telomere cells - i.e. senescent cells - are being destroyed and recycled, thus raising the average amongst remaining cells.

There are interesting intermediate destinations on the road to tissue engineered replacement organs. This is one of them: researchers have "invented the first artificial human ovary, an advance that provides a potentially powerful new means for conducting fertility research and could also yield infertility treatments for cancer patients. The team has already used the lab-grown organ to mature human eggs. ... An ovary is composed of three main cell types, and this is the first time that anyone has created a 3-D tissue structure with triple cell line. ... the ovary not only provides a living laboratory for investigating fundamental questions about how healthy ovaries work, but also can act as a testbed for seeing how problems, such as exposure to toxins or other chemicals, can disrupt egg maturation and health. ... To create the ovary, the researchers formed honeycombs of theca cells, one of two key types in the ovary, donated by reproductive-age (25-46) patients at the hospital. After the theca cells grew into the honeycomb shape, spherical clumps of donated granulosa cells were inserted into the holes of the honeycomb together with human egg cells, known as oocytes. In a couple days the theca cells enveloped the granulosa and eggs, mimicking a real ovary."

An open access paper: "The enthesis, which attaches the tendon to the bone, naturally disappears with aging, thus limiting joint mobility. ... Tendons and ligaments are fibers made up of dense connective tissue and they are critical for physiological movement and the stability of joints because of their attachment to bone. Injury to these structures can significantly destabilize joints, resulting in the development of degenerative joint diseases, especially in the upper limbs ... Surgery is frequently needed but the clinical outcome is often poor due to the decreased natural healing capacity of the elderly. This study explored the benefits of a treatment based on injecting chondrocyte and mesenchymal stem cells (MSC) [in rats] ... damage was repaired by classical surgery without cell injection (group G1) and with chondrocyte (group G2) or MSC injection (group G3). ... The spontaneous healing rate in the G1 control group was 40%, close to those observed in humans. Cell injection significantly improved healing (69%) ... A new enthesis was clearly produced in cell-injected G2 and G3 rats, but not in the controls. Only the MSC-injected G3 rats had an organized enthesis with columnar chondrocytes as in a native enthesis 45 days after surgery. ... Cell therapy is an efficient procedure for reconstructing degenerative entheses. MSC treatment produced better organ regeneration than chondrocyte treatment. The morphological and biomechanical properties were similar to those of a native enthesis."

Researchers continue to delve into the root causes of sarcopenia: "It is well known that the human aging process is associated with a progressive loss of muscular strength. Characteristic of this decline in muscle performance is the loss of skeletal muscle mass (sarcopenia) that occurs even in the healthy elderly. Indeed, humans can lose as much as 40% of their muscle mass from age 20 to 60. ... investigators used a combination of experimental approaches to phenotypically compare wild type old mice with mature mice lacking a novel muscle specific inositide phosphatase (MIP/MTMR14) that plays an important role in muscle calcium homeostasis. Interestingly, the mature MIP/MTMR14 knockout mice displayed phenotypes that closely resembled the muscles of old animals. Indeed, these relatively young knockout mice displayed impaired muscle calcium homeostasis, depressed muscle contractile force production and a loss of muscle mass that is commonly observed in senescent animals. Interestingly, the old wild type mice also displayed impaired muscle calcium homeostasis and decreases in muscle size and contractile function. Importantly, these old mice also possessed reduced muscle levels of MIP/MTMR14. The authors concluded that these findings were consistent with the hypothesis that an age-related loss in MIP/MTMR14 may be a contributory factor to sarcopenia."

Aggregates of unwanted proteins are important in aging, and researchers continue to investigate why it is that aggregates appear in the first place. Here, researchers "have solved a long-standing mystery of how cells conduct 'quality control' to eliminate the toxic effects of a certain kind of error in protein production. ... The new study suggests how cells in eukaryotic organisms, like humans, sense and destroy 'non-stop' proteins that remain stuck in the ribosome, the protein manufacturing plant of the cell. ... DNA is used to make RNA, which, in turn, is used to make proteins. In healthy cells, the ribosome translates the code carried by a messenger RNA (mRNA) to link together protein building blocks (amino acids) in a particular order to form specific proteins. But errors happen - which is why the body has a host of different quality control mechanisms to ensure that the proteins that emerge from this process are flawless. When aberrant proteins escape these surveillance mechanisms, they accumulate and form 'aggregates' that can be toxic to certain neuronal types, and disorders such as Alzheimer's and Parkinson's diseases can result. ... For some 15 years, scientists have understood the mechanism that identifies and destroys these problematic non-stop proteins in bacteria. In these organisms, non-stop proteins are tagged by a marker known as tmRNA or ssrA, which then leads to their destruction. In more complex eukaryotic organisms, which range from yeast to humans, though, the mechanism for identifying and eliminating such dangerous non-stop errors has remained a mystery - until now."

A press release from Tengion: "rodents with chronic kidney disease (CKD) were treated with healthy kidney cells to catalyze the regeneration of functional kidney tissue and delay disease progression, as evidenced by extended survival, improved kidney filtration, and reduced severity of kidney tissue pathology. The published data demonstrate that delivery of a selected population of kidney cells to the kidney significantly extended long-term survival and improved kidney function in rodents with chronic kidney disease during six months of follow-up. Further, the therapeutic effects reported in this study were more pronounced and more durable than have been previously reported with this animal model. ... Chronic kidney disease is a serious medical condition affecting millions of Americans and can lead to kidney failure requiring the need for transplant or lifelong dialysis. A treatment approach that can increase kidney tissue and improve function would be a significant advancement in the care of these patients. The scientific community has historically considered that CKD develops from an imbalance between tissue damage and the kidney's ability to repair and regenerate itself. These preclinical data provide clear evidence that regeneration of functional renal tissue can delay progression of CKD."



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