Longevity Meme Newsletter, March 16 2009

March 16 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.



- The Present Bottom Line on Calorie Restriction
- A Perspective on Neurodegeneration
- Discussion
- Latest Healthy Life Extension Headlines


Eating fewer calories while still obtaining adequate nutrition is good for you. That much is clear; the debate these days is over just how beneficial it is in humans. What does it do for us humans beyond dramatically reducing the risk of suffering most, possibly all, of the common age-related diseases?


"There are currently no interventions or gene manipulations that can prevent, stop or reverse the aging process. However, there are a number of interventions that can slow down aging and prolong maximal lifespan up to 60% in experimental animals. Long-term calorie restriction without malnutrition and reduced function mutations in the insulin/IGF-1 signaling pathway are the most robust interventions known to increase maximal lifespan and healthspan in rodents.

"Although it is currently not known if long-term calorie restriction with adequate nutrition extends maximal lifespan in humans, we do know that long-term calorie restriction without malnutrition results in some of the same metabolic and hormonal adaptations related to longevity in calorie restriction rodents. Moreover, calorie restriction with adequate nutrition protects against obesity, type 2 diabetes, hypertension and atherosclerosis, which are leading causes of morbidity, disability and mortality."


I thought I'd point your attention to a very readable open access paper that suggests our brains degenerate in later life as a consequence of evolutionary selection. Evolution, so the theory goes, favored early humans whose brains stopped using so much energy when their ability to hunt started to go downhill.


I can't say I'm completely sold on the high level conclusion, which seems to depend on relatively unsupported assumptions about the dominant selective pressures acting during specific decades of primitive hunter-gatherer life. Some thought-provoking points are made along the way, however, so I encourage you to read the whole thing.

Alternate theories of decline in the brain look at it as a consequence of damage: as our cells and tissue systems accumulate byproducts of metabolism that cannot be broken down, failing mitochondria, and other issues, their efficiency decreases. Eventually lost efficiency causes more catastrophic issues and failures - the age-related diseases we're familiar with:



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!




The Earnest Search For Longevity Mechanisms (March 13 2009)
The work of Genescient provides good insight into what the search for longevity genes - and biological mechanisms of metabolism connected to aging - looks like these days. As more automation is applied to the search, the pace of discovery is picking up: "Using genetically selected long lived Drosophila and the latest genetic tools, Genescient has identified over 100 gene networks that are altered in long lived strains of Drosophila melanogaster and that are also linked to longevity and age-related diseases in humans ... We then make maps of networks pointing to the genes appearing in our proprietary list and their relationships. This elucidates possible human therapeutics to treat chronic diseases of aging and improve function. Once found, we then quickly test these compounds in Drosophila for their effects on median lifespan, background mortality, and the rate of aging at different doses. ... Because the selected Drosophila genetic pathways are also linked to conserved age-related disease genes in humans, direct therapeutic effects on human health can be expected. In our first attempts at selection using this screening procedure, we have already initially tested 13 compounds on normal flies. We found 12 that extend significantly the normal Drosophila lifespan, reduce background mortality rates, or slow the rate of aging."

Healthy Life Extension At Convergence08 (March 13 2009)
From Future Current, a transcript of a panel on healthy life extension at Convergence08. Here, Aubrey de Grey points out that there are "an enormous number of millions of dollars already being applied to Alzheimer's research specifically over the developed world, added to all the other diseases of aging. The difficulty with that approach to combating these things is that by the time these diseases have gotten far enough along to actually be called diseases, things are getting pretty far out of hand and [intractable] ... The real reason why what I call 'the geriatrics approach' to combating aging is intractable is simply because it is not applying the really rather reliable principle of 'prevention is better than cure.' Essentially the targets for these interventions are consequences of stuff that is going on throughout life and progressively accumulates to result in various types of molecular and cellular damage that are side effects of our normal metabolism. As people get older, those side effects continue to accumulate. If you are attacking the side effects of those consequences, namely those particular diseases, then your job is just going to be getting harder and harder as time goes by. This geriatrics approach is therefore going to be a short-term approach, and a losing battle."

Decoys Versus RAGE (March 12 2009)
I've mentioned the role of RAGE, the receptor for advanced glycation end-products (AGEs), in aging before. As AGEs build up, RAGE is ever more triggered, causing cells to act inappropriately. Cell receptors could be considered as keyboards or buttons - hit them with the right sort of molecules and you're instructing the cell to take action. This sort of errant instruction of cells is particularly important in age-related conditions where AGE levels are very elevated, such as diabetes, but is a damaging consequence of age-related increase in AGE levels for all of us. RAGE is "involved in a wide spectrum of diseases, including diabetes mellitus, atherothrombosis, chronic renal failure, rheumatoid arthritis, neurodegeneration, cancer and aging. Circulating soluble forms of RAGE (sRAGE) [may] counteract RAGE-mediated pathogenesis by acting as a decoy. Several studies suggest that decreased levels of sRAGE [may] be useful as a biomarker of [RAGE hyperactivity] and inadequate endogenous protective response." Past work supports this sort of intervention: "administration of the ligand-binding decoy of RAGE, soluble or sRAGE, suppresses early initiation and progression of atherosclerosis in diabetic mice."

A Look Back at Deathism (March 12 2009)
Michael Anissimov here looks back at deathism past: "One of the more memorable life extension debates I've been to was a summer 2007 meeting of the Bay Area Future Salon where Aubrey de Grey went up against William Hurlbut, who used to work under Leon Kass on Bush's Religious Right-dominated President's Council on Bioethics. Unlike Kass, who is laughed at and rejected by mainstream bioethics for his nutty, highly quotable opinions (much to the disappointment of Wesley J. Smith), Hurlbut is somewhat more sane-sounding. He is intellectual and often presents his ideas using reasonable rather than bombastic uber-conservative language. ... Read up on the debate between Aubrey and Hurlbut at Future Current. Hurlbut was being so sincere and honest that I almost felt sorry for him trying to argue his points in a room full of transhumanists. But then again, he wants us all to die at a predetermined age, so you can’t have too much pity. If I may be allowed to suggest a motto for Hurlbut's philosophy: 'Be a man. Die.'"

Calorie Restriction Versus Cancer (March 11 2009)
Via Newswise, a look at the mechanisms behind the interaction of calorie restriction and tumor growth: "The connection between food consumption and tumor growth is not new. In the early 20th Century, scientists first noted the correlation between a restricted diet and decreased tumor size and incidence. However, some cancers' growth rate was unaffected by a decrease in food consumption. The reason for this difference remained unclear. ... researchers have [now] pinpointed a cellular pathway that determines whether cancerous tumors respond to dietary restriction during their development. Studying human cancer cell lines in mice, researchers have found that when this pathway, known as PI3K, is activated permanently via mutation, tumors grow and proliferate independent of food consumption. However, when the PI3K pathway operates normally, dietary restriction (defined as a 60% reduction in normal intake), results in smaller tumors. ... We already know that the United States has an epidemic of obesity and that obesity is probably the biggest contributor to cancer in the U.S., even more so than smoking. Does this research have anything to do with that correlation between obesity and cancer, that if we make animals really obese, that this pathway is also involved in determining their sensitivity to cancer? Answering that question is the next step."

Guided Tissue Self-Assembly (March 11 2009)
From the MIT Technology Review: "Cells coated with sticky bits of DNA can self-assemble into functional three-dimensional microstructures. ... Unlike top-down methods, in which scientists build cell structures on scaffolds, the new technique allows tissue engineers to dictate the precise geometric interactions of individual cells. ... So far these microstructures are rudimentary - far from the structural sophistication of a whole organ. But by tweaking the ratio of cell types, the density of DNA on the cells' surfaces, and the complexity of the DNA sequences, [researchers] hope to build larger and more intricate assemblies. ... even if this technique turns out not to scale up well [it] could in principle provide structural building blocks for use in other emerging bottom-up approaches, such as layer-by-layer tissue printing or laser manipulation. ... It has a lot of potential, and it may provide therapies in the future, but other challenges need to be overcome to make a clinically viable product."

Engineering a Capillary Network (March 10 2009)
Creating networks of tiny blood vessels is a major hurdle in tissue engineering. Fortunately, many groups are working away on a variety of strategies to address this issue. From Chemical Science: "Candy floss (also known as cotton candy) has been used by US scientists to create a web of microscopic tubes to mimic the capillary network that carries blood to human tissue. [Researchers] mimicked the capillary network structure by sticking two sugar rods to a candy floss ball. They poured a molten polymer over the candy floss, left it to solidify, then dissolved the sugar, leaving a complex network of channels connecting two larger inlet and outlet channels. They then injected fluorescently labelled blood into the system and followed its progress using a video fluorescence microscope. They found that the blood flowed through as it would in a real system. [This] method addresses a limitation in tissue engineering: how to make an artificial vascular system for the new tissue. Since blood can only diffuse a few hundred micrometres from a capillary, organs need these networks to deliver oxygen and nutrients to every cell. His technique is cheaper and less time consuming than existing methods for making the networks, such as layer-by-layer 2D structure stacking or 3D printing, where templates for growing cells are built up."

Regrowing Stroke-Damaged Brain Tissue (March 10 2009)
From ScienceDaily: "scientists reveal how they have replaced stroke-damaged brain tissue in rats. ... by inserting tiny scaffolding with stem cells attached, it is possible to fill a hole left by stroke damage with brand new brain tissue within 7 days ... Previous experiments where stem cells have been injected into the void left by stroke damage have had some success in improving outcomes in rats. The problem is that in the damaged area there is no structural support for the stem cells and so they tend to migrate into the surrounding healthy tissues rather than filling up the hole left by the stroke. ... Using individual particles of a biodegradable polymer called PLGA that have been loaded with neural stem cells, the team of scientists have filled stroke cavities with stem cells on a ready-made support structure. ... This works really well because the stem cell-loaded PLGA particles can be injected through a very fine needle and then adopt the precise shape of the cavity. In this process the cells fill the cavity and can make connections with other cells, which helps to establish the tissue ... We would expect to see a much better improvement in the outcome after a stroke if we can fully replace the lost brain tissue, and that is what we have been able to do with our technique."

Towards an End to Metastasis (March 09 2009)
If we could shut down metastasis, cancer would be a far less dangerous proposition, open to a broader range of less harmful therapies: "Cancer metastasis, where the cancer spreads from its original location, is known to be responsible for 90% of cancer-related deaths. ... scientists have found that an enzyme called LOX is crucial in promoting metastasis ... Drugs to block this enzyme's action could keep cancer at bay ... The researchers studied breast cancer in mice, but are confident that their findings will apply to humans with other cancer types too. LOX (lysyl oxidase) works by sending out signals to prepare a new area of the body for the cancer to set up a camp. Without this preparation process the new environment would be too hostile for the cancer to grow. ... it was the first time one key enzyme has been identified as responsible for effectively allowing the cancer to spread. ... the next stage will be to find out if the LOX protein can be switched off to stop cancer spreading."

The Gavrilovs on Aging and Evolution (March 09 2009)
Some of the basics on aging and evolution are covered again in this Psychology Today article: "How does it happen that, after having accomplished the miraculous success that led us from a single cell at conception through birth and then to sexual maturity and productive adulthood ... the developmental program formed by biological evolution fails even to maintain the accomplishments of its own work? ... humans need to have a life expectancy of only twenty-five to ensure continuance of the species. We are well equipped to reproduce as teens, and a life expectancy of twenty-five left us with enough young-elders to pass on the full amount of culture needed to survive and evolve on the African plain to our current biological form. Not only old age, but middle-age appears to be totally irrelevant to survival. ... The mutation accumulation theory embodies the idea that [a] mutant gene that kills children will not be passed on to the next generation, but a negative gene - e.g., Alzheimer's disease - will be neutral to natural selection. Over time, these genes [will] survive and accumulate in the human population. Related to mutation accumulation is the antagonistic pleiotropy theory, which is the idea that some genes that have a survival value for reproduction carry within themselves negative effects as we age. Pleiotropic genes have more than one effect--in aging, antagonistic effects."



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