Fight Aging! Newsletter, July 18th 2011

July 18th 2011

The Fight Aging! 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 Fight Aging!



- An Open Cures Progress Report
- Tissue Engineered Teeth in Mice
- Three Studies on the Biochemistry of Human Longevity
- Ways to Accelerate Aging are Not Necessarily Interesting
- Discussion
- Latest Headlines from Fight Aging!


Work continues in the opening months of the Open Cures initiative:

"Open Cures is an initiative aimed at speeding up progress along the best and most logical path for commercial development of demonstrated longevity-enhancing biotechnologies. Which is to say that they should be developed overseas, outside the reach of the FDA, and then accessed via medical tourism - just like all the cutting edge medical technologies that are available only outside the US, thanks to massive regulatory overkill.

"Open Cures kicked off in earnest in May 2011, so this is still very much the stage of telling people about the idea and letting the community of potential supporters know that the initiative even exists. One part of that effort is a series of essays, the latest of which was published at h+ Magazine today under the title "Longevity Science Needs Documentation". Open Cures is a phased initiative, and the article is a deeper look at why Phase 1 of Open Cures involves the production of documentation - pulling out the best and most promising of present biotechnologies of longevity buried in research papers, and producing textbook quality how-to documents that are comprehensible to people who are not cutting edge researchers:"


Researchers have already grown new teeth in mice by implanting stem cells in the jaw, but here they grow a complete and correctly formed tooth outside the body, put it into the jaw whole, and demonstrate that it embeds and becomes fully functional:

"In this proof of concept study [a] bioengineered tooth unit comprising mature tooth, periodontal ligament and alveolar bone, was successfully transplanted into a properly-sized bony hole in the alveolar bone ... Partial bone integration was observed at 14 days after transplantation, and full bone integration around a bioengineered tooth root was seen at 30 days after transplantation ... [The] engrafted bioengineered tooth displayed physiological tooth functions such as mastication, periodontal ligament function for bone remodeling and responsiveness to noxious stimulations. ... These findings indicate that whole tooth regenerative therapy is feasible through the transplantation of a bioengineered mature tooth unit. This study also provides the first reported evidence of entire organ regeneration through the transplantation of a bioengineered tooth."


The number of research studies that search for genetic and biochemical differences in long-lived human lineages is growing:

"There are a fair number of these efforts at the present time, a combination of decades-long longitudinal studies which now consist of a cohort of exceptionally old survivors, combined with new studies launched over the past decade as academic interest in the genetics of human longevity grew. As it turns out, long-lived human lineages differ from the rest of us in a number of identifiable ways - and given that it's really only been a handful of years that these sorts of study have been underway, I would imagine that many more characteristic genetic differences remain to be identified. ... While interesting, and probably the basis for what will eventually be a massive industry of drug development aimed at gently slowing down the aging process, this sort of work is still something of a sideshow. Understanding the contributions of metabolic differences to the pace of aging and resistance to frailty and degeneration will not lead to a true cure for aging. Repair and reversal of aging, the foreseeable biotechnologies that can make the old young once again, can only come from lines of research like those undertaken by the SENS Foundation."


A caveat for those who follow research in the field:

"If you spend time following life science research, you'll see a fair amount of work in which scientists remove a piece of biological machinery in laboratory animals so as to try to figure out what it does - the changes that occur in the studied animals will hopefully allow researchers to piece together the surrounding biology and place the machinery in the full context of what is already known. In many cases this reduces life span or accelerates the pace of some form of damage that normally increases with aging - but that outcome doesn't necessarily mean that the machinery removed is connected to aging in any significant way, or that it has any relevance to ways to slow aging and extend healthy life.

"I'm sure, if you put your mind to it, you could think of a dozen ways to slowly ruin the type of machine you are most familiar with (clog up the spark plugs, remove the oil, pull out the filter head, and so forth), and few of them can be extrapolated the other way into ways to make a perfectly maintained machine last much longer than it normally does.

"So it is with the biochemical machinery of life. The only true test of relevance to aging is to demonstrate that you can use the mechanism in question to extend life beyond the normal limits for a healthy individual in that species, or reduce some form of biological damage to levels far below what is normally the case at a given age. If all you are showing is that you can increase damage and shorten life span, then there's no doubt interesting science involved, but it's too soon to be getting excited."


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!



Friday, July 15, 2011
RasGrf1 is the gene associated with longevity in engineered mice with two female parents, and a deficiency in the gene achieved through other means boosts life span as well. Here is more theorizing on what it all means: "Interestingly, RasGrf1 is one of parentally imprinted genes transcribed from paternally-derived chromosome. Erasure of its imprinting results in RasGrf1 downregulation and has been demonstrated in a population of pluripotent adult tissues-derived very small embryonic like stem cells (VSELs), stem cells involved in tissue organ rejuvenation. ... downregulation of RasGrf1 in VSELs [protects] from premature depletion from adult tissues. Thus, the studies in RasGrf1-/- mice indicate that some of the imprinted genes may play a role in ontogenetic longevity and suggest that there are sex differences in life span that originate at the genome level. All this in toto supports a concept that the sperm genome may have a detrimental effect on longevity in mammals." So in summary, one of the ways in which RasGrf1 extends life seems to involve improvement in the capacity of stem cells in the older organism, and a significant effect on longevity can emerge from the contributions of one parent through the epigenetic imprinting process.

Friday, July 15, 2011
From the Technology Review: "In a bid to harness the potential of embryonic stem cells, surgeons in California have implanted lab-grown retinal cells into the eyes of two patients going blind from macular degeneration. ... The two patients, whose names weren't released, are among the first volunteers ever to receive a treatment created using embryonic stem cells. ... We are excited about this treatment, because we think this has the potential to slow the disease progression. This company has had their ups and downs, and I am really happy to see they got into the clinic. We've had our fingers crossed. ... During a recent visit to Advanced Cell's laboratories, a research technician adjusted a microscope to show off the company's lead product: cube-shaped retinal pigment epithelial cells growing in a petri dish. Some were translucent, while others already had the brownish coloring of a mature cell. (The pigment absorbs stray light in the eye, acting as a kind of glare shield.) These retinal cells are the type that are killed off in macular degeneration, eventually leading to the death of photoreceptors, and the gradual loss of central vision. Advanced Cell believes that injecting new, lab-grown cells into the eye may cure the condition. ... It's no accident [that] both early studies of embryonic stem-cell therapies - those of Geron and Advanced Cell - involved cells of the nervous system. The reason is that embryonic stem cells naturally want to make neuroectoderm, a cell lineage in the embryo that forms the nervous system. ... Embryonic stem cells have a mind of their own, and they want to do certain things ... Efforts to produce other cell types, such as liver cells, have proved far more difficult."

Thursday, July 14, 2011
At the Wall Street Journal: "At his lab in the Bronx, geneticist Nir Barzilai has spent more than a decade trying to unlock the biology of aging. His secret weapon: some of the New York area's oldest Jews. One of his major studies analyzes the genetic make-up and life habits of the oldest of the old: 500 physically and cognitively healthy individuals living well past the century mark. ... Research that began with some of the oldest New Yorkers is now set to spread throughout the U.S. Barzilai's work is the template for a ambitious national study to create a full sequencing of the genomes of 100 ethnically and geographically diverse centenarians. ... Barzilai's work seeks to improve the quality of life for the elderly. His research has found, to his surprise, that the 100-plus crowd has less than sterling health habits. As a group, they were more obese, more sedentary and exercised less than other, younger cohorts. ... Biologically speaking, what has allowed the centenarians in his study to live so long, even with life habits that often lead to disease and death in others? ... Barzilai and his team at Einstein's Institute for Aging Research have so far discovered three uncommon genotype similarities among the centenarians: one gene that causes HDL, good cholesterol, to be at levels two- to three-fold higher than average; another gene that results in a mildly underactive thyroid, which slows metabolism; and a functional mutation in the human growth hormone axis that may be a safeguard from age-related diseases, like cancer. He suspects there may be additional genotypes that scientists have yet to locate."

Thursday, July 14, 2011
Organovo is the bioprinting startup whose investors include the Methuselah Foundation: "Organovo has been generating enough revenue from a series of new partnerships that [the company] put off an expected Series A venture round. ... the company has raised just over $2 million from private investors to develop 'bio-printing' technology that operates much like an inkjet printer. Instead of laying down ink, however, Organovo's bio-printer lays down a pattern of cultured cells and a jello-like hydrogel that supports the cells in a 3-D structure. In this way, Organovo already has been able to grow bio-engineered blood vessels, and to lay more ambitious plans to create kidneys, livers, and other vital organs in the same way. ... the work is still highly experimental, so getting regulatory approval to graft a bio-engineered blood vessel in a living patient will take years. In the meantime, [Organovo] found a burgeoning market among pharmaceutical companies by [creating] 3-dimensional 'constructs' of diseased or dysfunctional human cells that can be used as models for testing new drugs. Creating a 3-D matrix of cells enables each cell to interact with adjoining cells, so they react to drug compounds much as they would in the body. ... one of the pharmaceutical partnerships is with Pfizer to create 3-D constructs for drug discovery in two therapeutic areas. Organovo also is in talks with several additional partners ... One of the things that's been good about the past six months is that the promise of our technology is holding true. The constructs we're creating robustly build [blood vessels] with collagen, so the blood vessel grows stronger over time. The next challenge is getting to greater and greater vascularization of the construct. The emerging story is going to be, 'Who can make thicker tissues with more blood vessels inside?'"

Wednesday, July 13, 2011
An introductory open access review paper looks briefly at some of the theories of aging: "Ageing and senescence are related words and are often used interchangeably as both processes are characterized by progressive changes in the tissue of the body, eventually leading to a decline in function and death of the organism. Senescence refers to a post-maturational process that leads to diminished homeostasis and increased vulnerability of the organism to death. Ageing, in contrast, refers to any time-related process and is a continuous process that starts at conception and continues until death. The mechanisms involved in ageing are partially intrinsic to the organism, like genetic and epigenetic factors, and partially to the external origin, such as nutrition, radiation, temperature and stress. ... Various theories have evolved to improve our understanding of the ageing process so as to formulate strategies that enhance extension of life. The theories of ageing are classified based on the level at which the ageing mechanism is targeted: 1. Evolutionary theories, 2. Systemic theories, 3. Molecular and cellular theories ... Evolutionary theories state that ageing results from a decline in the force of natural selection. As evolution acts primarily to maximize reproductive fitness in an individual, longevity is a trait to be selected only if it is beneficial for fitness. Life span is, therefore, the result of selective pressures and may have a large degree of plasticity within an individual species as well as among species. ... In systemic theories, the ageing process is related to the decline of organ systems essential for control and maintenance of other systems within the organism. ... [Molecular and cellular theories] theories attempt to discern the mechanisms of ageing process at the cellular and subcellular levels."

Wednesday, July 13, 2011
Another good reason for researchers to better understand the biochemical roots of regeneration in lower animals such as newts and salamanders: "Goro Eguchi has shown that a newt's healing powers don't diminish with age. As long as they live, they retain the ability to efficiently regrow their body parts (or at least, the lenses of their eyes), even if they have to do so over and over again. We've known about the abilities of newts and other salamanders for over 200 years, thanks initially to Lazzarro Spallanzini, an Italian biologist and Catholic priest. But the limits of this ability have been unclear. Spallanzani once amputated limbs from a salamander six times over three months, and watched them grow back. ... The salamanders could repeatedly regrow their limbs, but eventually, abnormalities crept in. For example, the animals would occasionally develop missing bone structures. Both Spallanzani and Bonnet (and, indeed, Charles Darwin after them) held that newts regenerate their body parts less efficiently as they get older, especially if they accrue repeated injuries. But Eguchi thinks that these experiments, while historically important, were also flawed. The exposed stumps of the severed legs would have been exposed to the messy environment, which might have scuppered a clean regeneration. To truly test the extent of these animals' powers, Eguchi set up a 16-year-long experiment. In 1994, he collected several Japanese fire-bellied newts (Cynops pyrrhogaster) and successfully kept them in captivity. During that time, Eguchi periodically anaesthetised the animals and carefully removed the lens from their eyes. The surgeries involve a small nick to the cornea that quickly sealed, creating a protected environment where the lens could regenerate without any influence from the outside world. This happened 18 times in total. Eguchi found that the 17th and 18th lenses were exactly the same as the original ones, and those from untouched newts of the same age."

Tuesday, July 12, 2011
Demonstrations of transdifferentiation, converting one cell type directly into another, have been picking up of late. Like research into creating stem cells, it has the potential to enable a new generation of regenerative therapies, or make existing therapies more effective and less costly. Here is an example of the present state of research: "For the past decade, researchers have tried to reprogram the identity of all kinds of cell types. Heart cells are one of the most sought-after cells in regenerative medicine because researchers anticipate that they may help to repair injured hearts by replacing lost tissue. Now, [researchers] are the first to demonstrate the direct conversion of a non-heart cell type into a heart cell by RNA transfer. Working on the idea that the signature of a cell is defined by molecules called messenger RNAs (mRNAs), which contain the chemical blueprint for how to make a protein, the investigators changed two different cell types, an astrocyte (a star-shaped brain cell) and a fibroblast (a skin cell), into a heart cell, using mRNAs. ... The method the group used, called Transcriptome Induced Phenotype Remodeling, or TIPeR, is distinct from the induced pluripotent stem cell (iPS) approach used by many labs in that host cells do not have to be dedifferentiated to a pluripotent state and then redifferentiated with growth factors to the destination cell type. TIPeR is more similar to prior nuclear transfer work in which the nucleus of one cell is transferred into another cell where upon the transferred nucleus then directs the cell to change its phenotype based upon the RNAs that are made. "

Tuesday, July 12, 2011
In light of the recent sequencing of the naked mole rat genome, here's a paper on why the species is of interest: "Reactive oxygen species (ROS), by-products of aerobic metabolism, cause oxidative damage to cells and tissue and not surprisingly many theories have arisen to link ROS-induced oxidative stress to aging and health. While studies clearly link ROS to a plethora of divergent diseases, their role in aging is still debatable. Genetic knock-down manipulations of antioxidants alter the levels of accrued oxidative damage, however, the resultant effect of increased oxidative stress on lifespan are equivocal. Similarly the impact of elevating antioxidant levels through transgenic manipulations yield inconsistent effects on longevity. Furthermore, comparative data from a wide range of endotherms with disparate longevity remain inconclusive. Many long-living species such as birds, bats and mole-rats exhibit high-levels of oxidative damage, evident already at young ages. Clearly, neither the amount of ROS per se nor the sensitivity in neutralizing ROS are as important as whether or not the accrued oxidative stress leads to oxidative-damage-linked age-associated diseases. In this review we examine the literature on ROS, its relation to disease and the lessons gleaned from a comparative approach based upon species with widely divergent responses. We specifically focus on the longest lived rodent, the naked mole-rat, which maintains good health and provides novel insights into the paradox of maintaining both an extended healthspan and lifespan despite high oxidative stress from a young age." The current best explanation for this state of affairs is the membrane pacemaker hypothesis, in which it is theorized that differences in chemical composition of cellular membranes affect their resilience to oxidative damage.

Monday, July 11, 2011
Scientists are making steady progress in developing the foundational knowledge that will support the next generation of stem cell therapies: "researchers discovered the fate - or destination - of human pluripotent stem cells is encoded by how their DNA is arranged, and this can be detected by specific proteins on the surface of the stem cells. ... It's like going on secret trip. When you decide to go to Jamaica, you pack your toothbrush, underwear, and of course shorts, t-shirts and swimsuits. But if, at the last minute, you get rerouted to Alaska, you unpack a few things but the basic elements, like your toothbrush, are going to be the same. You may just trade the shorts and swimsuits for long pants and a sweater. ... Until now, common scientific belief has been that all pluripotent stem cells are equivalent and keep all options open at the same time. But that's really not the case. ... This study showed that pluripotent cells are not all equal. They are all pluripotent. You can force a cell that normally would love to become a neural cell to turn into blood, just like you can force the vacationer to go Alaska instead of Jamaica. They'll do it, but not very well and not happily. ... For the study, [the] research team found stem cells with roadmaps and specifically packed suitcases for the blood and neural destinations. The researchers discovered when they isolated these stem cells by new protein markers on the surface of cells, they were able produce a greater number of specialized cells - nearly five times as many blood cells and twelve times as many neural cells compared to when the stem cells had to be forced into those cell types."

Monday, July 11, 2011
A commentary by researcher Anthony Atala: "Is it possible for humans to regenerate a damaged body part the way starfish and salamanders can? Will doctors one day be able to replace cancer-ridden organs with healthy ones engineered in a lab? Will lengthy waiting times for organ transplants eventually become a thing of the past? Whenever lecturing about the field of regenerative medicine, I always enjoy hearing questions like these from audience members as they excitedly imagine the future applications of regenerative medicine. In fact, scenarios like these aren't outside the realm of possibility. Regenerative medicine therapies are already helping small groups of patients through clinical trials; and scientists around the world are working both to expand the applications of these therapies and to bring them into more widespread use. The effort to harness the body's natural healing powers has been called a new frontier in medicine because it offers the promise to actually cure, rather than just treat, disease. It has a several components: injectable cell therapies to promote healing; replacement tissues and organs engineered in the lab; and the use of bio-compatible materials or small molecules to prompt tissue regeneration from within the body."



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