Longevity Meme Newsletter, April 05 2010

April 05 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.



- The NewOrgan Prize Launches
- A Bone Tissue Engineering Update
- Six Hours of Extra Life Each Day
- The Longevity of PAPP-A Knockout Mice
- Discussion
- Latest Healthy Life Extension Headlines


The Methuselah Foundation announced a new research prize this month, aimed at speeding the development of replacement organs built from a patient's own cells, and expanding the community of people who support efforts to engineer greater human longevity:


"In April 2010 Methuselah Foundation challenges researchers: Find the solution to organ failure. We seek, support and reward science that extends healthy lifespan. And we believe a permanent solution to organ failure can be found. That's why we are announcing two initiatives:

"1) NewOrgan Prize: Prizes result in amazing leaps forward in science; we challenge scientists to construct and successfully transplant a whole new organ (one of heart, lung, liver, kidney, or pancreas) made from a patient's own cells by 2020.

"2) NewOrgan Network: A social community, powered by our partner My Bridge 4 Life, where those in need of replacement organs can reach out to friends and family for personal support."

You'll find more information on this new initiative at the Methuselah Foundation blog:



Researchers are making impressive inroads into building the simpler forms of tissue, such as bone. Here is news of researchers building precisely shaped whole replacement bones:


"Gordana Vunjak-Novakovic, a professor of biomedical engineering at Columbia University, has solved one of many problems on the way to successful bone implants: how to grow new bones in the anatomical shape of the original. ... Dr. Vunjak-Novakovic, Dr. Warren L. Grayson and other members of the team used digital images of the joint to guide a machine that carved a three-dimensional replica, called a scaffold, from cleansed bone material. The team turned the bare scaffold into living tissue by putting it into a chamber molded to its exact shape, and adding human cells, typically isolated from bone marrow or liposuctioned fat. A steady source of oxygen, growth hormones, sugar and other nutrients was piped into the chamber, or bioreactor, so the bone would flourish."

This is a form of recellularization work, where donor tissue is stripped of its own cells and then seeded with the patient's cells before transplant. It is a step up from straight transplantation, as it removes all risk of immune rejection, but we would still like to see the need for organ donors removed as well.


Over the past 170 years, in the countries with the highest life expectancies, the average life span has grown at a rate of 2.5 years per decade, or about 6 hours per day:


"An article from the Duke University media outlet reminds us of the bigger historical picture of human life expectancy: continual incremental improvement ever since the Industrial Revolution. ... From the perspective of the reliability theory of aging and longevity, the historical increase in life expectancy has occurred because better and more widespread availability of medical technology lowers the rate at which biological damage accumulates. Prevention of chronic infectious disease, for example, falls into this category: disease applies a damage load to an individual, and that damage reduces the mean time to failure of bodily systems. ... We're living longer because people are reaching old age in better health. Deterioration, instead of being stretched out, is being postponed."


Here is more information on one of the handful of known longevity gene manipulations in mice that appears to be all upside, with no undesirable side effects:


"The gene that encodes for pregnancy-associated plasma protein-A (PAPP-A) is of interest because knocking it out - a method of rendering the gene inoperative - extends healthy life span in mice. This genetic manipulation is one of a number of ways to beneficially alter the insulin-like growth factor system to increase life span in lower animals. It also appears to slow the decline of the immune system with age. ... In this study, PAPP-A KO mice had significantly increased mean (27%), median (27%), and maximum (35%) life span compared with wild-type (WT) littermates. End-of-life pathology indicated that the incidence of [cancer] was not significantly different in the two groups of mice; however, it occurred in older aged PAPP-A KO compared with WT mice. Furthermore, PAPP-A KO mice were less likely to show degenerative changes of age. ... In summary, the major contributors to the extended life span of PAPP-A KO mice are delayed occurrence of fatal [cancers] and decreased incidence of age-related degenerative changes. "


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 DAF-16 gene in nematode worms such as C. elegans is thought to be the fulcrum of a metabolic feedback loop that switches between long-lived stress resistant and short-lived reproduction focused states. "Ageing is a process that all organisms experience, but at very different rates. We know that, even between closely related species, average lifespans can vary enormously. We wanted to find out how normal ageing is being governed by genes and what effect these genes have on other traits, such as immunity. To do that, we looked at a gene that we already knew to be involved in the ageing process, called DAF-16, to see how it may determine the different rates of ageing in different species. ... Researchers compared longevity, stress resistance and immunity in four related species of worm. ... They also looked for differences in the activity of DAF-16 in each of the four species and found that they were all quite distinct in this respect. And, importantly, the differences in DAF-16 corresponded to differences in longevity, stress resistance and immunity between the four species - in general higher levels of DAF-16 activity correlated with longer life, increased stress resistance and better immunity against some infections."

One day, it will be possible to replace nerves with entirely artificial conduits. This is a branch of medical technology that will compete with regenerative medicine, and ultimately lead to more effective and resilient body parts. But today, the foundations are still being designed. A long road lies ahead. Here, the New Scientist looks at early work: "Schiefer is describing an experiment in which pulses of electricity are used to control the muscles of an unconscious patient, as if they were a marionette. It represents the beginnings of a new generation of devices that he hopes will allow people with paralysed legs to regain control of their muscles and so be able to stand, or even walk again. His is one of a raft of gadgets being developed that plug into the network of nerves that normally relay commands from the spinal cord to the muscles, but fall silent when a spinal injury breaks the chain. New ways to connect wires to nerves [allow] artificial messages to be injected to selectively control muscles just as if the signal had originated in the brain. Limbs that might otherwise never again be controlled by their owners can be brought back to life. ... Nerves contain tens of thousands of axons, each capable of being controlled by the ultimate puppeteer: the brain. Learning to pull even a few of those strings, though, could restore partial function to a person's limb, restoring some control to an arm or leg that was previously paralysed."

At the Maximum Life Foundation blog: "Since the Industrial Revolution, alarmists screamed doom and gloom about overcrowding and limited resources (backed by their "statistics"). However, the opposite has happened. The population increased by 740% since then, and standards of living have soared. It's not so much a question of resources as it is one of education, individual productivity and distribution—social problems, not life-extension problems. As long as people produce more than they consume, it's impossible to run out of resources. Common sense and intuition say there should be a demographic catastrophe, if people were actually immortal and continued to reproduce. But what would the science (mathematics) say? Recently, Drs. Leonid and Natalia Gavrilov answered that question with a study sponsored by the SENS/Methuselah Foundation. They proved it is possible to have sustainable population dynamics in a future hypothetical non-aging society. ... A general conclusion of this study is that population changes are surprisingly small and slow in their response to dramatic life extension. Even in the case of the most radical life extension scenario, population growth could be relatively slow and may not necessarily lead to overpopulation. Therefore, the real concerns should be placed not on the threat of overpopulation, but rather on such potential obstacles to a successful biomedical war on aging, such as scientific, organizational and financial limitations."

From ScienceDaily: researchers "used a non-viral, synthetic nanoparticle carrier to improve and save the sight of mice with retinitis pigmentosa, an inherited disease characterized by progressive vision loss and eventual blindness. ... [Researchers] used groups of mice with the retinal degeneration slow (Rds) gene, which causes retinitis pigmentosa. The mice received one of three types of 'treatments:' nanoparticles containing the normal copy of the Rds gene, the normal gene alone, or saline solution. After these treatments were delivered to the mice, the structure and function of the retina were analyzed by comparing them to untreated mice with retinitis pigmentosa and healthy mice with the normal Rds gene. Researchers also measured the level and pattern of Rds gene expression, as well as functional, structural and biochemical improvements in disease symptoms. They discovered that mice receiving the nanoparticle gene therapy show significant signs of healing. These mice had structural improvement in their retinas, as well as functional vision improvements, which lasted throughout the duration of the study. The mice that received the gene alone or saline continued to lose their vision. The nanoparticles were safe and well-tolerated with no adverse effects."

A paper on mitochondrial DNA (mtDNA) damage and its role in aging: "Mitochondrial dysfunction is heavily implicated in the multifactorial aging process. Aging humans have increased levels of somatic mtDNA mutations that tend to undergo clonal expansion to cause mosaic respiratory chain deficiency in various tissues, such as heart, brain, skeletal muscle, and gut. Genetic mouse models have shown that somatic mtDNA mutations and cell type-specific respiratory chain dysfunction can cause a variety of phenotypes associated with aging and age-related disease. There is thus strong observational and experimental evidence to implicate somatic mtDNA mutations and mosaic respiratory chain dysfunction in the mammalian aging process. The hypothesis that somatic mtDNA mutations are generated by oxidative damage has not been conclusively proven. Emerging data instead suggest that the inherent error rate of mitochondrial DNA (mtDNA) polymerase gamma (Pol gamma), [a protein responsible for mitochondrial DNA replication and repair], may be responsible for the majority of somatic mtDNA mutations. The roles for mtDNA damage and replication errors in aging need to be further experimentally addressed."

From the Wall Street Journal: "a growing number of researchers have been seeking to understand how telomeres work. One feat researchers have accomplished in the lab is using telomerase to 'immortalize' human cells. Scientists [have] shown they can keep certain types of cells living forever, including those from the breast, skin, retina and, recently, the colon, by adding telomerase to keep telomeres intact or repair those that became too short. Now researchers are studying how telomerase-based therapies could help repair damaged cells and play an major role in cancer research. ... What our goal should be isn't increasing life span, but healthy life span. Is there some way we can intervene and slow down some of the problems? ... if a telomerase-based therapy could be given to specific cells temporarily, say for a week or two, it could be a therapeutic 'home run,' repairing telomeres and allowing cells to keep dividing ... Such a therapy - which would actually occur on a patients' own cells grown in a lab dish - could help people with conditions where cells have been injured and have used up their allotment of telomeres, such as anemia or skin sores or conditions involving inflammation. Many cancer researchers are trying to figure out how to turn off telomerase and potentially treat cancer. ... In experiments with lung cells, [scientists] are exploring how telomerase could be an alternative - and potentially easier - way of using stem cells to grow healthy tissue, without turning them all the way back to their embryonic state."

Here is an interesting theory on the contribution of nuclear DNA damage to aging, and double strand breaks in particular: "Advancing age remains the largest risk factor for devastating diseases, such as heart disease, stroke, and cancer. The mechanisms by which advancing age predisposes to disease are now beginning to unfold, due in part, to genetic and environmental manipulations of longevity in lower organisms. Converging lines of evidence suggest that DNA damage may be a final common pathway linking several proposed mechanisms of aging. The present review forwards a theory for an additional aging pathway that involves modes of inherent genetic instability. Long interspersed nuclear elements (LINEs) [such as L1 are] retrotransposons that compose about 20% of the human genome. ... While principally active only during embryogenesis, L1 transcripts are detected in adult somatic cells under certain conditions. The present hypothesis proposes that L1s act as an 'endogenous clock', slowly eroding genomic integrity by competing with the organism's double-strand break repair mechanism. Thus, while L1s are an accepted mechanism of genetic variation fueling evolution, it is proposed that longevity is negatively impacted by somatic L1 activity. The theory predicts testable hypotheses about the relationship between L1 activity, DNA repair, healthy aging, and longevity."

Researcher Steven Austad lists the advances made by the mainstream of aging research last year: "Among the notable trends seen in this year's highlights in mammalian aging research is an awakening of interest in the assessment of age-related measures of mouse health in addition to the traditional focus on longevity. One finding of note is that overexpression of telomerase extended life and improved several indices of health in mice that had previously been genetically rendered cancer-resistant. In another study, resveratrol supplementation led to amelioration of several degenerative conditions without affecting mouse lifespan. A primate dietary restriction (DR) study found that restriction led to major improvements in glucoregulatory status along with provocative but less striking effects on survival. Visceral fat removal in rats improved their survival although not as dramatically as DR. An unexpected result showing the power of genetic background effects was that DR shortened the lifespan of long-lived mice bearing Prop1(df) whereas a previous report in a different background had found DR to extend the lifespan of Prop1(df) mice. Treatment with the mTOR inhibitor, rapamycin, enhanced the survival of even elderly mice and improved their vaccine response. Genetic inhibition of a TOR target made female, but not male, mice live longer. This year saw the mTOR network firmly established as a major modulator of mammalian lifespan."

Here, h+ Magazine looks at Methuselah Foundation supported tissue printing company Organovo: "The December 2009 press release created quite a stir: Organovo, a San Diego-based company that specializes in regenerative medicine announced a new $200,000 bioprinter that prints artificial organs using inkjet technology. Partner engineering firm Invetech in Melbourne, Australia designed and developed what may well turn out to be the world's first production model 3D bioprinter ... Since the 2009 press release, Invetech has cemented its plans to ship a number of 3D bioprinters to Organovo during 2010 and 2011. Organovo will then distribute them globally to researchers at world-class medical research centers. These initial units will be capable of printing only very basic tissues like blood vessels, not full-blown organs. Nevertheless, this technology has attracted the attention of longevity pioneer Aubrey de Grey and his Methuselah Foundation. What better way to counteract a damaged or aging heart, kidney, or liver than to replace it with a new one? Rather than wait for a donor organ, simply print one. That might just add a few years to your life. ... You give us your cells: we grow them, we print them, the structure forms and we are ready to go. I am pretty sure that full organs will be on the market [one day]."

From the SENS Foundation, an update on allotopic expression of mitochondrial DNA - the SENS approach to eliminating the contribution of mitochondrial DNA damage to aging. Vulnerable but essential mitochondrial genes are copied into the protected cell nucleus, and one of a variety of strategies are then used to ensure the encoded proteins get back to the mitochondria where they are needed: "To date, three of the thirteen OXPHOS genes still encoded in the mitochondria have been allotopically expressed (AE) in human cells ... In work funded by SENS Foundation, Corral-Debrinski's group have used their improved AE technique of relocalizing translation of AE genes to the mitochondrial surface [to] reverse blindess in rats caused by exposure to mutations in this gene ... Now we have the first report of a new gene, COX2, being allotopically expressed in yeast, by mutating the gene to overcome the hydrophobicity of the mitochondrial membrane ... This is an exciting advance [and] the first allotopic expression of this respiratory chain component in a species in which evolution has never accomplished the feat for itself. The next step, of course, is to do it in mammalian cells - preferably, of our own species. And the same broad strategy likely applies to many of the other remaining [thirteen genes of interest]; indeed, during his work sponsored by SENS Foundation, Mark Hamalainen developed software that models hydrophobicity of proteins, and it predicts that a relatively small number of relatively minor amino acid changes would lower the hydrophobicity [sufficiently] to make them importable when the native gene likely is not."



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