Fight Aging!

FIGHT AGING! NEWSLETTER
November 7th 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!

______________________________

CONTENT

- Demonstrating the Value of Destroying Senescent Cells
- An Open Cures Update
- Ben Best on SENS5
- The Indeterminate Nature of Poorly Funded Research
- Discussion
- Latest Headlines from Fight Aging!

DEMONSTRATING THE VALUE OF DESTROYING SENESCENT CELLS

The big news this past week was the publication of a method of destroying senescent cells in mice, which caused a large enough difference in the trajectory of health to validate the build up of these cells as a root cause of aging:

https://www.fightaging.org/archives/2011/11/a-demonstration-of-the-merits-of-apoptosens.php

"At any given time a whole bunch of cells in your body need to be destroyed before they cause harm - cells that are past the productive stage of their life cycle and have become senescent, cells that are damaged and malfunctioning, and so forth. The majority of these cells are indeed destroyed, either by the immune system or through self-destruction mechanisms that evolved to trigger when vital cellular processes begin to run ragged. But this protective culling fails with age, and the accumulation of cells that should have been destroyed but were not is one of the driving forces of degenerative aging.

"Scientists at the Mayo Clinic, in the US, devised a way to kill all senescent cells in [mice genetically engineered to age more rapidly than normal, and therefore accumulate senescent cells more rapidly than normal]. ... when they were given a drug, the senescent cells would die. The researchers looked at three symptoms of old age: formation of cataracts in the eye; the wasting away of muscle tissue; and the loss of fat deposits under the skin, which keep it smooth. Researchers said the onset of these symptoms was 'dramatically delayed' when the animals were treated with the drug. When it was given after the mice had been allowed to age, there was an improvement in muscle function. [The study] suggests if you get rid of senescent cells you can improve [physical traits] associated with ageing and improve quality of life in aged humans."

The next step is to repeat this in normal mice. The exact method used involves genetic engineering, so it's probably not going to be the basis for a therapy in humans. It does involve identifying senescent cells by their distinctive biochemistry, however, and the cancer research community is developing all sorts of different discriminating cell-killing technologies that work by checking the characteristics of the target cells - so all in all this is a very promising step forward towards the ability to repair this portion of the cause of aging.

AN OPEN CURES UPDATE

A short report on what is going on with the Open Cures initiative:

https://www.fightaging.org/archives/2011/11/an-open-cures-update.php

"I should preface this post by noting that my work on any given project tends to take place in waves, and the past couple of months have been a trough of comparatively low activity for Open Cures. The earlier part of this year was a crest in which planning was accomplished, discussions held, an email group and web site site up, posts and articles written, and a few thousand dollars expended to test the waters for paid writing of protocol documents, largely through contractors with life science backgrounds met via the oDesk marketplace. A start, in other words, for something that I anticipate will run at a more modest rate for a number of years.

"You never get as far as you'd like in any given period of time, of course, and the rest of the world rarely cooperates by conforming to initial expectations. Since the last update posted here, work on finding reliable authors and writing has proceeded at a slow but steady pace. I'm comfortable with my ability to source these folk now - there are a surprisingly large number of life science graduates and researchers offering their services on the global market for distance work. So the focus has been on establishing high quality baseline documents as examples, templates to help future writers toe the line, and similar issues. One of the slowdowns here has been a matter of dealing with the questions that bedevil the setup for any process: what exactly do we want the results to look like, what is the best way to obtain them, how does it all fall into place in detail."

BEN BEST ON SENS5

Cryonics industry figure Ben Best was at the fifth Strategies for Engineered Negligible Senescence conference, and recently published his notes on the event

https://www.fightaging.org/archives/2011/11/ben-best-on-sens5.php

"People who attend SENS conferences are the demographic that is the most receptive to cryonics of any identifiable group I have yet found. They are mostly scientists interested in intervening in the aging process. ... great progress has been made in starting research programs on each of the SENS strategies, and by 2012 research on all the strategies is expected to be in progress. ... In addition to my oral presentation on cryonics I also had a poster. Scientific conferences usually have poster sessions where scientists present research, reviews, or ideas in the form of a poster. Poster presenters stand by their posters at scheduled times to discuss their work on a one-to-one basis with individuals rather than to an audience. My poster dealt with challenging the concept of biological age and denying the possibility of a biomarker of aging that could determine biological age. I contended that biological age and biomarkers of aging assume a singular underlying aging process, which I denied on the grounds that aging is multiple forms of damage."

THE INDETERMINATE NATURE OF POORLY FUNDED RESEARCH

The ability to predict research and development outcomes with any reliability is only possible at higher levels of funding, and even there only when you a have a pretty good idea as to the path ahead:

https://www.fightaging.org/archives/2011/11/the-indeterminate-nature-of-poorly-funded-research.php

"For reference, the fully funded SENS scenario called for a budget of $100 million per year over ten years the last time I checked, those funds spread between work on the seven categories of repair biotechnology required to prevent and reverse the degenerations of aging. That scenario is proposed to give a fifty-fifty shot at mouse rejuvenation by the end of the ten year period. As the clock keeps ticking without funding at that level materializing, one would expect the cost estimates to fall somewhat over time even if no-one is working on SENS: the cost of research and development in biotechnology is falling across the board, and in addition researchers benefit from a steady rate of progress throughout the fundamental life sciences. Some things that were obscure will become clear and some things that were hard will become easier because of progress in related areas of the broader field.

"If SENS work stopped tomorrow and someone were to return to the drawing board ten years from now and run the numbers again, would rejuvenation in mice still be ten years and $100 million? Quite possibly yes on the ten years, and no on the $100 million - I think the cost would be significantly lower. But that doesn't mean it would take less time: as I've argued in the past there is a certain lower limit in the time taken for human endeavors. Organization of large projects, large-scale fundraising, and sequential tasks that depend upon one another can't be brought down below a certain minimum length of time for so long as there are humans in the decision loop. From this perspective, spending tens of millions of dollars on research in a few years is just as large and complex an undertaking as raising venture capital and starting a company - you can't expect to get much of anywhere without it taking a few years, no matter how good your tools and ideas are.

"If funding of $100 million per year results in a big enough research group to allow for an averaging of the risks and reasonable predictions for a decade of work, then $1 million a year (the 2010 budget of the SENS Foundation) is far removed from predictability. If that continues for ten or twenty years, who can say what will result - certainly not fully implemented SENS, but my point is that no prediction of the actual resulting science and technology can be reasonable at these levels of funding. The lesson to take away here is that we should view the SENS research program as a growth endeavor, and success in the long term goal of building a toolkit for human rejuvenation can only come through tremendous growth. These are still the early, formative years in a curve spanning decades."

DISCUSSION

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!

______________________________

LATEST HEADLINES FROM FIGHT AGING!

A REVIEW OF BIOARTIFICIAL LUNG ENGINEERING
Friday, November 4, 2011
https://www.fightaging.org/archives/2011/11/a-review-of-bioartificial-lung-engineering.php
A review paper on one of the trailing areas of tissue engineering - lungs present a harder and more complex challenge than many other organs: "End-stage lung disease is a major health care challenge. Lung transplantation remains the definitive treatment, yet rejection and donor organ shortage limit its broader clinical impact. Engineering bioartificial lung grafts from patient-derived cells could theoretically lead to alternative treatment strategies. Although many challenges on the way to clinical application remain, important early milestones toward translation have been met. Key endodermal progenitors can be derived from patients and expanded in vitro. Advanced culture conditions facilitate the formation of three-dimensional functional tissues from lineage-committed cells. Bioartificial grafts that provide gas exchange have been generated and transplanted into animal models. Looking ahead, current challenges in bioartificial lung engineering include creation of ideal scaffold materials, differentiation and expansion of lung-specific cell populations and full maturation of engineered constructs to provide graft longevity after implantation in vivo. A multidisciplinary collaborative effort will not only bring us closer to the ultimate goal of engineering patient-derived lung grafts, but also generate a series of clinically valuable translational milestones such as airway grafts and disease models."

RESEARCH ON BACTERIAL AGING
Friday, November 4, 2011
https://www.fightaging.org/archives/2011/11/research-on-bacterial-aging.php
The aging of bacteria grants us insight into the very earliest evolutionary origins of aging: "When a bacterial cell divides into two daughter cells and those two cells divide into four more daughters, then 8, then 16 and so on, the result, biologists have long assumed, is an eternally youthful population of bacteria. Bacteria, in other words, don't age - at least not in the same way all other organisms do. ... [But] not only do bacteria age, but [their] ability to age allows bacteria to improve the evolutionary fitness of their population by diversifying their reproductive investment between older and more youthful daughters. ... Aging in organisms is often caused by the accumulation of non-genetic damage, such as proteins that become oxidized over time. So for a single celled organism that has acquired damage that cannot be repaired, which of the two alternatives is better - to split the cellular damage in equal amounts between the two daughters or to give one daughter all of the damage and the other none? ... bacteria appear to give more of the cellular damage to one daughter, the one that has 'aged,' and less to the other, which the biologists term 'rejuvenation' ... In a bacterial population, aging and rejuvenation goes on simultaneously, so depending on how you measure it, you can be misled to believe that there is no aging. ... We ran computer models and found that giving one daughter more the damage and the other less always wins from an evolutionary perspective. It's analogous to diversifying your portfolio."

PGC-1 AND FLY LONGEVITY
Thursday, November 3, 2011
https://www.fightaging.org/archives/2011/11/pgc-1-and-fly-longevity.php
PCG-1 is known to be connected to the benefits of calorie restriction in a range of species, and here researchers are working with flies: "One of the few reliable ways to extend an organism's lifespan, be it a fruit fly or a mouse, is to restrict calorie intake. Now, a new study in fruit flies is helping to explain why such minimal diets are linked to longevity and offering clues to the effects of aging on stem cell behavior. Scientists [found] that tweaking a gene known as PGC-1, which is also found in human DNA, in the intestinal stem cells of fruit flies delayed the aging of their intestine and extended their lifespan by as much as 50 percent. ... While little is known about the biological mechanisms underlying this phenomenon, studies have shown that the cells of calorie-restricted animals have greater numbers of energy-generating structures known as mitochondria. In mammals and flies, the PGC-1 gene regulates the number of these cellular power plants, which convert sugars and fats from food into the energy for cellular functions. ... The researchers found that boosting the activity of dPGC-1, the fruit fly version of the gene, resulted in greater numbers of mitochondria and more energy-production in flies - the same phenomenon seen in organisms on calorie restricted diets. When the activity of the gene was accelerated in stem and progenitor cells of the intestine, which serve to replenish intestinal tissues, these cellular changes correspond with better health and longer lifespan."

DEDIFFERENTIATION AND STEM CELL TRANSPLANT EFFECTIVENESS
Thursday, November 3, 2011
https://www.fightaging.org/archives/2011/11/dedifferentiation-and-stem-cell-transplant-effectiveness.php
Via EurekAlert!: "Research into differentiation has led to a variety of breakthroughs as stem cell researchers harvest cells from one part of the body and genetically adapt them to fulfill a specialized role. However, if the implanted cells are too much like the cells of the targeted area they may not have the plasticity to engraft and repair the injured tissue. ... Stem cell differentiation and transplantation has been shown to improve function in conditions including degenerative diseases and blood supply disorders. However, the survival rate of transplanted cells in patients limits their overall effectiveness, which is a barrier to clinical use. ... To overcome this issue [researchers] explored de-differentiation, a process that reverts specialized, differentiated cells back to a more primitive cell. The team focused their research on multipotent stem cells, (MSCs) which can be altered into a variety of cell types through differentiation. Bone marrow MSCs have the potential to differentiate into each of the three basic types of lineage cells which form bone (osteocytes), cartilage (chondrocytes) and fat tissue (adipocytes). The team first differentiated bone marrow MSCs towards a neuronal lineage, but then removed the differentiation conditions, allowing the cell to revert back to a form with more basic cellular characteristics. Following this process the team recorded increased cell survival rates following transplants. In an animal model de-differentiated cells were found to be more effective in improving cognitive functions and in aiding recovery from strokes, compared to un-manipulated stem cells both in living specimens and in laboratory experiments."

ASSEMBLY OF CELLS AND VESICLES FOR ORGAN ENGINEERING
Wednesday, November 2, 2011
https://www.fightaging.org/archives/2011/11/assembly-of-cells-and-vesicles-for-organ-engineering.php
An interesting open access review paper - the full thing is in PDF format only: "The development of materials and technologies for the assembly of cells and/or vesicles is a key for the next generation of tissue engineering. Since the introduction of the tissue engineering concept in 1993, various types of scaffolds have been developed for the regeneration of connective tissues in vitro and in vivo. Cartilage, bone and skin have been successfully regenerated in vitro, and these regenerated tissues have been applied clinically. However, organs such as the liver and pancreas constitute numerous cell types, contain small amounts of extracellular matrix, and are highly vascularized. Therefore, organ engineering will require the assembly of cells and/or vesicles. In particular, adhesion between cells/vesicles will be required for regeneration of organs in vitro. ... adhesive materials and technologies will work as 'glues' for assembling various kinds of cells. The adhesive materials should be degraded when cells themselves biosynthesize cell adhesion molecules ... Although integration of newly developed materials and technologies will be required for the regeneration of organs in vitro, this will ultimately lead to the creation of three-dimensionally engineered organs with functions similar to those of natural organs."

MORE DATA ON AGE AND STEM CELL TRANSPLANTATION
Wednesday, November 2, 2011
https://www.fightaging.org/archives/2011/11/more-data-on-age-and-stem-cell-transplantation.php
Making therapies that can work in older patients despite their frailty and damage is an important part of progress in stem cell medicine of all sorts: "Age alone no longer should be considered a defining factor when determining whether an older patient with blood cancer is a candidate for stem cell transplantation. That's the conclusion of the first study summarizing long-term outcomes from a series of prospective clinical trials of patients age 60 and over ... the five-year rates of overall and disease-progression-free survival among mini-transplant patients were 35 percent and 32 percent, respectively. Patients in three age groups - 60 to 64, 65 to 69 and 70 to 75 - had comparable survival rates, which suggested that age played a limited role in how patients tolerate the mini-transplant. ... Conventional transplants, which are generally not perfomed on people over age 60 or others who are medically unfit, use high doses of total-body irradiation and potent chemotherapy to eliminate leukemic cells. The intense treatment destroys the blood and immune system and is fatal unless the patient is rescued by infusion of donor bone marrow or stem cells isolated from peripheral blood. The mini-transplant, in contrast, relies on the ability of donor immune cells to target and destroy the cancer - without the need for high-dose chemotherapy and radiation. Instead, low-dose radiation and chemotherapy is used to suppress the immune system rather than destroy it. This helps the body accept the donor stem cells, which then go to work to attack cancer cells - called the graft-vs.-leukemia effect - and rebuild the immune system."

AGE DIMINISHING AS A BARRIER IN REGENERATIVE MEDICINE
Tuesday, November 1, 2011
https://www.fightaging.org/archives/2011/11/age-diminishing-as-a-barrier-in-regenerative-medicine.php
Over the last few years there have been a series of positive developments in stem cell research that suggest the age of a patient will not be a significant hurdle in generating useful cells for therapeutic use. Here is another: "Researchers were able to successfully transform cells from patients as old as 100 into stem cells virtually identical to those found in embryos. If these can be used to grow healthy tissue which can safely be transplanted into elderly patients it could open up new avenues of treatment for the elderly. ... This is a new paradigm for cell rejuvenation ... the age of cells is definitely not a barrier to reprogramming. ... scientists can use a method of taking normal cells from adults and reversing them to an unspecialised state, known as induced pluripotent stem cells (iPS), making them almost indistinguishable from embryonic stem cells. But experts are divided over whether the technique can work efficiently in elderly patients, who have the most to gain from the potential treatments, because their cells have deteriorated further. By adding two new ingredients, known as transcription factors, to the method of generating adult stem cells, they were able to overcome this hurdle and 'reset' many of the key markers of ageing in cells."

CALORIE RESTRICTION AND CELLULAR ANTIOXIDANTS
Tuesday, November 1, 2011
https://www.fightaging.org/archives/2011/11/calorie-restriction-and-cellular-antioxidants.php
Some forms of naturally produced antioxidant in our cells can be manipulated to extend life - for example, mice engineered to produce more catalase at their mitochondria live longer. This can be taken as an indication of the importance of oxidative damage in the mitochondria as a cause of aging. Here is research in yeast to show that calorie restriction, another way of extending life, may also act partially through cellular antioxidants: "We are able to show that caloric restriction slows down ageing by preventing an enzyme, peroxiredoxin, from being inactivated. This enzyme is also extremely important in counteracting damage to our genetic material. ... active peroxiredoxin 1, Prx1, an enzyme that breaks down harmful hydrogen peroxide in the cells, is required for caloric restriction to work effectively. The results [show] that Prx1 is damaged during ageing and loses its activity. Caloric restriction counteracts this by increasing the production of another enzyme, Srx1, which repairs Prx1. Interestingly, the study also shows that ageing can be delayed without caloric restriction by only increasing the quantity of Srx1 in the cell. Repair of the peroxiredoxin Prx1 consequently emerges as a key process in ageing. ... Peroxiredoxins have also been shown to be capable of preventing proteins from being damaged and aggregating, a process that has been linked to several age-related disorders affecting the nervous system, such as Alzheimer's and Parkinson's. The researchers are accordingly also considering whether stimulation of Prx1 can reduce and delay such disease processes."

TALKING ABOUT TIMELINES FOR SENS RESEARCH
Monday, October 31, 2011
https://www.fightaging.org/archives/2011/10/talking-about-timelines-for-sens-research.php
An article on the work of Aubrey de Grey and the SENS Foundation: "In the simplest of terms, SENS is about combating ageing, which according to de Grey is in essence, damage on the molecular and cellular levels caused by the metabolism. The SENS model breaks aging down to 7 major classes of damage; cancer-causing nuclear mutations, Mitochondrial mutations, intracellular junk, extracellular junk, cell loss and atrophy, cell senescence and extracellular crosslinks. ... In the SENS Foundation research center we currently focus on two major projects. Two of our senior postdoctoral fellows are working on a project to make mitochondrial mutations harmless, by putting modified copies of the mitochondrion's DNA into the cell nucleus. Mitochondrial mutations are one of the seven key types of damage that are described in SENS, and this is the most complete way to address it. ... The second project which is currently pursued by another senior postdoc in de Grey's staff deals with the accumulation of molecular 'garbage' which de Grey says our bodies are not built to dispose of. ... back in 2006, de Grey outlined the SENS research being conducted and was received with positive reviews from the attendees. Back then, de Grey predicted that with this research, if enough funding and attention was drawn to it, could see direct benefits being applied to people alive today. He believes the first human to reach the age of 300, if given the treatment before ageing does too much damage, may have already been born. The first human to live to a thousand would only be a decade younger. Unfortunately, the economic crisis plaguing a large portion of the globe means funding for research becomes tighter and tighter. De Grey remains optimistic however, as he believes that 'the financial crisis has probably slowed things down a little, but not massively.' ... I think 20 years is optimistic, but I still think we have a 50 percent chance of getting there within 25 years. However, that all assumes that we make rapid progress in persuading the public, especially wealthy people, that this is a really important mission. Our research is indeed going really well. It's still at an early stage, that's for sure, but we're making progress all the time. Also, I should mention that we're focusing on the very hardest parts of SENS; there are easier parts, already being pursued by others, and those are going extremely well too."

______________________________