Fight Aging! Newsletter, December 17th 2012

December 17th 2012

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!



- Recommended Charitable Causes in Longevity Science
- Peter Singer on SENS and Radical Life Extension
- The Life-Long Regenerative Capacity of Zebrafish
- Discussion
- Latest Headlines from Fight Aging!
    - A Look at Tissue Engineering Research
    - A Decade in Life Expectancy Gained Since 1970
    - Embryonic Versus Induced Pluripotent Stem Cells
    - The Genetics of Extreme Longevity
    - Seeking Correlations Between Fertility and Longevity in Humans
    - On Targeting Senescent Cells to Treat Aging
    - β-hydroxybutyrate in Calorie Restriction
    - Changing the Behavior of Old Skin Cells
    - Targeting Cancer Stem Cells Via DNA Repair Mechanisms
    - Engineered T Cells Versus Leukemia


The year heads towards its close again, and it seems somewhat traditional for people to make charitable 501(c)3 or equivalent donations around this time. I was asked for recommendations a few times in the past month, and here they are:

1) SENS Foundation

At the head of my list is the SENS Foundation, the best organized and most central of the small number of groups working on ways to rejuvenate the old by repairing the cellular and molecular damage that causes aging. The SENS Foundation is a research organization: they put money to work in the laboratory. Given that rejuvenation of the old is the goal, the Strategies for Engineered Negligible Senescence (SENS) is far more attractive as a charitable cause when compared to most aging research. The vast majority of researchers in the field of aging and longevity aim at best to modestly slow aging, if they are even working on the basis for therapies. If we want to see significant progress towards engineered human longevity in our lifetimes, it is very important to support work that credibly aims to do more than simply slow the degenerations of aging a little.

At this point in the ebb and flow of advocacy and research programs, SENS would benefit from a more rapid flow of tangible research results, preferably attractive and easily comprehended by the public at large. Bootstrapping from modest funding to grand funding is a matter of side-by-side progress in advocacy on the one hand and results in the lab on the other - neither can really move too far ahead of the other. The best way to help progress at this time is to donate and persuade others to donate, as money creates results. The SENS Foundation is a very efficient engine for turning philanthropic funds into progress in the best sort of longevity science.

If you know enough about the work under development and which approaches you favor you might even consider calling the SENS Foundation folk to talk about more directed donations - for example, if you are intrigued by the UK-based work on breaking down glucosepane. But for most of us the reason to donate to a trusted organization staffed by smart and knowledgeable folk is because they can do a better job of directing funds to the goal of engineered longevity than we can: they know the researchers, are familiar with who is doing what in which laboratories, and all the tricks of the trade when it comes to stretching funds as far as they can go. You are not going to find a better place to put money if progress towards therapies of human rejuvenation is your goal.

2) New Organ Prize

The New Organ initiative is driven by the folk at the Methuselah Foundation, in alliance with tissue printing company Organovo and a range of other advocates. They are building a crowdsourced research prize to speed development in tissue engineering of complex organs. As you might know, the Methuselah Foundation runs the Mprize for longevity science, and was the umbrella organization for SENS research prior to the formation of the SENS Foundation.

It will likely require decades to move from present day technology demonstrations in growing small amounts of structured tissue to the ability to print functional hearts, livers, and lungs to order. There is plenty of room to accelerate that process - and research prizes have shown their worth in this and many other fields of human endeavor. The faster it goes, the more lives can be saved.

Research prizes offer a purse for specific goals in development, and tend to encourage far more activity in a field than would otherwise take place. A well run prize acts as incentive, beacon, watering hole, loudspeaker, and clearing house for research and development - enlivening the field, drawing attention and funding. If you recall the way in which the Mprize for longevity science grew back when it was the Methuselah Mouse Prize - well, the New Organ Prize something like that, but with the benefit of social networks, modern online donation management services, and a focus on tissue engineering and organ printing.


Aubrey de Grey, Chief Science Officer of SENS Foundation and the world's most prominent advocate of anti-aging research, argues that it makes no sense to spend the vast majority of our medical resources on trying to combat the diseases of aging without tackling aging itself. [In] developed countries, aging is the ultimate cause of 90% of all human deaths; thus, treating aging is a form of preventive medicine for all of the diseases of old age. Moreover, even before aging leads to our death, it reduces our capacity to enjoy our own lives and to contribute positively to the lives of others.

On the other hand, we still need to pose the ethical question: Are we being selfish in seeking to extend our lives so dramatically? And, if we succeed, will the outcome be good for some but unfair to others? People in rich countries already can expect to live about 30 years longer than people in the poorest countries. If we discover how to slow aging, we might have a world in which the poor majority must face death at a time when members of the rich minority are only one-tenth of the way through their expected lifespans.

Whether we can overcome these objections depends on our degree of optimism about future technological and economic advances. De Grey's response to the first objection is that, while anti-aging treatment may be expensive initially, the price is likely to drop, as it has for so many other innovations, from computers to the drugs that prevent the development of AIDS. If the world can continue to develop economically and technologically, people will become wealthier, and, in the long run, anti-aging treatment will benefit everyone. So why not get started and make it a priority now?

De Grey has set up SENS Foundation to promote research into anti-aging. By most standards, his fundraising efforts have been successful, for the foundation now has an annual budget of around $4 million. But that is still pitifully small by the standards of medical research foundations. De Grey might be mistaken, but if there is only a small chance that he is right, the huge pay-offs make anti-aging research a better bet than areas of medical research that are currently far better funded.


Zebrafish, like a number of lower animals, have far greater regenerative abilities than we mammals. They can regrow fins and even large portions of some of their major organs. As is the case for salamanders, there is a research community working on understanding the mechanisms of this regeneration, with an eye to seeing whether it can be brought to humans anytime soon. One school of thought suggests that we and other mammals still possess the necessary biological machinery for regeneration of limbs and organs, but it is buried and inactive - after all, just like the fish, we grow from embryos. So there is at least one program for growing limbs and organs hidden in there somewhere.

Nonetheless, it remains to be seen whether it is in fact the case that a mammal can be made to regrow major body structures by following this path of salamanders and fish: there are reasonable arguments to be made for both yes and no, and it's still too early to say which it will turn out to be. There is no necessary reason for limb regeneration in one species to be in any way present but dormant in another, and there is no necessary reason for limb regeneration to be some form of re-running of the initial program of embryonic growth. These could all be different, distinct processes - and for that matter, there could be distinct, different processes of regrowth in different species with these strong regenerative abilities. Biology is always more complex than you'd like it to be.

Putting all this to one side, there is another interesting reason to study regeneration in zebrafish - their ability to regrow tissue and heal wounds doesn't decline all that much with age. From a recent paper:

"Their average lifetime is about 3 years, and recent studies have shown that zebrafish exhibit aging-related degeneration, suggesting the possibility that aging might affect regenerative potential. In order to investigate this possibility, we compared regeneration of the fin and heart after experimental amputation in young (6-12 month old) and old (26-36 month old) fish. Comparison of recovery rate of the caudal fin, measured every two or three days from one day post amputation until 13 days post amputation, show that fins in young and old fish regenerate at a similar rate. In the heart, myocardium regeneration and cardiomyocyte proliferation occurred similarly in the two groups. Our results demonstrate that zebrafish preserve a life-long regenerative ability of the caudal fin and heart."


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, December 14, 2012
MIT news here looks at the present state of tissue engineering, with a focus on work that is taking place at their own institution: "In the 1970s and 1980s, tissue engineers began working on growing replacement organs for transplantation into patients. While scientists are still targeting that goal, much of the tissue engineering research [is] also focused on creating tissue that can be used in the lab to model human disease and test potential new drugs. Another near-term goal for tissue engineers is developing regenerative therapies that help promote wound healing. [Healthy cells] sitting adjacent to diseased tissues can influence the biology of repair and regeneration, [which might be achieved via] implantable scaffolds embedded with endothelial cells, which secrete a vast array of proteins that respond to injury. Endothelial cells, normally found lining blood vessels, could help repair damage caused by angioplasty or other surgical interventions; smoke inhalation; and cancer or cardiovascular disease. The implants are now in clinical trials to treat blood-vessel injuries caused by the needles used to perform dialysis in patients with kidney failure. One major challenge for designing implantable organs is that the tissues need to include blood vessels that can connect to the patient's own blood supply. [Researchers] are working on inducing blood vessels to form by growing cells on nanopatterned surfaces, [and] recently developed 3-D liver tissues that include their own network of blood vessels. Though still a long-term goal, being able to regenerate new organs could have a great impact on the future of health care. "It's the kind of thing that can transform society. You can't have a drug that will grow a new liver or a new heart, so this could be huge.""

Friday, December 14, 2012
Previous estimates of ongoing gains in life expectancy at birth put it at around a fifth of a year every year. Life expectancy at 60 rises at about half that pace - a tenth of what is needed for actuarial escape velocity. This has been incidental life extension, achieved without any deliberate attempt to tackle aging. New data suggests a slightly higher pace for gains in life expectancy at birth, with a decade gained since 1970. This is probably largely driven by increased wealth and accompanying reductions in childhood mortality: "In the first Global Burden of Disease Study 2010 paper [the] authors present new estimates of life expectancy for the last four decades in 187 different countries. While overall life expectancy is increasing globally, the gap in life expectancy between countries with the highest and lowest life expectancies has remained similar since 1970. The new estimates show that, globally, in 2010 a man's average life expectancy at birth had increased by 11.1 years (19.7%) since 1970, from 56.4 years in 1970, to 67.5 years in 2010. For women, life expectancy increased by 12.1 years (19.8%) during the same period, from 61.2 years in 1970, to 73.3 years in 2010. Deaths in children under five years old have declined by almost 60% since 1970, from 16.4 million deaths in 1970 to 6.8 million in 2010."

Thursday, December 13, 2012
A review paper here looks over the biochemistry, similarities, and differences between embryonic stem cells and induced pluripotent stem cells, both of which are presently used in the development of new therapies, but the former is far more limited by regulation than the latter: "Embryonic stem cells (ESCs) are derived from the inner cell mass of the blastocysts and are characterized by the ability to renew themselves (self-renewal) and the capability to generate all the cells within the human body. In contrast, inducible pluripotent stem cells (iPSCs) are generated by transfection of four transcription factors in somatic cells. Like embryonic stem cells, they are able to self-renew and differentiate. Because of these features, both ESCs and iPSCs, are under intense clinical investigation for cell-based therapy. Since the first isolation of human Embryonic Stem Cells (ESCs) huge interest has developed in the scientific and clinical communities and in the public in general because of their therapeutic potential. In particular, attention has focused on their potential use in cell-based therapy for diseases that are refractory to conventional treatments, such as neurodegenerative diseases and immunodeficiency, because of their ability to be programmed into new mature differentiated cells of all lineages. Although our knowledge of the molecular mechanisms that control the self-renewal and differentiation of stem cells has grown considerably during the past decade, we still need more basic research in order to understand the molecular mechanisms that regulate proliferation, survival and differentiation of stem cells particularly after transplantation and in the pathological environment."

Thursday, December 13, 2012
An open access review of the New England Centenarian Study: "The New England Centenarian Study (NECS) was founded in 1994 as a longitudinal study of centenarians to determine if centenarians could be a model of healthy human aging. Over time, the NECS along with other centenarian studies have demonstrated that the majority of centenarians markedly delay high mortality risk-associated diseases toward the ends of their lives, but many centenarians have a history of enduring more chronic age-related diseases for many years, women more so than men. However, the majority of centenarians seem to deal with these chronic diseases more effectively, not experiencing disability until well into their nineties. Unlike most centenarians who are less than 101 years old, people who live to the most extreme ages, e.g., 107+ years, are generally living proof of the compression of morbidity hypothesis. That is, they compress morbidity and disability to the very ends of their lives. Various studies have also demonstrated a strong familial component to extreme longevity and now evidence particularly from the NECS is revealing an increasingly important genetic component to survival to older and older ages beyond 100 years. It appears to us that this genetic component consists of many genetic modifiers each with modest effects, but as a group they can have a strong influence."

Wednesday, December 12, 2012
The results from this paper suggests that efforts to find any correlation between fertility and longevity in humans will be challenging, as in most data sets it will be swamped by associations with wealth, use of medical technologies to control fertility, and so forth: "The disposable soma theory proposes a trade-off between fertility and longevity but existing findings on this association have been mixed. This study used data from 15,622 twins born between 1901 and 1925 ascertained from the population-based Swedish Twin Registry to test the child-longevity association and whether it is accounted for by individual-level factors or by genetic and environmental factors shared by family members. Based on survival analysis, both women and men with children had significantly longer survival relative to the childless, with a slightly higher relative advantage in men. Adjustments for demographic factors and cotwin fertility did not mediate the parenting-survival association, indicating that this association is attributable to individual-level factors associated with fertility rather than family-level environmental or genetic factors shared by cotwins. These results, derived from a large, population-based sample, are inconsistent with the disposable soma theory as applied to modern human populations."

Wednesday, December 12, 2012
Senescent cells accumulate with age, disrupting the tissues they are in, promoting inflammation, and undertaking a range of other bad behavior. Their presence is one of the causes of degenerative aging, and thus targeting them for destruction or reversal of their senescent state is a priority in longevity science: "Research has revealed that the presence of senescent cells is worse than one might think. These cells assume a special secretory form (SASP) in which they release various chemical signals that harm the health of nearby cells. In a domino effect they then damage their neighbors further accelerating the aging process. A breakthrough study earlier this year showed that using specialized genetic methods to remove senescent cells throughout the lifespan of rats reduced signs of aging in the animals. The current state of the science review article [is] written by two of the scientists who performed that study. In the paper they describe how senescent cells lead to aging in many tissues in the body. They further point out that aging of tissue is the reason for the development of diseases. "Therapeutic intervention in normal aging may prevent comorbidity and delay mortality in the elderly," they write. "In this way, targeting of senescent cells during the course of normal aging would be a preventative strategy rather than a treatment." It is also pointed out that senescent stem cells may poison stem cell niches reducing the ability to regenerate and rejuvenate tissue so that removing them there could have diffuse age reducing benefit. Of course the big question is how senescent cells could be regularly removed from all over and within the human body other than embedding programmable genes before birth like was done in lab rats. The answers remain vague but the authors offer an idea, and some hope: "If a common signature is identified for senescent cells in vivo, strategies to alleviate these effects with compounds or drugs, whether by dampening the SASP profile or by completely removing the senescent cells, can begin to be elucidated.""

Tuesday, December 11, 2012
Here is one research result among the many generated by scientists investigating the biochemistry of calorie restriction, seeking after a greater understanding of how it improves health and extends life: "[Researchers] examined the role of the compound β-hydroxybutyrate (βOHB), a so-called "ketone body" that is produced during a prolonged low-calorie or ketogenic diet. While ketone bodies such as βOHB can be toxic when present at very high concentrations in people with diseases such as Type I diabetes, Dr. Verdin and colleagues found that at lower concentrations, βOHB helps protect cells from "oxidative stress" - which occurs as certain molecules build to toxic levels in the body and contributes to the aging process. "Over the years, studies have found that restricting calories slows aging and increases longevity - however the mechanism of this effect has remained elusive. Here, we find that βOHB - the body's major source of energy during exercise or fasting - blocks a class of enzymes that would otherwise promote oxidative stress, thus protecting cells from aging." The researchers found that calorie restriction spurs βOHB production, which blocked the activity of a class of enzymes called histone deacetylases, or HDACs. Normally HDACs keep a pair of genes, called Foxo3a and Mt2, switched off. But increased levels of βOHB block the HDACs from doing so, which by default activates the two genes. Once activated, these genes kick-start a process that helps cells resist oxidative stress."

Tuesday, December 11, 2012
The visible signs of skin aging are reflected by a similar loss of elasticity and function in important tissues inside the body, driven by declining function in stem cells that support these tissues, a steep growth in the number of senescent cells that hamper maintenance of tissue integrity, the accumulation of AGEs - largely glucosepane - and the other mechanisms that cause aging. These root causes must be dealt with, but comparatively few scientists are trying to tackle them directly. The more usual research focuses on ways to try to patch over consequences by making use of other mechanisms - somewhat akin to trying to deal with a broken dam by bailing rather than fixing the holes. Here researchers manage to reverse a fraction of the effects of skin aging: "[The] extracellular matrix, or ECM, acts like the scaffold that skin cells roost in. It's made of tiny fibrils of collagen, produced by the cells (fibroblasts). Over time, as skin ages, the ECM becomes fragmented, which causes cells to lose their connections to that scaffold - and the lack of support accelerates their decline further. The same thing may happen in other types of tissue. [Scientists] injected the skin of 21 volunteers in their 80s with a filler often used cosmetically to reduce facial wrinkles. The filler bolsters the ECM, filling in the spaces left by aging. The researchers did not receive funding from the product's manufacturer, nor did they get input on the design or results from the company. Rather, they were using the product as a way to increase the mechanical forces within the volunteers' skin. The result: over three months, the fibroblasts began expressing collagen-related genes, producing more collagen, and connecting better to the ECM. The entire layer of skin grew thicker, and more blood vessels, which nourished the cells were seen. "Fragmentation of the extracellular matrix plays an important role in skin aging, but by altering the matrix using an external filler and increasing the internal pressure, we've shown that we can essentially trigger a signal for cells to wake up. This shows that skin cells in elderly people have the capacity to respond robustly in a very positive way to alterations in the mechanical property of their environment. We still need to know more about how cells sense their environment, but in general it appears we have made a real difference in the structural integrity of skin.""

Monday, December 10, 2012
The next generation of cancer therapies will involve ways to target and destroy cancer cells with far greater precision than is possible through presently available treatments, leading to highly effective therapies with few side effects. One branch of this research and development effort involves targeting cells by characteristic differences in surface chemistry, but there are many others. This is one recent example: "In a series of experiments in mice with cancer and in cancer cells, [researchers] have shown that they can block the process by which leukemia stem cells repair themselves by targeting a particular protein, RAD52, which the cells depend on to fix genetic mistakes. The findings may lead to a new strategy to help overcome drug resistance that hinges on cancer stem cells gone awry. In chronic myeloid leukemia (CML), an enzyme called ABL1 goes into overdrive because of a chromosomal mix-up that occurs in bone marrow stem cells that are responsible for the generation of all blood components. The genes ABL1 and BCR become fused and produce a hybrid BCR-ABL1 enzyme that is always turned on. This overactive BCR-ABL1 protein drives the excessive production of white blood cells that is the hallmark of CML. In CML cells, the BCR-ABL1 protein shuts down the main DNA repair system and leukemia cells have to rely on a backup pathway for repair. Previous experiments in mice bone marrow cells lacking RAD52, a key protein in the backup system, showed that its absence abrogated the development of CML, proving that CML DNA repair depended on RAD52. [Researchers] then used an "aptamer," a peptide that mimicked the area where the RAD52 protein binds to DNA, to see the effects of blocking RAD52 from binding to DNA. The investigators found that when the aptamer was added to BCR-ABL1-positive bone marrow cells, RAD52 was prevented from binding to DNA and the leukemic bone marrow cells accumulated excessive double-strand breaks and eventually died. The aptamer had no effect on normal cells. "With this treatment in hand, we eventually hope to generate a small molecule inhibitor with which we will be able to target leukemia patients based on their oncogenic profiles. We've started to use microarrays to look at the expression profiles of the DNA repair genes in other cancers, and based on these profiles, predicted if they would be sensitive to [this] approach.""

Monday, December 10, 2012
The positive results of a cancer immunotherapy trial are noted here: "Nine of twelve leukemia patients who received infusions of their own T cells after the cells had been genetically engineered to attack the patients' tumors responded to the [therapy]. Two of the first three patients treated with the [protocol] remain healthy and in full remissions more than two years after their treatment, with the engineered cells still circulating in their bodies. The findings reveal the first successful and sustained demonstration of the use of gene transfer therapy to turn the body's own immune cells into weapons aimed at cancerous tumors. The protocol for the new treatment involves removing patients' cells through an apheresis process similar to blood donation, and modifying them in [a] vaccine production facility. Scientists there reprogram the patients' T cells to target tumor cells through a gene modification technique using a HIV-derived lentivirus vector. The vector encodes an antibody-like protein, called a chimeric antigen receptor (CAR), which is expressed on the surface of the T cells and designed to bind to a protein called CD19. The modified cells are then infused back into the patient's body following lymphodepleting chemotherapy. Once the T cells start expressing the CAR, they focus all of their killing activity on cells that express CD19, which includes [tumor] cells, and normal B cells. All of the other cells in the patient that do not express CD19 are ignored by the modified T cells, which limits systemic side effects typically experienced during traditional therapies. In addition to initiating the death of the cancer cells, a signaling molecule built into the CAR also spurs the cell to produce cytokines that trigger other T cells to multiply - building a bigger and bigger army until all the target cells in the tumor are destroyed."



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