Longevity Meme Newsletter, July 06 2009
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LONGEVITY MEME NEWSLETTER
July 06 2009

The Longevity Meme Newsletter is a weekly e-mail containing news, opinions, and happenings for people interested in healthy life extension: making use of diet, lifestyle choices, technology, and proven medical advances to live healthy, longer lives.

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CONTENTS

- A Look at Genescient
- Senescent Cells in Aging and What to Do About Them
- Still Necessary to Argue that Aging is Bad
- Discussion
- Latest Healthy Life Extension Headlines

A LOOK AT GENESCIENT

One of the fellows at young biotech company Genescient - who volunteered for the Methuselah Foundation a while back, as it happens - has been asking me to talk about their work:

https://www.fightaging.org/archives/2009/06/genescient-envisioned-as-sirtris.php

"In essence, you might envision Genescient as what you get when you add very rapid progress in biotechnology (and falling cost in biotech tools) to the basic aims of Sirtris. Find longevity genes and manipulate their expression for benefit and profit in other words, but where Sirtris's initial development back before 2004 focused on just a few genetic networks, Genescient is aiming for 'all of them.' Even in five years, costs have fallen and tools improved significantly - think about the computer you were using in 2003, for example, and compare it to the machine you're using today.

"Like Sirtris, Genescient is firmly an outgrowth of the 'work to slow down aging via metabolic and genetic manipulation' faction of aging research. They are not aiming to identify and repair biochemical damage, but rather shift the operation of human biochemistry into a more beneficial state for long-term operation. I'd insert the obligatory comment on how this approach is not the Strategies for Engineered Negligible Senescence, and even if wildly successful in decades to come will do little for those already old, but you're all probably all tired of hearing it by now."

But just in case, here's that argument in a longer form:

https://www.fightaging.org/archives/2008/09/the-scientific-debate-that-will-determine-how-long-we-all-live.php

SENESCENT CELLS IN AGING AND WHAT TO DO ABOUT THEM

Three lines of research aimed at repairing the damage of aging appear to be within a decade of useful application (regulatory hurdles aside): making mitochondrial DNA damage go away, breaking down damaging byproducts of metabolism that clutter our cells, and destroying senescent cells using the emerging generation of targeted therapies developed for use against cancer. Here we'll look at senescent cells via the work of Dominick Burton at the Ageing Research blog:

https://www.fightaging.org/archives/2009/07/a-brace-of-posts-on-senescent-cells-in-aging-and-what-to-do-about-them.php

"So-called 'senescent' cells are those that have lost the ability to reproduce themselves. They appear to accumulate in quite large numbers in just one tissue (the cartilage in our joints), but even in these small numbers they appear to pose a disproportionate threat to the surrounding, healthy tissues, because of their abnormal metabolic state. Senescent cells secrete abnormally large amounts of some proteins that are harmful to their neighbours, stimulating excessive growth and degrading normal tissue architecture.

"At present, no drug-based system exists which can specifically identify senescent cells and remove them. However, there is currently great interest in the development of drugs which specifically target and remove cancer cells. The problem with current cancer treatments (such as drugs used in chemotherapy) is that they are non-specific and as such can cause damage and undesirable changes to non-cancerous cells, causing side-effects. The development of cell-specific drug targeting is greatly needed and such research could be adapted to target senescent cells."

As you may know, work on targeted therapies is producing exciting technology demonstrations in the laboratory on monthly basis these days. For examples, see the links below:

http://www.longevitymeme.org/news/view_news_item.cfm?news_id=4249
http://www.longevitymeme.org/news/view_news_item.cfm?news_id=4174
http://www.longevitymeme.org/news/view_news_item.cfm?news_id=4057

STILL NECESSARY TO ARGUE THAT AGING IS BAD

When you spend your time following aging research and debates taking place within the pro-engineered longevity community, it is easy to lose sight of the fact that your knowledge and opinions are far from what passes for the norm. The reaction of the widespread majority of people - whose support is very necessary for the long-term goal of a large longevity science research community - is still to say that aging and death are both good and needed:

https://www.fightaging.org/archives/2009/07/aging-and-death-are-good-and-needed-is-still-the-expected-opinion.php

This shows that in terms of advocacy for longer healthy lives, it is still very necessary to keep plugging away at the most basic concepts with the wider audience: that aging is not set in stone, that all the suffering and death it causes can be alleviated, and that we should set forth to achieve that goal as soon as possible.

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!

Reason


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LATEST HEALTHY LIFE EXTENSION HEADLINES

Boosting Repair Mechanisms Beneficial in Alzheimer's (July 03 2009)
http://www.longevitymeme.org/news/vnl.cfm?id=4275
One might expect that improving repair and maintenance systems in the brain would provide some benefit irrespective of how present damage came about, and this may be the case: "The granulocyte-colony stimulating factor (GCSF) significantly reduced levels of the brain-clogging protein beta amyloid deposited in excess in the brains of the Alzheimer's mice ... The growth factor prodded bone-marrow derived microglia outside the brain to join forces with the brain's already-activated microglia in eliminating the Alzheimer's protein from the brain. Microglia are brain cells that act as the central nervous system's main form of immune defense. Like molecular 'Pac-men,' they rush to the defense of damaged or inflamed areas to gobble up toxic substances." This is still a rearguard action against end-stage consequences, however - the underlying chain of causes is not addressed. Repair of final consequences isn't a viable long-term strategy for dealing with an ever-worsening root cause, as those consequences will rapidly exceed the ability to repair them. At some point you have to address the origin of the problem in order to prevent it from spiraling out of control.

Immune Therapy Versus Leukemia Stem Cells (July 03 2009)
http://www.longevitymeme.org/news/vnl.cfm?id=4274
Via EurekAlert!, an example of progress in using the immune system to target specific cells for destruction: acute myeloid leukemia (AML) "is a cancer of the white blood cells that has an extremely poor prognosis and does not respond well to conventional chemotherapy. ... The cellular and molecular basis for this dismal picture is unclear. However, previous research has suggested that leukemia stem cells (LSCs) may lie at the heart of post-treatment relapse and chemoresistance ... [researchers] exploited the fact that the molecule CD123 is expressed at very high levels on LSCs but not on normal blood cells. CD123 is part of the interleukin-3 receptor, a protein that interacts with a growth factor (called a cytokine) that influences cell survival and proliferation. The researchers created a therapeutic antibody that recognized and bound to CD123 with the hope that this antibody would selectively interfere with AML-LSC survival. When AML-LSCs from human patients were transplanted into mice treated with the antibody, called 7G3, cytokine signaling in the tumor cells was blocked. Further, 7G3 impaired migration of the AML-LSCs to bone marrow and activated the innate immune system of the host mouse to destroy the AML-LSCs. Overall, treatment with 7G3 substantially improved mouse survival."

Collecting Cellular Junk (July 02 2009)
http://www.longevitymeme.org/news/vnl.cfm?id=4273
Newer longevity science blog Green Light Go here looks at the harmful accumulation of metabolic byproducts and other junk such as lipofuscin in our cells with age: "I just finished an entry for the SOA timeline on the 1970s discovery that nematodes collect inactive enzymes and molecules as they grow older. The main idea being that the body is unable to clear out the junk inside cells and that the energy cost of carrying this junk leads to senescence, or aging. The theory reminded me of a similar finding by Coleen Murphy who found that long lived daf-16 elegans mutants lived longer in part because they encoded antimicrobial lysosomes, that helped to clear out microbes that would get "packed" inside the nematodes precipiating senescence and eventually their death. As far as I know, the reason for the slow decline in enzyme activity and for the collection of intracellular junk is still unknown. Why isn't our body clearing this stuff out and selling it on ebay? The SENS foundation, which is perhaps the biggest player in anti-aging research, is pushing forward with a solution anyway. Their strategy is to find enzymes manufactured by soil bacteria and fungi that can then be applied therapeutically to help clear junk out of cells. ... It is going to be interesting in the future to see what result comes of this. Both for understanding the chemical mechanism of the collection of junk, and the therapeutic solutions which can get rid of it."

Regenerating Salamanders and Their Blastemas (July 02 2009)
http://www.longevitymeme.org/news/vnl.cfm?id=4272
Progress in understanding the mechanisms by which salamaders regenerate lost limbs from The Scientist: "The cells responsible for the salamander's famed ability to regenerate amputated limbs aren't pluripotent, as scientists have thought ... They're retaining their memory of the tissues they came from, and they go on to form cells of that same type. That's not what most people thought was going on ... That's good news for regenerative medicine: If the mechanism salamander cells use for regrowing body parts doesn't depend on pluripotent stem cells, it may be easier than researchers have assumed to mimic that organism's regenerative strategy in potential therapies. ... Salamanders' regenerative abilities were thought to rely on the dedifferentiation of cells near the damaged limb to a pluripotent state -- a feat that mammalian cells are normally incapable of. ... Instead of trying to generate multipotent or pluripotent cells, [researchers] should try to understand how these cells get the appropriate signals to make a new limb in terms of organizing the different tissue types."

An Overview of Induced Pluripotency (July 01 2009)
http://www.longevitymeme.org/news/vnl.cfm?id=4271
The Technology Review here looks at the technology of induced pluripotency: "Scientists have been talking about the medical promise of stem cells for more than a decade, even before human embryonic stem cells were successfully isolated in 1998. Most of the public attention has focused on their regenerative power: since stem cells can renew themselves and differentiate into specialized cell types, they could potentially be used to build replacement organs, heal spinal-cord injuries, or repair damaged brain tissue. But the research world has also pursued another, even broader-reaching goal: using the cells of patients with various illnesses to derive pluripotent stem cells, which can give rise not just to the specialized cells in a particular organ or tissue but to virtually any cell type. Those cells could be used to create laboratory models of disease. For example, a cell from a Parkinson's patient could be turned into a neuron, which would exhibit the progressive molecular changes at work in the neurodegenerative disorder. This type of tool could capture the details of human disease with unprecedented accuracy, and it could revolutionize the way researchers search for new treatments."

The Compression of Morbidity School of Thought (July 01 2009)
http://www.longevitymeme.org/news/vnl.cfm?id=4270
This interview with Leonard Hayflick is illustrative of the thinking of gerontologists who aim not to extend human life (in this case because because he thinks it's an implausible goal) but to shorten the period of age-related disability. It's a view very much at odds with reliability theory, which suggests that any reduction in ongoing damage will extend healthy life, and with the many demonstrated extensions of lifespan in animals. "The facts are these. There are four aspects to the finitude of life: aging, longevity determination, age-associated diseases, and death. Aging is what we call a catabolic process - the breakdown of molecules. Longevity determination is the reverse - the repair or maintenance of molecules. Aging gets confused with longevity determination. The aging process increases vulnerability to age-associated diseases. These concepts are distinguishable from each other and fundamentally different. ... You cannot learn about the fundamental biology of aging by studying disease processes. Resolving age-associated diseases tells us nothing about the fundamental biology of aging, just as the resolution of childhood diseases, such as polio and childhood anemia, did not tell us one iota about childhood development."

Longevity and Biochemical Damage Resistance (June 30 2009)
http://www.longevitymeme.org/news/vnl.cfm?id=4269
Why do some mammal species live much longer than other, very similar mammal species? Here researchers look at resistance to biochemical damage: "Altered structure, and hence function, of cellular macromolecules caused by oxidation can contribute to loss of physiological function with age. Here, we tested whether the lifespan of bats, which generally live far longer than predicted by their size, could be explained by reduced protein damage relative to short-lived mice. We show significantly lower protein oxidation (carbonylation) in Mexican free-tailed bats (Tadarida brasiliensis) relative to mice, and a trend for lower oxidation in samples from cave myotis bats (Myotis velifer) relative to mice. Both species of bat show in vivo and in vitro resistance to protein oxidation under conditions of acute oxidative stress. These bat species also show low levels of protein ubiquitination in total protein lysates along with reduced proteasome activity, suggesting diminished protein damage and removal in bats. ... Together, these data suggest that long lifespan in some bat species might be regulated by very efficient maintenance of protein homeostasis." You might take a moment to compare this with research into naked mole rat biochemistry.

Exercise and Neurogenesis (June 30 2009)
http://www.longevitymeme.org/news/vnl.cfm?id=4268
Another benefit of regular exercise is proposed in this recent research: scientists "have, for the first time, been able to demonstrate that moderate exercise significantly increases the number of neural stem cells in the ageing brain. ... neuroscientists have known for some time that, in healthy brains, the creation of new neurons is an ongoing and lifelong mechanism. However, it has also been known for more than a decade that the number of new neurons we produce slowly declines with age. ... Investigating the mechanism by which neural stem cell numbers are altered will undoubtedly increase our understanding of how the brain responds to its environment. Ultimately, this should allow us to discover how to harness the brain's regenerative capacity, and to bring about new and effective treatments for conditions caused by trauma, disease, or even normal ageing. The brain's ability, even at an advanced age, to respond in a positive manner is very exciting as it extends the time-frame in which manipulation is possible."

Deciphering the Signals of Rheumatoid Arthritis (June 29 2009)
http://www.longevitymeme.org/news/vnl.cfm?id=4267
Researchers continue to work towards identifying the exact molecular mechanisms by which autoimmune conditions like rheumatoid arthritis produce pain and damage: "When a microbe infects the body, the body responds by turning on a molecular switch to set the immune system into action and protect the body from disease. Today's findings show that a signal molecule called tenascin-C can trigger the same molecular switch and also activate the immune system. High levels of tenascin-C present in joints therefore may cause the activated immune system to attack the joint leading to the persistent inflammation of rheumatoid arthritis. The molecular switch is called TLR4, and is found on the surface of immune cells. Previous research has shown that mice without TLR4 do not show chronic joint inflammation. The researchers hope scientists can develop new treatments that target the interaction between tenascin-C and TLR4, which may help to combat rheumatoid arthritis. ... We hope our new findings can be used to develop new therapies that interfere with tenascin-C activation of the immune system and that these will reduce the painful inflammation that is a hallmark of this condition."

"Minicells" as Targeting Mechanism (June 29 2009)
http://www.longevitymeme.org/news/vnl.cfm?id=4266
Effective per-cell-type targeting of therapies is a fundamental and very important technology platform for the future of medicine. Here's another way of doing it, distinct from methods using viruses or nanoparticles: "The minicells are generated from mutant bacteria which, each time they divide, pinch off small bubbles of cell membrane. The minicells can be loaded with chemicals and coated with antibodies that direct them toward tumor cells. No tumor cell, so far as is known, produces a specific surface molecule for toxins to act on. But 80 percent of solid tumors have their cell surfaces studded with extra-large amounts of the receptor for a particular hormone, known as epidermal growth factor. The minicells can be coated with an antibody that recognizes this receptor, so they are more likely to attach themselves to tumors than to the normal cells of the body. The tumor cells engulf and destroy the minicells, a standard defense against bacteria, and in doing so are exposed to whatever cargo the minicells carry. ... treatment arrested tumor growth in mice implanted with either human colon or human breast tumors, and enabled mice with drug-resistant human uterine tumors to eliminate the tumors altogether."

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