LONGEVITY MEME NEWSLETTER
June 09 2008
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.
- Senescent Cells and Aging
- Next Steps For SENS Longevity Science
- Latest Healthy Life Extension Headlines
SENESCENT CELLS AND AGING
One of the important structural changes of aging is the accumulation of senescent, non-dividing cells in your tissue:
"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 neighbors, stimulating excessive growth and degrading normal tissue architecture. These changes appear to promote the progression of cancer."
The first impulse might be to ask why this happens. Why is it that a 70-year old has so many more senescent cells than a 30-year old? This is one of the many situations in medical research where the answer will make any solution to the problem better, but where we can already see the path to a working solution - there's no excuse for not getting started on a fix right now.
The cancer research community is developing a wide array of precision cell killing techniques, such as toxin-bearing nanoparticles that home in on a very specific type of cell structure and destroy it without harming surrounding cells. These technologies are very adaptable - nanoparticles like the dendrimer are designed to allow ease of use with different homing devices and payloads - and so we can see the way to using them on every type of cell we don't want to have around, senescent cells included:
But back to current thinking as to why senescent cells accumulate with age:
"One possibility is that senescent cells are removed by the immune system. Senescent cells secrete cytokines to attract immune cells to their location (for their removal), secrete matrix degrading proteins to allow the immune cells easy access and secrete growth factors to stimulate the proliferation of surrounding cells for its replacement once the cell is removed. However, since the immune system itself is governed by ageing mechanisms, its ability to remove senescent cells gradually decreases, therefore the accumulation of senescent cells gradually increases."
Which is plausible - one more thing to blame on your age-damaged immune system, and one more good reason to look forward to progress in fixing that as well:
NEXT STEPS FOR SENS LONGEVITY SCIENCE
As it so happens, coaxing your aging immune system back into working shape is one of the items on the list for forthcoming Strategies for Engineered Negligible Senescence (SENS) research, funded by the Methuselah Foundation. I've thoughtfully provided a summary of what we can look forward to:
"During 2008, the Methuselah Foundation will launch a project to develop a procedure for clearing aged T cells from the blood of mice, and potentially thereafter in primates. This work will be supervised by one of the top professors in the immunosenescence field."
If you'll recall, the major issues with our immune system result from the fact that it evolved to protect 15-year-olds who lived in caves and probably wouldn't see the other side of 30. Evolution doesn't care about what happens to you after you pass on your genes, so the immune system is wonderfully engineered for the young ... and then later runs headlong into the consequences of short-term optimizations.
One of those optimizations is a limit to the number of T cells. That limit gets progressively eaten up over a normal modern life span by an accumulation of memory T cells specialized for what turns out to be a useless job - remembering varieties of the harmless cytomegalovirus. That growing horde of do-nothing memory cells eventually leaves little capacity left for new T cells intended to fight serious infections, suppress cancer, destroy senescent cells, and so forth.
So, here we have more cells we don't want. As for the senescent cells, killing them seems to be a quick win, rapidly stopping a form of age-related damage by freeing up capacity in the immune system, provided we have the tools to hunt them down without harming other cells. Of course, these tools are presently emerging from the cancer research community, as I described above.
So I think we have cause to be optimistic, even if this research remains underfunded at this time. Lack of funding can be changed, and we can all help to make that happen - not having a course of action is a much harder problem to fix.
The highlights and headlines from the past week follow below.
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LATEST HEALTHY LIFE EXTENSION HEADLINES
To view commentary on the latest news headlines complete with links and references, please visit the daily news section of the Longevity Meme: http://www.longevitymeme.org/news/
Towards Brain Regeneration (June 06 2008)
It may be possible to direct stem cells lying dormant in the brain to set forth and repair damage: scientists "have identified specific molecules in the brain that are responsible for awakening and putting to sleep brain stem cells, which, when activated, can transform into neurons (nerve cells) and repair damaged brain tissue. ... Chen believes that tapping the brain's dormant, but intrinsic, ability to regenerate itself is the best hope for people suffering from brain-ravaging diseases such as Parkinson's or Alzheimer's disease or traumatic brain or spinal cord injuries. Until these studies, which were conducted in the adult brains of mice, scientists assumed that only two parts of the brain contained neural stem cells and could turn them on to regenerate brain tissue ... Chen's team learned that stem cells existed everywhere in the brain by testing tissue from different parts of adult mice brains in cultures containing support cells (known as astrocytes) from the hippocampus, where stem cells do regenerate. ... In the [second] study, the team went on to discover the exact nature of those different chemical signals. They learned that in the areas where stem cells were sleeping, astrocytes were producing high levels of two related molecules ... They also found that removing these molecules (with a genetic tool) activated the sleeping stem cells."
Olfactory Stem Cells Versus Parkinson's (June 06 2008)
Another demonstration of stem cells used to generate new dopamine-generating neurons is announced via EurekAlert: "adult stem cells harvested from the noses of Parkinson's patients gave rise to dopamine-producing brain cells when transplanted into the brain of a rat. The debilitating symptoms of Parkinson's such as loss of muscle control are caused by degeneration of cells that produce the essential chemical dopamine in the brain. ... When stem cells from the nose of Parkinson's patients were cultured and injected into the damaged area the rats re-aquired the ability to run in a straight line. ... All animals transplanted with the human cells had a dramatic reduction in the rate of rotation within just 3 weeks ... This provided evidence the cells had differentiated to give rise to dopamine-producing neurons influenced by being in the environment of the brain. In-vitro tests also revealed the presence of dopamine. ... stem cells from the olfactory nerve in the nose are 'naive' having not yet differentiated into which sort of cells they will give rise to. ... They can still be influenced by the environment they are put into. In this case we transplanted them into the brain, where they were directed to give rise to dopamine producing brain cells."
One Approach to Hair Regeneration (June 05 2008)
Do people care more about their hair than their internal organs when it comes to rejuvenation through medical science? Possibly. Out of sight is out of mind, at least until things start to fail - which is a touch too late to wish you'd supported viable rejuvenation research back in the day. In any case, here's the Economist on one line of hair regeneration: "Some years ago it was discovered that when [dermal papilla] cells are relocated, an entirely new hair will grow. That observation is only useful, though, if you can multiply dermal papilla cells - and do so in a way that allows them to keep their ability to induce hair growth. For, in normal culture, dermal papilla cells quickly lose this sought-after ability. ... The long and short of it is that being able to multiply these cells while preserving their efficacy opens the way for unlimited supplies of head hair. Intercytex is therefore conducting a trial of the technology in Manchester. ... The trial's full results will not be available until March 2009, but the company has already said that at least two-thirds of its patients have generated new hair within six months. Unfortunately for eager baldies, regulations require more trials. As a result it is likely to be five years before any product is on the market."
Aubrey de Grey and the Pension Folk (June 05 2008)
Here's a podcast interview with biomedical gerontologist Aubrey de Grey, conducted by two commenters on the UK pension industry. You'll have to dig a little to get to the podcast page, and the podcast MP3 file itself. Those people in the business of making money from life insurance, pensions, tontines and the like find themselves in an interesting position these days: they are largely two or more steps removed from the aging research community, and so understanding the probable course of longevity science, and so the financial risks involved in their businesses, is a challenge. That is especially true given the wide divergence of very reputable predictions within the aging research community itself. Everything is poised for a massive leap forward in the medical technologies of longevity ... that may or may not come soon. Such great uncertainty is a form of pain for those who make money by managing mortality risk, and so it's not surprising to see such a keen interest.
Hacking Metabolism (June 04 2008)
Falling costs of biotechnology are making it ever more feasible to explore and experiment with the complexities of metabolism. I expect to see some success in engineering better mammalian biochemistry over the next two decades, with the aim of extending healthy life and slowing the changes and damage that cause aging. An example of the type: "Glucose tolerance progressively declines with age in humans and is often accompanied by insulin resistance and a high prevalence of type 2 diabetes. Little is known about the mechanism underlying the age-related changes in glucose metabolism. Here we reported that acid-sensing ion channel 3 (ASIC3) is functionally expressed in adipose cells. ASIC3(-/-) mice were protected against age-dependent glucose intolerance with enhanced insulin sensitivity. Acute administration of ASIC3-selective blocker APETx2 improved the glucose control and increased the insulin sensitivity in older (25-27 weeks) ASIC3(+/+) mice. ... Taken together, our data suggest that ASIC3 signaling might be involved in the control of age-dependent glucose intolerance and insulin resistance." It has been surprising to see just how many comparatively minor changes improve either the life span of mice, or the quality of their metabolic processes.
Update on Resveratrol Research (June 04 2008)
Researchers continue to explore resveratrol as a calorie restriction mimetic. There's a way to go yet before we see a weight of science to match plain old calorie restriction, but it looks more promising as evidence accumulates: "scientists included small amounts of resveratrol in the diets of middle-aged mice and found that the compound has a widespread influence on the genetic causes of aging. ... Caloric restriction is highly effective in extending life in many species. If you provide species with less food, the regulated cellular stress response of this healthy habit actually makes them live longer. In this study, the effects of low doses of resveratrol (on genes) were comparable to caloric restriction, the hallmark for life extension. ... Previous research has shown that high doses of resveratrol extend life in invertebrates and prevent early death in mice given a high-fat diet. The new study extends those findings, showing that resveratrol in low doses, beginning in middle age, can elicit many of the same benefits as a reduced-calorie diet. ... Resveratrol is active in much lower doses than previously thought. ... In the heart [there] are at least 1,029 genes whose functions change with age. In animals on restricted diets, 90 percent of those heart genes experienced alterations in gene expression, while low doses of resveratrol thwarted age-related change in 92 percent."
Becoming Ageless (June 03 2008)
A long article at COSMOS magazine, which opens as follows: "Developments in a number of scientific disciplines suggest that we may soon be able to increase life expectancies from the 70- to 80-year range already seen in the richest countries to well over 100 and, perhaps, to over 1,000. We shall, in one sense, have made ourselves immortal. We shall not be immortal in the sense that we cannot die; plainly we could still be killed in a car accident or by a cosmic event such as an asteroid striking the Earth. But we could not be killed by disease or age, our bodies would be immune to infection, dysfunction or the ravages of time. We would be medically immortal. Some say this will happen quickly within, perhaps, 30 years with the first clear signs that we are on the right track appearing within the next decade. Others think we are at least a century or two away from attaining medical immortality. Some consider it completely unattainable. But the majority of scientists and thinkers in this area now consider life extension and even medical immortality possible and likely." What's more, folk like you and I can all pitch in to help to make it happen by supporting organizations like the Methuselah Foundation.
The Importance of Cyborg Engineering (June 03 2008)
There's one very crucial hurdle to implanting artificial components and replacement parts into the human body: how to integrate implants with living tissue at the smallest scales. One could make a good argument that it is this barrier, over and above anything else, that has prevented advances in prosthetic replacements to match advances in materials science. All barriers fall eventually, however: "scientists describe how they took an elastic scaffold (the material that gives the artificial graft its shape) of compliant poly(carbonate-urea)urethane and incorporated human vascular smooth muscle cells and epithelial cells from umbilical cords. Then they took the artificial grafts and simulated blood flow in the laboratory to test their durability. They found that as the pulsing fluid flow slowly increased, the artificial graft's performance actually improved. ... The notion that any body part could be engineered in a lab, attach to existing tissue 'naturally,' and grow stronger as it is being used is something thought completely impossible just 20 years ago. It is only a matter of time before human tissues can be engineered to be at least as good as the originals, and this study moves us toward that reality." Prosthetics might still give tissue engineering a run for its money when it comes to building replacement organs.
The Drug Development Viewpoint (June 02 2008)
Wired provides insight into the viewpoint of those longevity researchers focused on drug development and manipulating metabolism to slow aging: "'It's not a matter of if, but when,' said gerontologist David Sinclair of a drug that promises a long and healthy life -- not quite a fountain of youth, but perhaps a fountain of fitness. ... Sinclair predicted that the drugs 'could have as big an impact as antibiotics in the 20th century, and it's just around the corner.' ... The biggest myth is that if we extend lifespan, that would involve more unhealthy years at the end. But we'll add years of healthy life. ... Every major pharmaceutical company is conducting research on the handful of genes activated by caloric restriction. ... Sirtris' resveratrol formulation is now in Phase II clinical trials for diabetes. When it hits the market in four or five years, [Sinclair] said, "It'll be on the market as a diabetes drug. It'll have to sell for $3 or $4 a pill, in order to stay competitive. And once it goes off-patent, companies will be able to make it for pennies. It'll be like aspirin.'" Slowing the damage of aging is a far cry from repairing the damage of aging, however, and given that the research and development costs are roughly similar, there's no reason to favor it.
The Origins of Aging (June 02 2008)
A layman's introduction to the origins of aging, and ongoing investigation into aging in bacteria once thought to be immortal, can be found at the Boston Globe: "For people, aging appears to be the result of damage that gradually accumulates in cells over a person's lifetime. Gene sequences get garbled, for example, and proteins become damaged and take on defective shapes. Cells have a more difficult time carrying out their functions and grow more and more slowly. Yet cells also have a remarkable capacity to repair themselves. They can proofread DNA and destroy defective proteins, replacing them with new ones. So why hasn't evolution favored perfect repair - in other words, immortality? ... To never get old, organisms would have to invest a huge amount of energy in repair. They'd be left with little energy to reproduce. Natural selection would instead favor other organisms that put less energy into repair and produced more offspring. A common solution to this trade-off is to set aside a special population of cells that will reproduce. Our bodies put a great deal of energy into keeping eggs and sperm from becoming damaged. They put much less care into repairing the rest of our cells."