Longevity Meme Newsletter, August 25 2008

August 25 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.



- A Great Interview With Aubrey de Grey
- Slowing Mitochondrial and Brain Function Decline
- The Viewpoint of Pro-Longevity Bioethicists
- Discussion
- Latest Healthy Life Extension Headlines


I missed this one when it came out earlier this month. It's long, and touches on a lot of areas that other interviews have skipped over. You should take a look:


"BH: what [engineered longevity] therapies will most likely become available first, and which will be developed last?"

"AdG: Some of them are already pretty close: probably the closest is in fact not the enzyme therapy you mention, but the use of vaccines to eliminate extracellular aggregates (especially amyloid). But when we consider the others, actually I wouldn't like to make the call, because the hardest ones are the ones that the Methuselah Foundation and I are prioritising in terms of the early research. In other words, we're hoping that they will start to catch up with the easier ones. I suspect that the challenge of genetically modifying a high proportion of cells by somatic gene therapy will have been largely solved before we complete the development of all the genes that we want to introduce."


A nice demonstration in mice shows that at least one genetic change exists that significantly slows the pace of age-related mitochondrial dysfunction and consequent degeneration of the brain. For the specific details, have a look at this Fight Aging! post:


"Mitochondrial transcription factor A (TFAM) is now known to have roles not only in the replication of mtDNA but also its maintenance. TFAM transgenic (TG) mice exhibited a prominent amelioration of an age-dependent accumulation of lipid peroxidation products and a decline in the activities of complexes I and IV in the brain.

"In the aged TG mice, deficits of the motor learning memory, the working memory, and the hippocampal long-term potentiation (LTP) were also significantly improved. The expression level of interleukin-1beta (IL-1beta) and mtDNA damages, which were predominantly found in microglia, significantly decreased in the aged TG mice."

Doing something about the decay of mitochondrial function has a number of evident benefits, as demonstrated above. But slowing things down is a second rate strategy at best - especially if it involves genetic engineering, a technology unlikely to be in widespread use for humans for another ten to twenty years. A slowing of damage does little for those who are already damaged and aged. What we really want to be capable of achieving is reversal of existing damage - to be able to restore old and damaged mitochondria to a pristine state. This goal is unlikely to be any more expensive or time-consuming than engineering a slowing of mitochondrial decay, so it should be the first priority.


I've never been fond of bioethics as a profession. At best, it looks like paying people to overthink common sense, and at worst it's a community of enablers for government employees and politicians who act to suppress research and destroy opportunities for scientific progress. But here are a couple of posts that look at representative views from bioethicists who support engineered longevity:


"Is it fair, the critic will ask, to divert resources dedicated to saving lives (e.g. with possible treatments for cancer, AD, etc.) to medical research that seeks to merely extend lives? Let us call this the Fairness Objection to prioritizing aging research. In this paper I will examine, and critique, this Fairness Objection to making aging research a greater priority than it currently is."


"Why has longevity become a source of dismay rather than a cause for celebration? How did we turn the greatest triumph of 20th century public health and medicine into a problem for the 21st century?"


The highlights and headlines from the past week follow below.

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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/

More Compelling Reasons To Exercise (August 22 2008)
Here is another study to add to the huge stack of research telling us that exercise is good for healthy longevity: "We determined whether reduced insulin sensitivity, mitochondrial dysfunction and other age-related dysfunctions are inevitable consequences of aging or secondary to physical inactivity. ... Insulin-induced glucose disposal and suppression of endogenous glucose production were higher in the trained young and older people but no age-effect was noted. Age-related decline in mitochondrial oxidative capacity was absent in endurance-trained individuals. Although endurance trained individuals exhibited higher expression of mitochondrial proteins, mtDNA, and mitochondrial transcription factors there were persisting effects of age. SIRT3 expression was lower with age in sedentary but equally elevated in endurance trained individuals. ... The results demonstrate that reduced insulin sensitivity is likely related to changes in [level of body fat] and physical inactivity rather than an inevitable consequence of aging. The results also show that regular endurance exercise partly normalizes age-related mitochondrial dysfunction, although there are persisting effects of age at the level of mtDNA abundance, nuclear transcription factors, and mitochondrial protein expression. Furthermore, exercise may promote longevity through pathways common to effects of caloric restriction."

Ouroboros On Biomarkers and Telomere Length (August 22 2008)
From Ouroboros: "How old are you? At present, the best experimental approach to that question is to inspect your driver's license; we are very good at measuring chronological age, but far worse at measuring physiological age. ... Until we have such a tool, questions like 'how rapidly is this individual aging?' and 'is this treatment having a positive effect on the rate of aging?' will be meaningless. ... So, the race is on to find useful biomarkers of aging. ... Telomere length is a tantalizing biomarker for the aging process: it's positively correlated with life expectancy and negatively correlated with stress and disease. If telomere shortening is a biomarker of aging, then the measurable consequences of telomere shortening should also function as biomarkers, i.e., aging bodies should contain high levels of factors secreted by cells with dysfunctional or critically short telomeres. According to a recent paper by Jiang et al., this is indeed the case. ... The proteins identified here accumulate with age - [and] they accumulate faster in subjects who are both aged and suffering from age-related disease; in other words, in people whom we might intuitively assign to the 'more rapidly aging' category."

Weight Gain Cast as a Result of Neural Damage (August 21 2008)
Hopefully you don't need more reasons to eat a sensible diet by now, but here's another. EurekAlert! passes on a theory to account for what happens to those of us who load up the carbohydrates over the years: "key appetite control cells in the human brain degenerate over time, causing increased hunger and potentially weight-gain as we grow older ... appetite-suppressing cells are attacked by free radicals after eating and [the] degeneration is more significant following meals rich in carbohydrates and sugars ... People in the age group of 25 to 50 are most at risk. The neurons that tell people in the crucial age range not to over-eat are being killed-off. ... When the stomach is empty, it triggers the ghrelin hormone that notifies the brain that we are hungry. When we are full, a set of neurons known as POMCs kick in. ... However, free radicals created naturally in the body attack the POMC neurons. This process causes the neurons to degenerate over time, affecting our judgement as to when our hunger is satisfied ... The free radicals also try to attack the hunger neurons, but these are protected by the uncoupling protein 2 (UCP2)." So eat more over the years and suffer neural damage that makes it harder not to eat more. We all have free will, but why make it harder for yourself?

Michael Rae On Repairing Liver Aging (August 21 2008)
Over at the Methuselah Foundation forums Michael Rae adds a lot more detail to news of lysosomal manipulations that halt liver aging in mice: "I think that we should regard this [as] supportive evidence for LysoSENS, rather than as an intervention that we should seek to translate for human use. I don't want to give the impression that this is anything less than an amazing result - I'm very impressed with the work itself, and excited by the actual effects on the animals --however, I think it's important to also see how [even] this sweeping result still suffers the standard flaws in the 'gerontological' approach to anti-aging medicine. ... note that in order to get the full effects of the intervention, the transgene had to be activated when the animals were 6 mo old - quite young ... because such 'gerontological' interventions slow down, but cannot reverse, the accumulation of aging damage, they are necessarily less effective the older people get. [This is] both because of their progressive rise in pre-existing aging damage, and the impairments in ability to adapt to and exploit such improvements due to other, independently-acting aging processes, making it hard to really benefit people who (as Dr. de Grey often puts it) 'have the misfortune to be already alive' - and especially people who are significantly older, in whom the need is greatest." You'll also find a detailed discussion of the science to back up those points.

Menstrual Blood as Source of Adult Stem Cells (August 20 2008)
Like heart damage, peripheral artery disease is open to comparatively simple stem cell therapies based on cell transplants. All that is needed is a low-cost source of suitable stem cells. From ScienceDaily: "Cells obtained from menstrual blood, termed 'endometrial regenerative cells' (ERCs) are capable of restoring blood flow in an animal model of advanced peripheral artery disease. A new study demonstrates that when circulation-blocked mice were treated with ERC injections, circulation and functionality were restored. ... [Researchers have] already performed clinical trials with adult stem cells for patients with peripheral artery disease. .... The advantage of ERCs is that they can be used in an 'off the shelf' manner, meaning they can be delivered to the point of care, do not require matching, and are easily injectable without the need for complex equipment." The ease with which a therapy can be implemented makes a great deal of difference to the speed with which it moves from laboratory to clinic.

Building Blood From Stem Cells (August 20 2008)
The Times has more on growing blood from stem cells: "Vials of human blood have been grown from embryonic stem cells for the first time during research that promises to provide an almost limitless supply suitable for transfusion into any patient. The achievement by scientists in the United States could lead to trials of the blood within two years, and ultimately to an alternative to donations that would transform medicine. If such blood was made from stem cells of the O negative blood type, which is compatible with every blood group but is often in short supply, it could be given safely to anybody who needs a transfusion. ... One of the biggest safety hurdles that must be cleared before stem-cell therapies enter clinical trials is the risk of uncontrolled cell growth causing cancer. Red blood cells, however, do not have nuclei that carry the genetic material that goes wrong in cancer, and thus should not present this danger. ... While a few red blood cells have been created from embryonic stem cells before, the ACT team is the first to mass-produce them on the scale required for medical use. They also showed that the red cells were capable of carrying oxygen, and that they responded to biological cues in similar fashion to the real thing."

A Profile of Robert Lanza (August 19 2008)
Discover Magazine looks at one of the noteworthies of the stem cell research community: "The value of therapeutic cloning has long been clear to Lanza, who did his early work with South African heart transplant pioneer Christiaan Barnard. Starting from those early days, Lanza understood that the barrier to tissue transfer was rejection by the recipient. From an entire organ to a dose of embryonic stem cells, if the tissue's DNA came from anyone else, the transplant would be rejected without the aid of harsh immunosuppressive drugs. 'The treatment could be worse than the problem,' Lanza found. But embryonic clones, the source of an endless supply of stem cells imprinted with one's personal DNA, could alter the equation in favor of the patient and augur a paradigm shift in medicine on par with the changes brought about by antibiotics and vaccines ... With the ability to become all of the blood cells - including your immune cells, red blood cells, all of your blood system, as well as vasculature, [hemangioblasts] have been biology's holy grail. What we discovered is that we can create literally millions or billions of these from human embryonic stem cells. ... we can use transient, intermediate cells like hemangioblasts as a toolbox to fix the adult so you don't have to have limbs amputated, so you may not have to go blind, to prevent heart attacks."

On Salamanders and Limb Regeneration (August 19 2008)
From the Technology Review: "While all animals can regenerate tissue to a certain extent - we can grow muscle, bone, and nerves, for example - salamanders and newts are the only vertebrates that can grow entire organs and replacement limbs as adults. When a leg is lost to injury, cells near the wound begin to dedifferentiate, losing the specialized characteristics that made them a muscle cell or bone cell. These cells then replicate and form a limb bud, or blastema, which goes on to grow a limb the same way that it forms during normal development. Scientists have identified some of the molecular signals that play a key role in the process, but the genetic blueprint that underlies regeneration remains unknown. Researchers hope that by uncovering these molecular tricks, they can ultimately apply them to humans to regrow damaged heart or brain tissue, and maybe even grow new limbs. ... One of the key questions yet to be answered is whether the salamander has unique genetic properties that enable regeneration, or whether all animals have that innate capability. ... If we come up with some totally unique gene only present in [salamanders], that would make it really hard to replicate."

Laron Dwarfism, Longevity, and Cancer (August 18 2008)
At first glance, Laron dwarfs appear to be the Ames dwarf mice of the human world - long-lived and resistant to cancer, due to a genetic mutation that suppresses the somatotrophe axis: "There are a little more than 300 people in the world with the condition Laron dwarfism, a third of whom live in remote villages in Ecuador's southern Loja province. Sufferers of Laron - believed to be caused by inbreeding - lack a hormone called Insulin-like Growth Factor 1, or IGF1. Research [suggests] this is the reason for their longevity and apparent immunity to cancer. ... We've discovered that people with Laron simply don't get cancer. Cancer can be detected in their relatives of a normal size, but never in my patients - not one single case. ... Laboratory work in mice, flies and worms has shown that if IGF1 is removed, the animals tend not to get cancer and to live longer. This is now mirrored in recent research into small humans, who turn out to have little or no IGF1." There are a few large factual mistakes in the article, as might be expected given the source, but it is most interesting to see this work in mice translate so faithfully to humans.

More DNA Damage Research, In Mice This Time (August 18 2008)
What does nuclear DNA damage have to do with aging? The correlation is clearly there - older animals have more random nuclear DNA damage - but the mechanism by which increased damage might lead to some portion of degenerative aging is up for debate. A recent paper shows that the correlation extends to calorie restriction and some genetic manipulations that extend life: "Genetic instability has been implicated as a causal factor in cancer and aging. Caloric restriction (CR) and suppression of the somatotroph axis significantly increase life span in the mouse and reduce multiple symptoms of aging, including cancer. To test if in vivo spontaneous mutation frequency is reduced by such mechanisms, we crossed long-lived Ames dwarf mice with a C57BL/6J line [to] measure mutant frequencies. ... Four cohorts were studied: (1) ad lib wild-type; (2) CR wild-type; (3) ad lib dwarf; and (4) CR dwarf. ... results indicate that two major pro-longevity interventions in the mouse are associated with a reduced mutation frequency. This could be responsible, at least in part, for the enhanced longevity associated with Ames dwarfism and CR."



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