So very much of the research we watch is conducted in mice, rats, and - increasingly - in naked mole rats and other more esoteric members of the rodent order of mammals. Some of this work is fairly directly applicable to we humans, and some of it is not. For example, the types and proportions of advanced glycation end-product (AGE) that accumulate to damage our cells in later life are very different between rodents and humans, and so early promising work in rats aimed at developing AGE-breaker drugs to wash out these unwanted compounds translated poorly to humans.

So how much attention should we give to promising results in mice? That can only be answered for any specific case by knowing more about the use of mice in the laboratory; it is very helpful for the layperson to have a better grasp as to the benefits, limitations, and expectations held by scientists when it comes to research in rodent species that is expected to be applicable to humans. On this note, let me draw your attention to a trio of long articles from Slate that examine the humble laboratory mouse:

The Mouse Trap

Just how ubiquitous is the experimental rodent? In the hierarchy of lab animal species, the rat and mouse rule as queen and king. A recent report from the European Union counted up the vertebrates used for experiments in 2008 - that's every fish, bird, reptile, amphibian, and mammal that perished in a research setting, pretty much any animal more elaborate than a worm or fly - and found that fish and birds made up 15 percent; guinea pigs, rabbits, and hamsters contributed 5 percent; and horses, monkeys, pigs, and dogs added less than 1 percent. Taken together, lab rats and lab mice accounted for nearly all the rest - four-fifths of the 12 million animals used in total,

The Trouble With Black-6

According to one estimate, distributors like Charles River and the scientists who buy from them have created at least 400 standard, inbred strains of mouse, and 200 inbred strains of rat. Yet one stands out from the rest as the model among models in biomedicine. If you want to set up a trading post for biology, a place where researchers from around the world can exchange and compare their data, then it helps to have a common coin - a stable currency that undergirds the system. In the global marketplace of discovery, the Black-6 mouse (more formally known as the "C57BL/6") serves as the U.S. dollar.

The Anti-Mouse

As a matter of taxonomy, the naked mole rat is closer to a guinea pig or porcupine than a mouse or a rat, but really it's neither one nor the other. Buffenstein knows that she's working with an oddball; she did a lot of the work that proves it. "[The naked mole rat] does have very unique mechanisms that are not seen in other animals," she says, referring both to its superficial quirks and to whatever private biochemistry helps it to shrug off cancer, deflect toxic chemicals, ignore painful stimuli, and otherwise live five times longer than one might expect.

...

Ten years ago, Buffenstein was one of just a handful of biologists studying naked mole rats in captivity; now her field comprises some three dozen labs around the world. Her colleagues have looked at why naked mole rats are immune to the pain caused by spicy foods, or how they avoid getting itchy when doused with histamine, or what allows their brains to get by without much oxygen and a shriveled pineal gland. In Rochester, N.Y., a pair of Russian-born biologists, Andrei Seluanov and Vera Gorbunova, are devoted to finding out exactly how naked mole rats keep from getting cancer.

If you read around the warnings of doom by laboratory rodent monoculture - good news sells no papers, and the story of mice as research tools is one of great success when considered at the high level - you'll find a great deal of fascinating information. It pays to understand more about how the sausage is made when it comes to longevity research, and mice are an important part of the process. Knowing more about the limitations helps to better place the steady flow of newly announced results into context.

Source:
http://www.longevitymeme.org/newsletter/latest_rss_feed.cfm

An open access commentary: "Aging is now viewed as a plastic phenotype that can be altered by nutritional, pharmacological and genetic manipulations. However, most pro-longevity mutations are discovered by systematic gene deletion or RNA interference screens, which mainly reveal abolished or diminished gene functions. In our recent publications, we used global acetylation proteome screens to study aging in yeast, and showed that enhancing the function of certain genes through specific acetylation can promote longevity. ... It is well known that acetylation of histone proteins in cultured human fibroblasts decreases during aging, which is believed to be directly related to decreased metabolic rate and reproductive capacity associated with aging. However, histone deacetylation is not likely to be a universal driving force of aging because histone acetylation and deacetylation mimetics similarly shortened life span, which could simply reflect nonspecific fitness decreases in both instances. Extension of lifespan promoted by certain genetic and/or pharmacological perturbations will more likely lead to identification of bona fide regulatory factors of aging. ... Aging is conventionally thought to be characterized by accumulation of molecular, cellular, and organ damage, leading to increased vulnerability to disease and death. Our data, on the contrary, support the idea that the gradual loss of a crucial component promoting 'healthy young status' might underlie an intrinsic aging process. Many of the mutations that extend life span decrease the activity of external nutrient signaling, such as the IGF (insulin-like growth factor)/insulin and the TOR (target of rapamycin) pathways, suggesting that they may induce a metabolic state similar to that resulting from periods of food shortage."

Link: http://impactaging.com/papers/v3/n10/full/100398.html

Source:
http://www.longevitymeme.org/newsletter/latest_rss_feed.cfm

If you can build new living tissue to be implanted in patients, then why not also give it the capacity to perform additional useful tasks? This is a technology platform with some potential: "combining gene therapy with tissue engineering could avoid the need for frequent injections of recombinant drugs. Patients who rely on recombinant, protein-based drugs must often endure frequent injections, often several times a week, or intravenous therapy. Researchers [have demonstrated] the possibility that blood vessels, made from genetically engineered cells, could secrete the drug on demand directly into the bloodstream. ... Such drugs are currently made in bioreactors by engineered cells, and are very expensive to make in large amounts. ... The paradigm shift here is, 'why don't we instruct your own cells to be the factory?' ... [Researchers] provide proof-of-concept, reversing anemia in mice with engineered vessels secreting erythropoietin (EPO). ... The researchers created the drug-secreting vessels by isolating endothelial colony-forming cells from human blood and inserting a gene instructing the cells to produce EPO. They then added mesenchymal stem cells, suspended the cells in a gel, and injected this mixture into the mice, just under the skin. The cells spontaneously formed networks of blood vessels, lined with the engineered endothelial cells. Within a week, the vessels hooked up with the animals' own vessels, releasing EPO into the bloodstream. Tests showed that the drug circulated throughout the body and reversed anemia in the mice."

Link: http://www.marketwatch.com/story/engineered-drug-secreting-blood-vessels-reverse-anemia-in-mice-2011-11-15

Source:
http://www.longevitymeme.org/newsletter/latest_rss_feed.cfm

We might look on aging as damage that happens as a stochastic, inevitable consequence of the operation of a biochemical system. So the buildup of chemical gunk between your cells is a part of aging, while those times you managed to break bones in your enthusiasm for life are not aging, despite the fact that what's left in the wake of those unfortunate accidents is definitely damage.

There are always special cases and grey areas worth thinking about, however. Such as teeth, for example, as I was reminded earlier today. Teeth have a pretty hard time of it, actually, when you stop to think about it. Even in this modern age our teeth maintenance technologies remain woefully inadequate in the face of bacterial species that break down enamel, and so our teeth are one of the most failure-prone and damage-prone parts of the body - and they get to the point of painful dysfunction far earlier than the rest of our organs if left to their own devices.

But that isn't aging - it's parasitism, no more aging than the consequences of contracting malaria. It's still something we need to fix, of course, and I post on this and related topics because it is of general interest to anyone who follows research into rejuvenation and regeneration. If most or all of us suffer a particular form of bacterial malfeasance that manages to be as damaging as that which chews upon our teeth, than dealing with that problem has to be included in any general toolkit for enhanced human longevity.

As an aside, I should note that the hard components of teeth do age:

enamel thickness related to age showed a steady decrease, beginning at approximately age 50.

There are apparently chemical composition changes, increased brittleness, and so forth - none of which seems to have much to do with the bacteria that cause cavities.

Another completely unrelated grey area is something I touch on frequently: the structural changes that take place in the <a href=adaptive immune system due to exposure to infectious agents. The adaptive component of the immune system performs throughout life just as it evolved to do - which means it devotes space and cells to remembering the pathogens it has encountered so that it can effectively destroy them in the future. But by continuing to function in this way, it becomes less and less effective over time: in later life too much of its capacity is taken up with memory cells and too little with killer cells. So quite aside from what we might think of as biological aging, the adaptive immune system succeeds itself into an increasingly broken state just by doing its job. Whether or not we call this process aging, it still has to be fixed, auch as by using targeted cell destruction therapies to eliminate memory cells and free up space.

There are other examples. But you get the point: not all of the degenerations that we suffer with advancing age are in fact aging per se, or at least they will not fit into the usefully narrow definitions of aging that I find helpful. They will still need to be addressed, prevented, and their consequences repaired.

Source:
http://www.longevitymeme.org/newsletter/latest_rss_feed.cfm

We might look on aging as damage that happens as a stochastic, inevitable consequence of the operation of a biochemical system. So the buildup of chemical gunk between your cells is a part of aging, while those times you managed to break bones in your enthusiasm for life are not aging, despite the fact that what's left in the wake of those unfortunate accidents is definitely damage.

There are always special cases and grey areas worth thinking about, however. Such as teeth, for example, as I was reminded earlier today. Teeth have a pretty hard time of it, actually, when you stop to think about it. Even in this modern age our teeth maintenance technologies remain woefully inadequate in the face of bacterial species that break down enamel, and so our teeth are one of the most failure-prone and damage-prone parts of the body - and they get to the point of painful dysfunction far earlier than the rest of our organs if left to their own devices.

But that isn't aging - it's parasitism, no more aging than the consequences of contracting malaria. It's still something we need to fix, of course, and I post on this and related topics because it is of general interest to anyone who follows research into rejuvenation and regeneration. If most or all of us suffer a particular form of bacterial malfeasance that manages to be as damaging as that which chews upon our teeth, than dealing with that problem has to be included in any general toolkit for enhanced human longevity.

As an aside, I should note that the hard components of teeth do age:

enamel thickness related to age showed a steady decrease, beginning at approximately age 50.

There are apparently chemical composition changes, increased brittleness, and so forth - none of which seems to have much to do with the bacteria that cause cavities.

Another completely unrelated grey area is something I touch on frequently: the structural changes that take place in the <a href=adaptive immune system due to exposure to infectious agents. The adaptive component of the immune system performs throughout life just as it evolved to do - which means it devotes space and cells to remembering the pathogens it has encountered so that it can effectively destroy them in the future. But by continuing to function in this way, it becomes less and less effective over time: in later life too much of its capacity is taken up with memory cells and too little with killer cells. So quite aside from what we might think of as biological aging, the adaptive immune system succeeds itself into an increasingly broken state just by doing its job. Whether or not we call this process aging, it still has to be fixed, auch as by using targeted cell destruction therapies to eliminate memory cells and free up space.

There are other examples. But you get the point: not all of the degenerations that we suffer with advancing age are in fact aging per se, or at least they will not fit into the usefully narrow definitions of aging that I find helpful. They will still need to be addressed, prevented, and their consequences repaired.

Source:
http://www.longevitymeme.org/newsletter/latest_rss_feed.cfm

From h+ Magazine: "As serious life extension appears on an ever nearer horizon simultaneous with a period of social and economic rebellion and an increasing sense of global chaos, this may be a good time to entertain these anxieties while thinking beyond the two extant competing simplistic arguments. The current conflicting views seem to be these: A: Hyperlongevity will be for rich people only and we can't afford to add to the population vs. B: Technologies get distributed to more and more people at an increasing rate of speed through the auspices of the free market. Demand increases. Production increases. The price gets lower. Demand increases. Production increases. The price gets lower... ad infinitum. In fact, the wealthy who are the early adopters of a new technology get to spend a lot of money on crappy versions of new technologies that are not ready for prime time. At the risk of being obvious, it seems like there's a lot of room in the middle for more nuanced, less certain views. ... Very few people would say that we shouldn't cure cancer or heart disease because only the wealthy will be able to afford it - and those who did would be seen by most as anti-human and/or insufferably whiny. Seen in this light, it becomes obvious that this whole 'only the rich will get hyperlongevity' mentality is pathetic in the extreme - a concession of defeat before the outset. If you think optimal health and longevity should be distributed, you won't say, 'Well, it won't be distributed so I'm against it.' You will try to make sure it gets distributed. Whether you believe in medical care for all through government or pushing these solutions towards a very large mass market or creating an open source culture that takes production and distribution into its own decentralized hands, you'll work or fight for one or several (or all) of these solutions."

Link: http://hplusmagazine.com/2011/11/15/live-long-and-prosper-umm-well-get-back-to-you-on-that-prosper-bit/

Source:
http://www.longevitymeme.org/newsletter/latest_rss_feed.cfm

Teeth are one of the first parts of our body to become seriously damaged as the years go by, thanks to bacterial agents, but that will soon enough be a thing of the past. On the one hand enamel regeneration is close to realization, and on the other hand so are ways of eliminating the agents of tooth decay: "A new mouthwash developed by a microbiologist at the UCLA School of Dentistry is highly successful in targeting the harmful Streptococcus mutans bacteria that is the principal cause tooth decay and cavities. In a recent clinical study, 12 subjects who rinsed just one time with the experimental mouthwash experienced a nearly complete elimination of the S. mutans bacteria over the entire four-day testing period. ... This new mouthwash is the product of nearly a decade of research conducted by Wenyuan Shi ... Shi developed a new antimicrobial technology called STAMP (specifically targeted anti-microbial peptides) [which] acts as a sort of 'smart bomb,' eliminating only the harmful bacteria and remaining effective for an extended period. ... With this new antimicrobial technology, we have the prospect of actually wiping out tooth decay in our lifetime."

Link: http://www.sciencedaily.com/releases/2011/11/111116045657.htm

Source:
http://www.longevitymeme.org/newsletter/latest_rss_feed.cfm

Loss of the p66(Shc) gene is a canonical example of the rampant complexity of metabolism when it comes to determinants of longevity. If you look back in the Fight Aging! archives, you'll see what I mean: years of work on p66(Shc) mutant mice that piles higher with each new paper, an accumulation of mechanisms, alterations, chains of cause and effect, altered feedback loops, and so forth - all spawned from knocking out this one gene.

It is the height of optimistic hubris to suppose that we'll be safely tinkering with human metabolism in the same way any time soon - which is one of the reasons why efforts to merely slow aging are the slow boat to China. The fast path is to work on ways to repair our existing metabolism; don't change it, just find methods to put it back the way it was when we were young. A great deal more is known about how to go about reversing aging than is known about how to slow aging.

But I digress, as I really did want to talk about p66(Shc). In addition to being a poster child for the complexities of metabolism and genetic determinants of longevity, this gene also turns out to be a good example to draw upon when explaining why it is that there are so many small genetic tweaks capable of extending life in mice. Why didn't evolution select for these small modifications in the first place? See this paper for a starting point:

Deletion of the p66(Shc) gene results in lean and healthy mice, retards aging and protects from aging-associated diseases, raising the question of why p66(Shc) has been selected, and what is its physiological role. We have investigated survival and reproduction of p66(Shc) -/- mice in a population living in a large outdoor enclosure for a year, subjected to food competition and exposed to winter temperatures. Under these conditions deletion of p66(Shc) was strongly counterselected. Laboratory studies revealed that p66(Shc) -/- mice have defects in fat accumulation, thermoregulation and reproduction, suggesting that p66(Shc) has been evolutionarily selected because of its role in energy metabolism. These findings imply that the health impact of targeting aging genes might depend on the specific energetic niche and caution should be exercised against premature conclusions regarding gene functions that have only been observed in protected laboratory conditions.

So in other words, lack of p66(Shc) only extends life and causes the mutants to prosper as individuals if they have the benefits of civilization and technology: secure food supplies, secure heating, protection from the elements, and so forth. If shoved out into the uncaring world, they fare poorly - and would soon enough vanish as a genetic line, out-competed by animals with shorter life spans but a better adapted metabolism. We might expect to see similar results for the range of other longevity genes discovered in small mammals: if there was an evolutionary benefit to their selection for animals in the wild, then we should expect that these longevity mutations would already have been selected.

Is this result anything other than just interesting for those of us following along at home? Well, it might help to further inform out thinking as to the odds of significant human longevity mutations - which I suspect are low, by the way, though I do think there will be many minor longevity genes found in humans, with very limited effects. We are already unusually long-lived for primates, and primates are long-lived in comparison to other similarly sized mammals, and that seems to have squeezed down the range of life span differences that can be created through metabolic tinkering - or at least this is currently the consensus based on what is known of the effects of calorie restriction on metabolism and health in humans.

Source:
http://www.longevitymeme.org/newsletter/latest_rss_feed.cfm

As knowledge of cellular programming and signaling systems increases, the future of cell therapies will most likely move away from transplants and towards controlling existing populations of cells in the body: "In order to regenerate damaged heart muscle as caused by a heart attack [simpler] vertebrates like the salamander adopt a strategy whereby surviving healthy heart muscle cells regress into an embryonic state. This process, which is known as dedifferentiation, produces cells which contain a series of stem cell markers and re-attain their cell division activity. Thus, new cells are produced which convert, in turn, into heart muscle cells. The cardiac function is then restored through the remodelling of the muscle tissue. An optimised repair mechanism of this kind does not exist in humans. Although heart stem cells were discovered some time ago, exactly how and to what extent they play a role in cardiac repair is a matter of dispute. It has only been known for a few years that processes comparable to those found in the salamander even exist in mammals. ... [Researchers have] now discovered the molecule responsible for controlling this dedifferentiation of heart muscle cells in mammals. The scientists initially noticed the high concentration of oncostatin M in tissue samples from the hearts of patients suffering from myocardial infarction. It was already known that this protein is responsible for the dedifferentiation of different cell types, among other things. ... Using a mouse infarct model, the [researchers] succeeded in demonstrating that oncostatin M actually does stimulate the repair of damaged heart muscle tissue as presumed. One of the two test groups had been modified genetically in advance to ensure that the oncostatin M could not have any effect in these animals. ... The difference between the two groups was astonishing. Whereas in the group in which oncostatin M could take effect almost all animals were still alive after four weeks, 40 percent of the genetically modified mice had died from the effects of the infarction."

Link: http://www.sciencedaily.com/releases/2011/11/111111095220.htm

Source:
http://www.longevitymeme.org/newsletter/latest_rss_feed.cfm

Here is an interesting application of cell therapy, which demonstrates the point that an artificial replacement for an organ doesn't necessarily have to replicate the form and structure of that organ: "Eight-month-old Iyaad Syed now looks the picture of health - but six months ago he was close to death. A virus had damaged his liver causing it to fail. Instead of going on a waiting list for a transplant, doctors injected donor liver cells into his abdomen. These processed toxins and produced vital proteins - acting rather like a temporary liver. The cells were coated with a chemical found in algae which prevented them from being attacked by the immune system. After two weeks his own liver had begun to recover. ... The question now is whether the technique could be used to benefit other patients with acute liver failure. The team [is] urging caution - a large clinical trial is needed to test the effectiveness of the technique. ... The principle of this new technique is certainly ground-breaking and we would welcome the results of further clinical trials to see if it could become a standard treatment for both adults and children."

Link: http://www.bbc.co.uk/news/health-15744176

Source:
http://www.longevitymeme.org/newsletter/latest_rss_feed.cfm