Fight Aging! Newsletter, March 11th 2013

March 11th 2013

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!



- SENS Research Foundation Forges Ahead
- A Mechanism By Which Fat Causes Chronic Inflammation
- The Transhumanist Reader
- Interviews and Commentary from the Transhumanist Community
- Discussion
- Latest Headlines from Fight Aging!
    - SENS Research Foundation's AGE-Breaker Research Programs
    - Investigating the Mechanisms of Liver Regrowth
    - Suggesting that Calorie Restriction Primarily Operates on Mitochondrial Function
    - A Switch to Increase Plasticity in the Adult Brain
    - Sexual Activity and Neurogenesis Rates in Mice
    - More Visceral Fat Means a Greater Risk of Intestinal Cancer
    - A "Calcium Hypothesis" of Declining Vision With Age
    - On Methionine Restriction
    - A Review of Known Links Between Growth Hormone and Aging
    - Casting Doubt on Latent Regenerative Mechanisms in Mammals


The SENS Research Foundation (SRF) funds research programs aimed at the development of rejuvenation biotechnology - i.e. the basis for medical therapies that can reverse degenerative aging and thus extend healthy, vigorous human life spans. These programs are based on the Strategies for Engineered Negligible Senescence (SENS) first outlined by Aubrey de Grey some years ago. I'm very much in favor of this: the work has to be done, the sooner the better, and the SRF is one of the few places in the world where you can make a donation and know that it's going directly towards high-impact, relevant medical research into human rejuvenation.

Getting the job done doesn't mean doing it all yourself, however. Completing a demonstration of SENS in mice is sketched in at a decade and a billion dollars if fully funded, but that's the opening scene in a longer play devoted to translating animal studies into human clinical medicine. The point of the SENS Research Foundation is to "completely redefine the way the world researches and treats aging and age-related diseases." Some directly funded research is necessary to this goal, such as when fields are neglected and the research community needs a mix of a kick in the pants and an influx of philanthropic funding - as is the case for work on clearing out advanced glycation end-products from our tissues. But the larger aim is persuasion: persuade a large enough fraction of the research community to agree with with SENS vision of aging, and they will form their own labs and research initiatives to help.

In this sense, SENS is a peaceful revolution of the sort that roll through the world's research communities with some regularity. In a way, SENS has already won its place as the forthcoming dominant paradigm, despite its minority status and tiny budget, and the process of getting to that dominance is all just details. You can tell that this is the case by the way that leaders in the research community are willing to become scientific advisers or host collaborative SENS research programs in their laboratories. Note the signing statement on the SENS Research Foundation advisory board page - it is in essence a refutation of much of what has been dominant in aging research for the past twenty years or so, and important figures in the research community now stand by that view:

"Unfortunately, the regenerative medicine approach to combating aging is not yet being adequately pursued by major funding bodies: only a small number of laboratories worldwide are funded (either publicly or privately) to develop therapies that could rejuvenate aged but otherwise undamaged tissues. SRF has risen to the challenge of filling this void in the biomedical research funding arena.

"As and when it is developed, this panel of therapies may provide many years, even decades, of additional youthful life to countless millions of people. Those extra years will be free of all age-related diseases, as well as the frailty and susceptibility to infections and falls that the elderly also experience. The alleviation of suffering that will result, and the resulting economic benefits of maintained productivity of the population, are almost incalculable. In our capacity as the overseers of SRF's research strategy, we urge you to do all you can to help SENS Research Foundation carry out this mission with maximum speed."

Once a critical mass of the movers and shakers in a field agree with you, then the rest is history. It might be a lot of work, but it will happen. The latest figure to join the SRF scientific board is a very well known name in the life science community:

"We are honored to welcome Dr. George Church as the newest member of SENS Research Foundation's Research Advisory Board. Dr. Church brings relevant expertise in a number of fields, genetics in particular. He is Professor of Genetics at Harvard Medical School and Director of, in addition to being the author of the book, Regenesis: How Synthetic Biology Will Reinvent Nature and Ourselves. His innovations in "next generation" genome sequencing and synthesis & cell/tissue engineering resulted in 12 companies spanning fields including medical genomics and synthetic biology as well as new privacy, biosafety & biosecurity policies. He is director of the NIH Center for Excellence in Genomic Science, and his honors include election to NAS & NAE and Franklin Bower Laureate for Achievement in Science."

So on the whole, things are going well, conforming to a progression that will lead to the SENS approach to aging - i.e. build the means of rejuvenation, and do it soon - becoming a large and important force in the medical research community of tomorrow. That is something of a necessary platform to build up the odds of receiving large-scale funding through the usual channels, rather than requiring visionary philanthropists and the crowdfunding efforts of interested communities to open the way.

It is still the case that one small, wealthy group could accelerate that progression by twenty years at this point by funding SENS to the tune of a few hundred million dollars. The odds of the necessary networking happening to create that event will continue to rise with progress in persuading the research community and existing constellation of funding institutions. Life is worth more than money, so the motivation to back rejuvenation research is strong, but people with access to large amounts of money tend to be very conservative in how they deploy it; only the most mainstream of initiatives can hope to be on the inside track for philanthropy. People like Peter Thiel or Dmitry Itskov are not commonplace, sadly.


A large weight of evidence shows that excess body fat - and specifically excess visceral fat - is bad for you in the long term. Put on weight and your life expectancy drops, even as your lifetime medical costs rise. You will most likely be less healthy for the rest of your life than your leaner peers, and they will outlive you. (Unless of course medical technology advances rapidly enough to save you from the consequences of your diet and lifestyle choices. But that's no certainty; why gamble when you don't have to?)

Some fraction of the consequences of being overweight are actually the consequences of a lack of regular exercise. Another fraction of the consequences of being overweight stem from the low-level reactions of your metabolism to the overnutrition required to create that excess body fat - the reverse of dietary restriction, but something that is not as well researched at the level of cells and genes, despite the vast real-life population study in overfeeding taking place in much of the world these days.

The real monster when it comes to fat tissue and long term health appears to be inflammation, however. Temporary inflammation is a necessary portion of the response to damage and disease by the immune system, but chronic, unremitting inflammation accelerates progress towards frailty and ill-health. Indeed, it shows up as a contributing factor in degenerative aging later in life as the immune system becomes increasingly damaged and erratic. Distinct from the aging of the immune system, fat tissue itself spurs chronic inflammation. This has been known for some time, and here researchers present a fairly detailed account of how they think fat cells are causing this issue:

"High calorie diets cause [fat] cells to make major histocompatibility complex II, a group of proteins usually expressed to help the immune system fight off viruses and bacteria. In overweight mice and humans the fat cells, or adipocytes, are issuing false distress signals - they are not under attack by pathogens. But this still sends local immune cells into a tizzy, and that causes inflammation.

"We did not know fat cells could instigate the inflammatory response. That's because for a very long time we thought these cells did little else besides store and release energy. But what we have learned is that adipocytes don't just rely on local resident immune cells for protection - they play a very active role in their own defense. And that's not always a good thing.

"Could the inflammation caused by a high fat diet serve any purpose, or is it a senseless response to an unnaturally caloric diet? The expression of MHCII in adipocytes does not seem to be helpful to the body. It is not at all clear what the advantage would be, given all the negative long-term consequences of fat tissue inflammation in people who are obese, including insulin resistance and, eventually, full diabetes. This just appears to be a runaway immune response to a modern high calorie diet. The bottom line is, you're feeding and feeding these fat cells and they're turning around and biting you back. They're doing the thing they're supposed to do - storing energy - but reacting negatively to too much of it."


The Transhumanist Reader: Classical and Contemporary Essays on the Science, Technology, and Philosophy of the Human Future, edited by Max More and Natasha Vita-More, will be published April 29, 2013. It is the "first authoritative and comprehensive survey of the origins and current state of transhumanist thinking", according to the editors, and the anthology includes a roster of leaders in transhumanist thought. "The rapid pace of emerging technologies is playing an increasingly important role in overcoming fundamental human limitations," say the editors.

Transhumanism is an important movement, even while now somewhat diffused into popular culture in comparison to the online salons of the late 1990s. Why is transhumanism important? Primarily, from my perspective, because a range of the most important present ventures in biotechnology and medicine are informed, supported by, and connected to figures in the transhumanist community. There is cryonics, to pick the most obvious example - and one might argue that modern transhumanism was a offshoot of the cryonics communities and related futurists of the 1960s and 1970s. To pick another example, a great deal of the early funding and enthusiasm for SENS research into the repair of aging, back when it was conducted under the umbrella of the Methuselah Foundation, came from transhumanist circles.

From where I stand, transhumanism is nothing more than common sense about technology and the human condition. We can improve things, so why not improve things? We live in far greater comfort and for more years in good health in comparison to our ancestors precisely because those ancestors created new technologies that change the human condition - lengthening healthy life, removing causes of pain and suffering. As technologies become more sophisticated we have the opportunity to move from such things as defeating smallpox to such things as reliably repairing the cellular and molecular damage that causes aging. These are only matters of degree.

Yet many people, even in this age of constant change, are very much up in arms and threatened by such prospects. It's an odd world we live in, in which folk partake in a wealth of new choices and improvements to their standard of living - things that their parents didn't have - while at the same time decrying efforts to build further improvements for their own children. Rationality is in short supply.


With the publicity for a new book on transhumanist thought, I noticed a couple of interviews and articles emerge from the community in recent days. Follow the link above for pointers and quotes.

Building medical technologies to repair and reverse degenerative aging is one part of a much broader set of transhumanist ideals: aging is only one of many current limits on the human condition that we can work to transcend through applied technology. It is a very important one, far and away the most important one in my opinion, but still one among many. Transhumanism exists as a named brand of thought and vision that some see as being separate from simple common sense about technology (i.e. use it to make things better) because we are moving, quite rapidly, from an age in which we could only crudely change ourselves into an age where the sky is the limit in terms of changing our biology and our minds. To some eyes there is a line in the sand somewhere past our present medical technology and somewhere before being able to regrow limbs, reverse aging, or build artificial intelligences.

Yet I think we've all seen that line shift ever forward as medicine and other technologies advance. Yesterday's uproar over any specific biotechnology is today's acceptance (take stem cell research as a recent line item, for example). It is a grand flaw in the human condition that people fight so much against all that is new, even while taking full advantage of the benefits provided by everything their parents fought against. It's dumb behavior. It slows things down - and in the case of finding ways to treat and ultimately cure degenerative aging, that has a staggering cost in lives and suffering.


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, March 8, 2013
One of the root causes of aging is the formation of advanced glycation end-products (AGEs), something that happens much faster in a diabetic metabolism, but which nonetheless happens to all of us and causes progressively greater harm as the years pass. AGEs gum together and disable vital protein machinery, and also hammer on cell receptors in ways that cause chronic inflammation and other ills. Past work on ways to break down AGEs - AGE-breaker drugs - largely occurred prior to the present rapid pace of development in biotechnology, and was both laborious and ultimately of little use in people despite promising animal studies. It turned out that the most important types of AGE in long-lived humans are not the same as in short-lived rodents, and thus drugs that help rats do little for people. However, one single form of human AGE - glucosepane - does make up the vast, overwhelming majority of AGEs in tissues such as skin. So it is a very viable, narrow target now that the research community knows enough to identify it as the primary target. A safe way to remove glucosepane is needed in order to largely eliminate this contribution to degenerative aging. Sadly, as for much of the foundations of future rejuvenation therapies, little work and funding is directed to this end. This is thus one of the areas in which the SENS Research Foundation hopes to step in and spur greater interest and progress. Here are some notes on the current research programs funded by the Foundation to this end: "Chemical "crosslinking" of the structural proteins of our arteries slowly stiffens them with age, leading to more rigid blood vessels, rising "systolic" blood pressure (the first or top number in a blood pressure reading), and eventually to the loss of the ability of the kidneys to filter toxins from our blood, and a rising risk of stroke with age. Rejuvenation biotechnology can prevent these scourges at their source. New medicines that break apart these molecular "handcuffs" would allow the proteins of the arteries could move freely again, restoring the supple flexibility and cushioning capacity of aging arteries to youthful health and functionality. As a result, damage to the kidneys would be prevented, and strokes averted. With a generous donation from software entrepreneur Jason Hope, SENS Research Foundation and the Cambridge University Institute of Biotechnology have established a new SENS Research Foundation Laboratory at Cambridge. With no one else taking on this challenging, critical research, the scientists in the Cambridge SENS lab will initiate work on biomedical solutions to glucosepane crosslinks starting from the ground up - with research to develop reagents that can rapidly and specifically detect proteins that have been crosslinked by glucosepane. The development of such reagents is an indispensible enabling technology for the development and testing of candidate glucosepane-breaking drugs. In parallel, SENS Research Foundation is also providing funding to Dr. David Spiegel's group at Yale University, which has special expertise in making glycation crosslinks and which has recently been studying the mechanisms and chemical vulnerabilities of precursors of glucosepane. Dr. Spiegel's group has also recently published a report clarifying how the first generation crosslink-breaking drug worked. Once the Cambridge SRF lab has successfully established methods for identifying proteins that have been handcuffed together by glucosepane, Dr. Spiegel's group will use them to begin developing potential glucosepane-cleaving agents. Completing the cycle, candidate agents can then be tested at the Cambridge center - initially in tissue culture, and eventually in vivo. Once developed, any glucosepane-labeling reagents that emerge from the first phase of this work will made available as openly as possible, to accelerate research into the role of crosslinks in disease and aging, and into ways to combat them."

Friday, March 8, 2013
The liver is one of the few organs capable of significant regeneration in humans - but even this is more a case of compensatory growth than true regeneration of the sort seen in lower animals. Still, there is probably value in finding out how and why this happens in the liver and not in other organs: "[Researchers have] identified a protein complex that acts as a molecular switch turning on a self-regeneration program in the liver. The protein complex furthermore fine tunes liver metabolism, allowing this to run efficiently in parallel with the tissue damage repair. The new knowledge challenges the current focus on stem cells and may point towards future simplification of treatments used for repairing tissue damage. "Our new data challenge the predominant 'stem cell-mania' as the results reveal important molecular mechanisms that enable ordinary liver cells to divide and repair tissue damage. This may point to ways of using ordinary liver cells for therapeutic purposes, as these cells may be easier to use than stem cells." Tissue renewal [is] a job for the stem cells present in our body. One exception is the specialised cells of the liver called hepatocytes. They are responsible for the metabolic functions of the liver, but can at the same time produce new liver cells. "Our results show how a protein complex is changed upon damage to the liver, making it function as a 'switch' turning on a self-renewal program in the hepatocytes. The protein complex literally turns on selected genes that enable division of the hepatocytes, while maintaining their metabolic functions." The extraordinary ability of the liver cells to divide almost indefinitely resembles the ability of stem cells to self-renew and this finding challenges the current focus on stem cells and stem cell therapy. The new results [are] consistent with new studies of self-renewal in the group of white blood cells called macrophages. "We see a clear overlap in the molecular mechanisms controlling self-renewal in hepatocytes and macrophages and that could indicate the existence of a more general self-renewal program used by specialised cell types. If this is the case, it can really change the current perception that only stem cells are responsible for renewal of our tissues.""

Thursday, March 7, 2013
Mitochondrial damage is important in aging, and a range of evidence suggests it to be perhaps the most important contribution to aging. You might look at the membrane pacemaker theory of aging for example, which points to differences in susceptibility to mitochondrial damage between similar species with divergent life spans, where greater damage resistance correlates to longer life spans. Mitochondria damage themselves quite readily in the course of the normal operations. They generate the fuel used by other cellular processes, and in the course of doing so also create a flurry of oxidizing compounds - free radicals - that can react with and harm protein machinery. There are natural antioxidant compounds localized to the mitochondria that slow this process down by getting to the free radicals first. Researchers have shown that life span in mice can be extended by boosting the presence of some of these compounds. It works the other way too; removing or mutating SOD1, one of these antioxidants, shortens mouse life span. Here is an interesting demonstration showing that calorie restriction reverses this effect. That suggests that, while researchers have shown that the benefits of calorie restriction depend on the cellular recycling process of autophagy in some species, the primary mode of operation might be to alter mitochondrial function. Perhaps this occurs through an enhanced autophagic recycling of damaged mitochondria, but other mechanisms are possible: "Dietary restriction is a powerful aging intervention that extends the life span of diverse biological species ranging from yeast to invertebrates to mammals, and it has been argued that the anti-aging action of dietary restriction occurs through reduced oxidative stress/damage. Using Sod1-/- mice, which have previously been shown to have increased levels of oxidative stress associated with a shorter life span and a high incidence of neoplasia, we were able to test directly the ability of dietary restriction to reverse an aging phenotype due to increased oxidative stress/damage. We found that dietary restriction increased the life span of Sod1-/- mice 30%, returning it to that of wild type, control mice fed ad libitum. Oxidative damage in Sod1-/- mice was markedly reduced by dietary restriction. Analysis of end of life pathology showed that dietary restriction significantly reduced the overall incidence of pathological lesions in the Sod1-/- mice fed the dietary restricted-diet compared to Sod1-/- mice fed ad libitum, including the incidence of lymphoma (27 vs 5%) and overall liver pathology. In addition to reduced incidence of overall and liver specific pathology, the burden and severity of both neoplastic and non-neoplastic lesions was also significantly reduced in the Sod1-/- mice fed the dietary restricted-diet. These data demonstrate that dietary restriction can significantly attenuate the accelerated aging phenotype observed in Sod1-/- mice that arises from increased oxidative stress/damage."

Thursday, March 7, 2013
Given an easy switch to increase the plasticity of the adult brain, boosting the pace at which new neurons and new neural connections are formed, researchers will gather much more data in the years ahead as to how effective this might be as a stop-gap therapy to slow or compensate for some of the effects of aging: "Scientists have long known that the young and old brains are very different. Adolescent brains are more malleable or plastic, which allows them to learn languages more quickly than adults and speeds recovery from brain injuries. The comparative rigidity of the adult brain results in part from the function of a single gene that slows the rapid change in synaptic connections between neurons. By monitoring the synapses in living mice over weeks and months, [researchers] have identified the key genetic switch for brain maturation. [The] Nogo Receptor 1 gene is required to suppress high levels of plasticity in the adolescent brain and create the relatively quiescent levels of plasticity in adulthood. In mice without this gene, juvenile levels of brain plasticity persist throughout adulthood. When researchers blocked the function of this gene in old mice, they reset the old brain to adolescent levels of plasticity. "These are the molecules the brain needs for the transition from adolescence to adulthood. It suggests we can turn back the clock in the adult brain and recover from trauma the way kids recover." Rehabilitation after brain injuries like strokes requires that patients re-learn tasks such as moving a hand. Researchers found that adult mice lacking Nogo Receptor recovered from injury as quickly as adolescent mice and mastered new, complex motor tasks more quickly than adults with the receptor."

Wednesday, March 6, 2013
With hindsight, it seems that this should be a fairly obvious development. Given that evolution leads to organisms that adjust the operation of their metabolism in response to the prospects for food availability (see calorie restriction and related mechanisms), since that impacts reproductive success and thus evolutionary fitness, then it shouldn't be surprising to find that these organisms also do so based on the prospects for actual reproductive activity. "Aging is associated with compromised hippocampal function and reduced adult neurogenesis in the dentate gyrus. As new neurons have been linked to hippocampal functions, such as cognition, age-related decline in new neuron formation may contribute to impaired hippocampal function. We investigated whether a rewarding experience known to stimulate neurogenesis in young adult rats, namely sexual experience, would restore new neuron production and hippocampal function in middle-aged rats. Sexual experience enhanced the number of newly generated neurons in the dentate gyrus with both single and repeated exposures in middle-aged rats. Following continuous long-term exposure to sexual experience, cognitive function was improved. However, when a prolonged withdrawal period was introduced between the final mating experience and behavioral testing, the improvements in cognitive function were lost despite the presence of more new neurons. Taken together, these results suggest that repeated sexual experience can stimulate adult neurogenesis and restore cognitive function in the middle-aged rat as long as the experience persists throughout the testing period. The extent to which changes in adult neurogenesis underlie those in cognition remain unknown." That said, it is worth noting that almost any environmental enrichment produces the same effect for rats as noted by these researchers, which might say more about the insufficiency of the standard laboratory rat environment than about potential ways to boost neurogenesis in the rest of us.

Wednesday, March 6, 2013
We know that removing visceral fat extends life in mice - even a drastic measure such as surgery to remove the fat increases mouse life span. Given that mice are little cancer factories, it shouldn't be surprising to see that at least part of this effect on life expectancy stems from reduced incidence of cancer: "There has been some skepticism as to whether obesity per se is a bona fide cancer risk factor, rather than the habits that fuel it, including a poor diet and a sedentary lifestyle. Although those other lifestyle choices play a role, this study unequivocally demonstrates that visceral adiposity is causally linked to intestinal cancer. Prior research has shown that obesity markedly increases the likelihood of being diagnosed with and dying from many cancers. [Researchers] sought to determine if removing visceral fat in mice genetically prone to developing colon cancer might prevent or lessen the development of these tumors. They randomly assigned the mice to one of three groups. Mice in the first group underwent a sham surgery and were allowed to eat an unrestricted "buffet style" diet, for the entirety of the study, which resulted in these mice becoming obese. Those in the second group were also provided an unrestricted diet and became obese, but they had their visceral fat surgically removed at the outset of the study. Mice in the third group also underwent a sham surgery, but were provided only 60 percent of the calories consumed by the other mice in order to reduce their visceral fat by dieting. "Our sham-operated obese mice had the most visceral fat, developed the greatest number of intestinal tumors, and had the worst overall survival. However, mice that had less visceral fat, either by surgical removal or a calorie-restricted diet, had a reduction in the number of intestinal tumors. This was particularly remarkable in the case of our group where visceral fat was surgically removed, because these mice were still obese, they just had very little abdominal fat.""

Tuesday, March 5, 2013
Researchers here propose that a mechanism associated with age-related cognitive decline is also involved in the poorly understood general declines in vision that occur with age. From the perspective of SENS and aging as damage, this is exactly the sort of thing we'd expect to be a secondary consequence of one of the fundamental changes that drive aging, such as a build up of aggregates or damage to cell mitochondria. Given the complexities of metabolism and cellular operation, the fastest and most efficient way to prove or disprove that - and many similar propositions - is to implement SENS and fix the underlying damage. "Extensive research in the CA1 region of the rat hippocampus has revealed an age-related increase in neuronal Ca2+ influx though L-type voltage-gated calcium channels (L-VGCCs) that is strongly linked with impaired synaptic plasticity and reduced cognitive function. Diminished visual performance is another important behaviorally-evident functional decline that occurs with aging, beginning in young adulthood, but whose underlying mechanisms are poorly understood. Concurrent declines in neuroretinal function, when measured by electroretinogram (ERG), have also been noted: rod sensitivity and the maximum amplitude of rod responses to light both decrease with age. However, [such] physiological changes were too modest to account for the age-related vision declines. Here, we test an alternative hypothesis: that changes in retinal ion influx via L-VGCCs occur with age, and are linked to visual performance declines. In Long-Evans rats we find a significant age-related increase in ion flux through retinal L-VGCCs in vivo [that] are longitudinally linked with progressive vision declines. Importantly, the degree of retinal Mn2+ uptake early in adulthood significantly predicted later visual contrast sensitivity declines. Furthermore, as in the aging hippocampus, retinal expression of a drug-insensitive L-VGCC isoform (α1D) increased - a pattern confirmed in vivo by an age-related decline in sensitivity to L-VGCC blockade. These data highlight mechanistic similarities between retinal and hippocampal aging, and raise the possibility of new treatment targets for minimizing vision loss during healthy aging."

Tuesday, March 5, 2013
Methionine is an essential amino acid, one that we do not manufacture ourselves but must obtain from what we eat. It seems that a large fraction of the benefits of calorie restriction derive from alterations in metabolism that are based on sensing levels of methionine. Here is a review: "Comparative studies indicate that long-lived mammals have low rates of mitochondrial reactive oxygen species production (mtROSp) and oxidative damage in their mitochondrial DNA (mtDNA). Dietary restriction (DR), around 40%, extends the mean and maximum life span of a wide range of species and lowers mtROSp and oxidative damage to mtDNA, which supports the mitochondrial free radical theory of aging (MFRTA). Regarding the dietary factor responsible for the life extension effect of DR, neither carbohydrate nor lipid restriction seem to modify maximum longevity. However protein restriction (PR) and methionine restriction (at least 80% MetR) increase maximum lifespan in rats and mice. Interestingly, only 7 weeks of 40% PR (at least in liver) or 40% MetR (in all the studied organs, heart, brain, liver or kidney) are enough to decrease mtROSp and oxidative damage to mtDNA in rats, whereas neither carbohydrate nor lipid restriction change these parameters. In addition, old rats also conserve the capacity to respond to 7 weeks of 40% MetR with these beneficial changes. Most importantly, 40% MetR, differing from what happens during both 40% DR and 80% MetR, does not decrease growth rate and body size of rats. All the available studies suggest that the decrease in methionine ingestion that occurs during DR is responsible for part of the aging-delaying effect of this intervention likely through the decrease of mtROSp and ensuing DNA damage that it exerts. We conclude that lowering mtROS generation is a conserved mechanism, shared by long-lived species and dietary, protein, and methionine restricted animals, that decreases damage to macromolecules situated near the complex I mtROS generator, especially mtDNA. This would decrease the accumulation rate of somatic mutations in mtDNA and maybe finally also in nuclear DNA."

Monday, March 4, 2013
The longest-lived genetically engineered mice are those in which growth hormone or growth hormone receptors have been diminished or removed entirely. This review looks at some of what is know about the mechanisms involved in this extended life: "Studies in mutant, gene knock-out and transgenic mice have demonstrated that growth hormone (GH) signalling has a major impact on ageing and longevity. Growth hormone-resistant and GH-deficient animals live much longer than their normal siblings, while transgenic mice overexpressing GH are short lived. Actions of GH in juvenile animals appear to be particularly important for life extension and responsible for various phenotypic characteristics of long-lived hypopituitary mutants. Available evidence indicates that reduced GH signalling is linked to extended longevity by multiple interacting mechanisms including increased stress resistance, reduced growth, altered profiles of cytokines produced by the adipose tissue, and various metabolic adjustments such as enhanced insulin sensitivity, increased oxygen consumption (VO2/g) and reduced respiratory quotient. The effects of removing visceral fat indicate that increased levels of adiponectin and reduced levels of pro-inflammatory cytokines in GH-resistant mice are responsible for their increased insulin sensitivity. Increased VO2 apparently represents increased energy expenditure for thermogenesis, because VO2 of mutant and normal mice does not differ at thermoneutral temperature. Recent studies identified GH- and IGF-1-dependent maintenance of bone marrow populations of very small embryonic-like stem cells (VSELs) as another likely mechanism of delayed ageing and increased longevity of GH-deficient and GH-resistant animals. Many of the physiological characteristics of long-lived, GH-related mouse mutants are shared by exceptionally long-lived people and by individuals genetically predisposed to longevity."

Monday, March 4, 2013
Demonstrations such as the unusual regenerative capacity of MRL mice have bolstered the idea that we mammals retain the vestiges of an ability to regenerate shared with lower animals such as salamanders - but suppressed or buried in some way. Hence work on deciphering the mechanisms of limb and organ regeneration in a variety of species could lead to the ability to turn on similar regeneration in humans. This work casts doubt on that view, however, suggesting that exceptional regeneration is not an ancient process shared across many species: "Tiny and delicate it may be, but the red spotted newt (Notophthalmus viridescens) has tissue-engineering skills that far surpass the most advanced biotechnology labs. The newt can regenerate lost tissue, including heart muscle, components of its central nervous system and even the lens of its eye. Doctors hope that this skill relies on a basic genetic program that is common - albeit often in latent form - to all animals, including mammals, so that they can harness it in regenerative medicine. Attempts to analyse the genetics of newts in the same way as for humans, mice and flies have so far been hampered by the enormous size of the newt genome, which is ten times larger than our own. [Researchers] therefore looked at the RNA produced when genes are expressed - known as the transcriptome - and used three analytical techniques to compile their data. The team compiled the first catalogue of all the RNA transcripts expressed in N. viridescens, looking at both primary and regenerated tissue in the heart, limbs and eyes of both embryos and larvae. The researchers found more than 120,000 RNA transcripts, of which they estimate 15,000 code for proteins. Of those, 826 were unique to the newt. What is more, several of those sequences were expressed at different levels in regenerated tissue than in primary tissue. [The] findings add to existing evidence that the ability evolved recently, [such as] evidence that regenerating tissue in salamanders express proteins that are not found in other vertebrates. "I no longer believe that there is an ancestral program that is waiting to be reawakened. However, I absolutely do believe it's possible to coax mammal tissues into regenerating to a greater degree with the lessons we learn from newts.""


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