Fight Aging!

It has been an interesting year, and I suppose it is traditional at the tail end of December to cast a thoughtful eye back at the highlights. Which I will do, and the following items are in no particular order of importance or chronology.

This was the year that marked the end of the Longevity Meme, launched in 2001 and finally shut down and folded into Fight Aging!

2011 was also the year that I finally redesigned Fight Aging! - something I'd been threatening to get around to since somewhere in the middle of 2005. Speed of action is not high on the list of things to expect around these parts.

The SENS Foundation issued research reports that showed definite signs of progress - a million dollar budget in the prior year and concrete results starting to emerge from the research program focused on the means to repair the biological damage of aging.

Speaking of SENS, the Strategies for Engineered Negligible Senescence, the fifth SENS conference was held only a few months ago. There have been a range of presentations posted to the Foundation YouTube channel as high quality videos.

An important confirmation of the role of senescent cells in aging was accomplished in mice. Find a way to remove senescent cells and health and longevity benefit - that has been shown in action, and now the research community needs to develop a way to accomplish that goal that is better suited to clinical development of a therapy for humans.

This past year the Methuselah Foundation has refocused their efforts on establishing the New Organ Mprize as a part of the comprehensive strategy to accelerate tissue engineering and organ creation - and with it improve human longevity.

Max More has been working away as CEO of Alcor for the past year, making changes aimed at improving the transparency, community relations, and long term prospects for that part of the cryonics industry.

Some noteworthy progress was made early in 2011 in selectively reversing some of the decline of the immune system with age - this adds weight to the evidence for immune rejuvenation through selective destruction of errant cells.

I launched Open Cures this year, an effort to do something about the ridiculous state of regulation and medical development of longevity science. It is a project that I need to get back to working on more aggressively as soon as possible; change doesn't make itself happen.

An study showing an unexpected five year effect on human longevity - a good half the expected effect of regular exercise, a magnitude highly unusual for an established medical treatment - came and went largely unremarked.

The Russian side of the longevity science community has continued to build connections with the English-speaking world. The Science for Life Extension Foundation puts out very attractive materials, the Russian cryonics company KrioRus continues to grow, and more data is emerging on mitochondrially targeted antioxidants under development by Vladimir Skulachev's group.

Resveratrol and indeed the whole sirtuin endeavor has fallen out of favor in the last year - looking like yet another dead end to add to the annals of overly optimistic pharmaceutical development. I would expect to see much more of this sort of thing until the research community switches more of their focus to working on SENS program goals. Try to fix the damage, not just dig up drugs that alter metabolism a little bit.

Tissue engineering in 2011 has been a matter of leaps and bounds - too many to mention. There has been pancreas regeneration, more engineered trachea transplants, building of urethras, blood vessels, and mouse teeth. Which is not to mention small intestine sections, decellularized lungs, and the construction of a working sphincter. And more; this is what an energetic, well funded field looks like.

The naked mole rat genome was sequenced earlier in the year. This is a big step forward for the contingent of researchers agitating for the genetic comparison of long-lived mammals. Why are they long-lived? What can we learn? The mole rat genome is doing the rounds, and researchers will refine their present investigations of the species' noteworthy longevity and cancer resistance.

Sonia Arrison published 100+, a book that aimed to introduce many of the topics here at Fight Aging!, and garnered a fair amount of attention from the mainstream.

And of course, a hundred other items that I'm omitting. It's been busy out there - we're slowly edging into the early barnstorming age of longevity science, in which novel ways to extend life in mice are arriving every couple of months and new longevity-related genes are cataloged at a much faster rate. We measure progress by the degree to which people like me stop talking about certain topics or reporting on certain forms of research because they have become commonplace. It's an exciting time, certainly, and shows no signs of slowing down yet.

Pulling together the connections in a review paper: "Obesity is a condition in which excess or abnormal fat accumulation may present with adverse effects on health and decreased life expectancy. Increased body weight and adipose tissue accumulation amplifies the risk of developing various age-related diseases, such as cardiovascular disease, Type 2 Diabetes Mellitus, musculoskeletal disorders, respiratory diseases and certain types of cancer. This imbalance in body composition and body weight is now recognized as a state of increased oxidative stress and inflammation for the organism. Increasing oxidative stress and inflammation affect telomeres. Telomeres are specialized DNA-protein structures found at the ends of eukaryotic chromosomes and serve as markers of biological aging rate. They also play a critical role in maintaining genomic integrity and are involved in age-related metabolic dysfunction. Erosion of telomeres is hazardous to healthy cells, as it is a known mechanism of premature cellular senescence and loss of longevity. The association of telomeres and oxidative stress is evident in cultured somatic cells in vitro, where oxidative stress enhances the process of erosion with each cycle of replication. Shorter telomeres have been associated with increasing body mass index, increased adiposity, and more recently with increasing waist to hip ratio and visceral excess fat accumulation. Furthermore, many of the metabolic imbalances of obesity (e.g. glycemic, lipidemic, etc.) give rise to organ dysfunction in a way that resembles the accelerated aging process."

Link: http://www.ncbi.nlm.nih.gov/pubmed/22186032

In aging there is a lot of correlation - many biological systems that are traditionally studied separately are declining at once, so most researchers are only looking in detail at one tiny part of aging. Part of the challenging facing researchers has always been how to figure out what is cause and what is consequence given the need for specialization to make progress in any given small area of the biology of aging. Here, researchers focus on the immune system, and you can see the biases inherent in being a specialist: "The aging process is accompanied by an impairment of the physiological systems including the immune system. This system is an excellent indicator of health. We have also observed that several functions of the immune cells are good markers of biological age and predictors of longevity. In agreement with the oxidation-inflammation theory that we have proposed, the chronic oxidative stress that appears with age affects all cells and especially those of the regulatory systems, such as the nervous, endocrine and immune systems and the communication between them. This fact prevents an adequate homeostasis and, therefore, the preservation of health. We have also proposed an involvement of the immune system in the aging process of the organism, concretely in the rate of aging, since there is a relation between the redox state and functional capacity of the immune cells and the longevity of individuals. A confirmation of the central role of the immune system in oxi-inflamm-aging is that several lifestyle strategies such as the administration of adequate amounts of antioxidants in the diet, physical exercise, physical and mental activity through environmental enrichment and hormetic interventions improve functions of immune cells, decreasing their oxidative stress, and consequently increasing the longevity of individuals."

Link: http://www.ncbi.nlm.nih.gov/pubmed/22188449

I note a symptom of the highly restrictive FDA regulations on development of clinical therapies:

The indictment alleges the four distributed stem cells and other biological products without federal Food and Drug Administration approval, and for unapproved treatments of cancer, amyotrophic lateral sclerosis, multiple sclerosis, and Parkinson's Disease. ... Court records unsealed Wednesday show that the scheme made more than $1.5 million in sales between January 2007 and April 2010, from procedures Morales performed in Mexico on patients he met in the United States.

This is the standard situation: when regulation makes it impossible to meet demand or to try to develop and offer meaningful products, a black market will arise. That market will be less transparent, more costly, and less effective at delivering quality products than a free market would be in the absence of regulation. A black market will also tend to attract a larger contingent of sellers willing to commit fraud than would otherwise be the case, as the buyers have lower chances of success in any legal action or other means of forcing restitution.

So these fellows may be frauds, or they may be legitimate businesspeople trying to operate a medical tourism business, offering services that are perfectly legal - and even admirable - outside the US, while within the US forthright invention and competition in medicine is pretty much forbidden. Either way, other would-be legitimate businesspeople are going to look at this and think twice about trying to make the world a better place by offering better medical services.

So it goes. The FDA and its legal penumbra are monstrosities that distort all of the usual incentives involving profit and progress, and steer them towards bad ends. The FDA must go if we are to see progress in medicine that approaches the pace of progress in less regulated industries like computing.

There is a very simple solution to the problems of medicine. It's called freedom: freedom for providers to develop and compete as they see fit, and freedom for people to choose or reject their offerings with the money in their own pockets and savings accounts. For progress and efficiency to reign in an industry, people have to pay for goods with their own funds, and providers have to be free to innovate. Competition and the care with which people manage their own money keeps both sides as honest as any human culture is going to be.

Look at fashion. Shoes. Computers. DNA sequencing. Or any one of a thousand other important goods whose value has fallen over time and continues to do so. These are less regulated markets, not stifled and buried beneath chains like the provision of medicine. They are vibrant, constantly innovating and competing, and this is exactly because people pay for these products with the money they care about most.

A commentary at the journal Aging: "In the past 15 years, genomics has penetrated all areas of the life sciences, and this dramatic change in the way science is done is often viewed as genome revolution. However, application of genomics to study senescence and aging lagged behind. Until this year, no genomes have been sequenced explicitly to understand aging. In this regard, the recent completion of the genome of the naked mole rat marks an important milestone, as this study was performed primarily to better understand the exceptional longevity of this rodent. Naked mole rats live in the subterranean niche in southeast Africa and are the longest-lived rodents (maximum lifespan of 32 years). Being the size of a mouse, naked mole rats can be conveniently studied in the laboratory setting and compared with other rodents. What have we learned from the initial analysis of the genome of this remarkable animal? First, the genome is characterized by the reduced level of polymorphism, consistent with low DNA mutation rate (although other explanations are also possible). Second, an unusual thermogenesis of naked mole rats, which may be linked to longevity through metabolic rate, is consistent with the altered sequence of a key thermoregulator, UCP1, which modified its sequences that mediate regulation by nucleotides and fatty acids. Another interesting finding is the unique sequence of a tumor suppressor p16, a protein whose mutations were linked to a variety of human diseases associated with aging. In addition, analyses of gene expression as a function of age distinguished naked mole rats from other mammals. ... The availability of the genome of the naked mole rat should be viewed as the first step in the process of understanding of the delayed aging of this mammal, and also as a useful resource for studying the aging process in general. It is clear that much of its value lies in comparison with the genomes of other mammals, both with long and short lifespans, as well as in downstream functional genomic studies that assess genetic and epigenetic regulation networks. Comparative genomics of short-lived and long-lived organisms offers great opportunities to understand evolutionary forces and molecular mechanisms that regulate lifespan."

Link: http://www.impactaging.com/papers/v3/n12/full/100417.html

Human studies may reveal a correlation between longevity and lower rates of reproduction: "A number of leading theories of aging, namely The Antagonistic Pleiotropy Theory (Williams, 1957), The Disposable Soma Theory (Kirkwood, 1977) and most recently The Reproductive-Cell Cycle Theory (Bowen and Atwood, 2004, 2010) suggest a tradeoff between longevity and reproduction. While there has been an abundance of data linking longevity with reduced fertility in lower life forms, human data have been conflicting. We assessed this tradeoff in a cohort of genetically and socially homogenous Ashkenazi Jewish centenarians (average age ~100 years). As compared with an Ashkenazi cohort without exceptional longevity, our centenarians had fewer children (2.01 vs 2.53, p<0.0001), were older at first childbirth (28.0 vs 25.6, p<0.0001), and at last childbirth (32.4 vs 30.3, p<0.0001). The smaller number of children was observed for male and female centenarians alike. The lower number of children in both genders together with the pattern of delayed reproductive maturity is suggestive of constitutional factors that might enhance human life span at the expense of reduced reproductive ability."

Link: http://www.impactaging.com/papers/v3/n12/full/100415.html

This year saw a demonstration showing noteworthy benefits to health and longevity from the targeted destruction of senescent cells in mice - an expected result for many researchers, but one that had yet to happen up to that point. Senescent cells, cell that have removed themselves from the cycle of proliferation, are an evolutionary response to the growing threat of cancer with age, but once in a senescent state they progressively cause harm to surrounding cells and tissue. The immune system destroys many senescent cells, but becomes much worse at this task - along with all its other duties - as time progresses because it suffers from its own age-related issues. As the numbers of senescent cells grow, so does their contribution to the physical failures and declines of aging.

But this entire portion of the basis for degenerative aging could be removed with a therapy that destroyed senescent cells sufficiently well. This is why the earlier mentioned demonstration of senescent cell destruction - and corresponding health benefits - in mice was a welcome advance. Unfortunately, the method used was based on some clever genetic engineering and while effective at eliminating senescent cells without harming other cells in the engineered mouse breed, it has little direct application to the development of human clinical medicine.

Meanwhile, the cancer and immunotherapy research communities are making great strides in developing many forms of nanoscale technology that can be coupled to a sensor and sent to destroy those cells that the sensor reacts with - and without harming any other nearby cells. Researchers have used nanoparticles, antibodies, viruses, and bacteria to home in on cells with specific surface markers or other characteristics, and there deliver some form of killing blow. The trick here is not so much the killing blow, as many of the successful demonstrations of targeted cancer cell destruction did no more than deliver old-style chemotherapy drugs - just in very small doses and on a cell-by-cell basis rather than flooding the whole body. That works very well to minimize side-effects and maximize harm to the cancer.

The point of this sidebar is that these technology platforms could be quickly repurposed to attack senescent cells, but only when there emerges a robust way of distinguishing between senescent and non-senescent cells. So now we watch with interest for published research that touches on that topic, such as this recent open access paper:

Changes in the shape of the nuclear lamina are exhibited in senescent cells, as well as in cells expressing mutations in lamina genes. To identify cells with defects in the nuclear lamina we developed an imaging method that quantifies the intensity and curvature of the nuclear lamina. We show that this method accurately describes changes in the nuclear lamina. Spatial changes in nuclear lamina coincide with redistribution of lamin A proteins and local reduction in protein mobility in senescent cell. We suggest that local accumulation of lamin A in the nuclear evelope leads to bending of the structure. A quantitative distinction of the nuclear lamina shape in cell populations was found between fresh and senescent cells, and between primary myoblasts from young and old donors. Moreover, with this method mutations in lamina genes were significantly distinct from cells with wild-type genes. We suggest that this method can be applied to identify abnormal cells during aging, in in vitro propagation, and in lamina disorders.

As an aside, you might recall that mutant lamin A is the culprit in progeria, and has been postulated to be a low-level contribution to normal aging as well. Expect to see more interest in progeria and potential therapies for that condition if more evidence emerges to link it to cellular senescence and ways to reliably distinguish senescent cells.

A recent paper: "Birds generally age slower and live longer than similar sized mammals. For birds this occurs despite elevated blood glucose levels that for mammals would in part define them as diabetic. However these data were acquired in respiration states that have little resemblance to conditions in healthy tissues and mitochondrial [reactive oxygen species] production is probably minimal in healthy animals. Indeed mitochondria probably act as net consumers rather than producers of [reactive oxygen species]. Here we propose that (1) if mitochondria are antioxidant systems, the greater mitochondrial mass in athletic species, such as birds, is advantageous as it should provide a substantial sink for [reactive oxygen species]. (2) The intense drive for aerobic performance and decreased body density to facilitate flight may explain the relative insensitivity of birds to insulin, as well as depressed insulin levels and apparent sensitization to glucagon. Glucagon also associates with the sirtuin protein family, most of which are associated with caloric restriction regulated pathways, mitochondrial biogenesis and life span extension. (3) We note that telomeres, which appear to be unusually long in birds, bind Sirtuins 2 and 4 and therefore may stabilize and protect nuclear DNA. Ultimately these flight driven responses may suppress somatic growth and protect DNA from oxidative damage that would otherwise lead to ageing and non-viral cancers."

Link: http://www.ncbi.nlm.nih.gov/pubmed/22198369

Here is another of the many theories aiming to explain why women live longer than men: "One of the most significant achievements of the twentieth century is the increase in human lifespan. In any period studied, females live longer than males. We showed that mitochondrial oxidative stress is higher in males than females and that the higher levels of estrogens in females protect them against ageing, by up-regulating the expression of antioxidant, longevity-related genes. The chemical structure of estradiol confers antioxidant properties to the molecule. However, the low concentration of estrogens in females makes it unlikely that they exhibit significant antioxidant capacity in the organism. Therefore we studied the mechanisms enabling estradiol to be antioxidant at physiological levels. Our results show that physiological concentrations of estrogens activate estrogen receptors and the MAPK and NFKB pathway. Activation of NFkB by estrogens subsequently activates the expression of Mn-SOD and GPx. Moreover, we have demonstrated that genistein, the most abundant phytoestrogen in soya, reproduces the antioxidant effect of estradiol at nutritionally relevant concentrations by the same mechanism ... We conclude that estrogens and phytoestrogens up-regulate expression of antioxidant enzymes via the estrogen receptor and MAPK activation, which in turn activate the NFkB signalling pathway, resulting in the up-regulation of the expression of longevity-related genes."

Link: http://www.ncbi.nlm.nih.gov/pubmed/22188448

So what is the Methuselah Foundation up to these days? As you might know, the Foundation has administered the Mprize for longevity science since 2003: a multi-million dollar prize fund that encourages researchers to find ways to extend healthy life in mice - a good marker for technologies that may then be applicable to other mammals, such as we humans. Last year, the Foundation inaugurated a new prize, the NewOrgan prize that aims to spur greater progress in tissue engineering and the creation of functional new organs from a patient's own cells. This dovetails with the Foundation's investment strategy: helping to fund companies that focus on advanced tissue engineering, such as Organovo, and solving organ transplant issues, such as Silverstone Solutions.

The Methuselah Foundation sent out a sneak peek email yesterday with a pointer to the New Organ Mprize website and the first pledge drive with matching funds: this will be the big thing for the coming year. Here is the text:

Time for something new and personal.

In 2012, the next chapter for Methuselah and the journey for an enduring answer for millions will begin. We are excited to share this preview with our closest supporters and friends.

Introducing New Organ Mprize.

Think of a time when no one has to suffer and die waiting for an organ that never arrives. New Organ is creating the public prize that builds urgency for that future.

Sneak peek.

While we're finishing the campaign's site, we'd like to give you a preview of its homepage. We hope you like it as much as we do. Look for more pages in a few weeks.

Showing momentum.

Our goal is $200,000 by February 28th. To help achieve this and establish traction at launch, Organovo's Keith Murphy has pledged to match gifts up to $25,000.

Become a New Organ Founder.

We invite you to join us at the beginning. Let’s start New Organ with 25% of the job done. Kickstart the prize!

My yearly round of donations remain divided between the SENS Foundation and Methuselah Foundation - the two organizations to appear prominently on the Fight Aging! Take Action page. Both are worthy causes, consistently achieving a great deal more behind the scenes in networking and persuasion with the scientific and research funding communities than is apparent from the front end. A large fraction of the sea change in the aging research community in recent years can be attributed to the communities centered on these organizations.

Aiming to extend the healthy human life span has come to be a respectable goal in the scientific community over the past ten years. That wasn't always the case, and it's easy to forget just how much of a sea change has taken place since the [turn of the century].

One of the predictions of reliability theory is that individual life expectancy has a fair dependency on very early life development and circumstances: we are all born with different initial levels of biological damage at the cellular and molecular level, and that damage matters in the long term. Data suggesting that birth month influences life expectancy can be lumped in with possible solar radiation effects as supporting evidence: "This study explores the effects of month of birth (a proxy for early-life environmental influences) on the chances of survival to age 100. Months of birth for 1,574 validated centenarians born in the United States in 1880-1895 were compared to the same information obtained for centenarians' 10,885 shorter-lived siblings and 1,083 spouses. Comparison was conducted using a within-family analysis by the method of conditional logistic regression, which allows researchers to control for unobserved shared childhood or adulthood environment and common genetic background. It was found that months of birth have significant long-lasting effect on survival to age 100: siblings born in September-November have higher odds to become centenarians compared to siblings born in March. A similar month-of-birth pattern was found for centenarian spouses. These results support the idea of early-life programming of human aging and longevity."

Link: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3236478/

An immunotherapy approach is turned to treating autoimmune conditions: scientists have "turned the tables on an autoimmune disease. In such diseases, including Crohn's and rheumatoid arthritis, the immune system mistakenly attacks the body's tissues. But the scientists managed to trick the immune systems of mice into targeting one of the body's players in autoimmune processes, an enzyme known as MMP9. ... [Researchers] have spent years looking for ways to home in on and block members of the matrix metalloproteinase (MMP) enzyme family. These proteins cut through such support materials in our bodies as collagen, which makes them crucial for cellular mobilization, proliferation and wound healing, among other things. But when some members of the family, especially MMP9, get out of control, they can aid and abet autoimmune disease and cancer metastasis. Blocking these proteins might lead to effective treatments for a number of diseases. ... rather than attempting to design a synthetic molecule to directly attack MMPs [an] MMP immunization would trick the body into creating antibodies that block the enzyme at its active site. [Researchers] created an artificial version of the metal zinc-histidine complex at the heart of the MMP9 active site. They then injected these small, synthetic molecules into mice and afterward checked the mice's blood for signs of immune activity against the MMPs. ... when they had induced an inflammatory condition that mimics Crohn's disease in mice, the symptoms were prevented when mice were treated with [the new synthetic molecules]. We are excited not only by the potential of this method to treat Crohn's, [but] by the potential of using this approach to explore novel treatments for many other diseases."

Link: http://www.eurekalert.org/pub_releases/2011-12/wios-nsm122211.php

It's that time again - the season to arrange your last charitable gifts for the 2011 tax year. The SENS Foundation founders have put out a call for donations:

Dear Friends,

The diseases of aging - heart disease, Alzheimer's, macular degeneration - are not only terrible, tragic, and debilitating, but potentially preventable. SENS Foundation is working to use regenerative medicine to repair the cellular and molecular damage that accumulates in all of our bodies over time. With the right application of such treatments, we could slow, or even reverse, the pathology of aging.

We call these innovative, damage-repairing treatments rejuvenation biotechnologies. In human and economic terms, their successful development would represent an incredible victory. And yet, research into rejuvenation biotechnologies has received virtually no public funding. SENS Foundation has yet to receive monetary support from any government body. Other organizations in the field are in a similar position - the Mayo Clinic, for instance, was recently denied funding by the NIH for follow-up work on its landmark senescent cell study published in Nature.

If rejuvenation biotechnologies are to be developed, private donors will need to step forward. SENS Foundation has led, and continues to lead, the charge towards robust therapies that address the diseases of aging. We are working ceaselessly to advance rejuvenation biotechnologies in the following ways:

• We fund scientific work at universities and research institutes across the world - including, next year, a new project and lab at Cambridge University.
• We conduct our own in-house research at the rapidly-expanding SENS Foundation Research Center in Mountain View, California, which has nearly doubled its staff in 2011.
• We develop the next generation of researchers focused on the development of rejuvenation biotechnologies through our Academic Initiative, which continues to award research grants to talented and enthusiastic university students.
• We conduct outreach and forge new connections between individuals and organizations to grow the rejuvenation biotechnology field.
• We hold conferences, most recently SENS5 in September of this year, to bring some of the world's most capable scientists together in one room to discuss the future of medicine.

SENS Foundation is a pioneer in the fledgling industry of rejuvenation biotechnology. We have a highly talented and ever-growing team of researchers, expanding facilities, and considerable experience in the field. Out work has the potential to make modern treatments for age-related diseases markedly more effective, but is gravely underfunded. For this reason, your contribution could have a huge impact on our organization and, as a result, on medicine itself.

We deeply appreciate the donations we have received thus far, and urge you to consider contributing to our cause. We know of none greater: that is why we have focused our careers on overcoming the diseases of aging. Either way - whether or not you choose to give - please accept our whole team's warmest holiday wishes.

SENS Foundation is, in my view, the best place for most people to invest in the future of human longevity. The Foundation continues to strongly influence the research community behind the scenes, and that influence will grow as the Foundation gains the funding to prove ever more of the SENS view of rejuvenation biotechnology correct. The progress made to date has already drawn the support of renowned scientists in the fields of aging research and regenerative medicine, and as this train continues to pick up speed, it will convert ever more of the research community into supporters and participants in the development of rejuvenation biotechnology.

Folk like you and I have made this a going concern over the past seven years by supporting the Methuselah Foundation and then SENS Foundation after the SENS research program was spun off into its own organization. These foundations have grown from simple ideas an a couple of small early donations to become multi-million dollar organizations on the strength of our support. That was just the start - and we can help keep this momentum going through our donations. I strongly recommend that you look over the last annual reports issued by the SENS Foundation, so that you can see just how much work is being done and read about progress in their research programs:

• From the SENS Foundation: 2010 Research Report and SENS5 News
• SENS Foundation Year End Report for 2010 Now Available

Researchers here use simple measures of cognitive function to look at differential rates of aging between regions and populations: "Comparing the burden of aging across countries hinges on the availability of valid and comparable indicators. The Old Age Dependency Ratio allows only a limited assessment of the challenges of aging, because it does not include information on any individual characteristics except age itself. Existing alternative indicators based on health or economic activity suffer from measurement and comparability problems. We propose an indicator based on age variation in cognitive functioning. We use newly released data from standardized tests of seniors' cognitive abilities for countries from different world regions. In the wake of long-term advances in countries' industrial composition, and technological advances, the ability to handle new job procedures is now of high and growing importance, which increases the importance of cognition for work performance over time. In several countries with older populations, we find better cognitive performance on the part of populations aged 50+ than in countries with chronologically younger populations. This variation in cognitive functioning levels may be explained by the fact that seniors in some regions of the world experienced better conditions during childhood and adult life, including nutrition, duration and quality of schooling, lower exposure to disease, and physical and social activity patterns." This might best be viewed in the context of reliability theory: if we consider aging and cognitive function as outcomes based on accumulation of damage within the system of the body and brain, then we would expect that people with lower levels of damage will tend to be more robust and capable.

Link: http://dx.doi.org/10.1073/pnas.1112173109

Significant loss of the senses of smell and taste, a condition known as anosmia, can occur with aging. Here, researchers investigate stem cell related mechanisms; this may be another case of functionality fading because the stem cell population necessary to support it is shutting down with advancing age: "Experts estimate that about 2 percent of the U.S. population suffers from [a] lack of smell known as anosmia. And research by neuroscientists [provides] hope of new therapies for those who have lost their sense of smell, whether due to aging, trauma or a viral infection. In the study published this month [the researchers found] a genetic trigger responsible for renewing smell sensors in the nose. That gene, known as p63, tells olfactory stem cells whether to replace themselves or to change into different types of cells. Under normal circumstances [there] is a balance between the two outcomes. But when p63 is absent, the cells only turn into other types of mature cells, which [could] eventually lead to the complete depletion of olfactory cells. One reason for the onset of anosmia could be that the stem cells age and are less able to regenerate, or they are just depleted. Finding a way to promote stem cell renewal could help maintain sensory functions, such as the sense of smell."

Link: http://www.sfgate.com/cgi-bin/article.cgi?f=/c/a/2011/12/25/BA8M1MA4MP.DTL

We live in a world of oral fixation, or whatever equivalent post-Freudian term you'd like to use. It's not too hard to drawn the lines that lead unbroken from the magic of early human societies, insofar as it touched on beliefs regarding the consumption of various things, and the magical thinking of modern societies illustrated by the popularity of useless potions and pills. On the one hand tricksters cloaked as shamans, and on the other hand tricksters cloaked as marketing professionals pretending to use the methods of science. For every hot field of medical science, there are frauds out there somewhere selling edible goods to the credulous, trying to claim some of the mantle.of legitimacy enjoyed by the scientific community while practicing what is in effect an anti-science of belief and deception.

But back inside the real scientific community, we see the oral fixation at work in the amount and range of work on ingested substances. On diet, on tiny portions of diet, on the ingestion of specific substances beyond count, looking for results of significance. Funding for this sort of thing is evergreen, and I think that much of it is a grand waste. The path to longevity is not a freeway passing through the human stomach, but from the weight of research devoted to what we eat you might be forgiven for thinking otherwise. Would that these researchers were spending their time on something more useful, but the fixation of broader society on the mouth and what we put into it steers the strategic direction of research and research funding.

Here are a couple of examples:

Mediterranean diet gives longer life

Scientists at the Sahlgrenska Academy have now studied the effects of a Mediterranean diet on older people in Sweden. They have used a unique study known as the "H70 study" to compare 70-year-olds who eat a Mediterranean diet with others who have eaten more meat and animal products. The H70 study has studied thousands of 70-year-olds in the Gothenburg region for more than 40 years. ... The results show that those who eat a Mediterranean diet have a 20% higher chance of living longer. "This means in practice that older people who eat a Mediterranean diet live an estimated 2 3 years longer than those who don't", says Gianluca Tognon, scientist at the Sahlgrenska Academy, University of Gothenburg.

Are there differences in mortality among wine consumers and other alcoholic beverages?

Wine consumers, especially in comparison with spirits drinkers, have been shown to have higher levels of education and income, to consume a healthier diet, be more physically active, and have other characteristics that are associated with better health outcomes. However, epidemiologic studies have been inconsistent in showing that, after adjustment for all associated lifestyle factors, consumers of wine have lower risk of cardiovascular disease and mortality than do consumers of other beverages. A study based on the long-term follow up of a group of older Americans concluded that the associated lifestyle habits and environmental factors of wine consumers largely explained their better health outcomes.

We live in a world in which ingestion of alcohol has a greater and more active research community associated with it than is the case for serious efforts to develop the means to reverse aging. There will be more and greater publicity and funding generated by debates over tiny changes in life span and risk of disease through alcohol in the diet than there will be for the most important advance in longevity research this year, or any of the other high points in longevity science from the past twelve months. Sad but true. Real longevity science and biotechnology doesn't have much to do with sticking things into your mouth - it's largely low-level manipulation of cells and biomolecules - and in this world of oral fixation that's something of a disadvantage when it comes to publicity and support.

An example of the sort of screening work presently taking place, in China in this case: "Damaged heart tissue is not known for having much inherent capacity for repair. But now, scientists are closing in on signals that may be able to coax the heart into producing replacement cardiac muscle cells. Using a zebrafish model system, researchers have identified a family of molecules that can stimulate stem cells to develop into beating heart muscle cells. ... Despite advances in modern medicine, management of myocardial infarction and heart failure remains a major challenge. There is intense interest in developing agents that can influence stem cells to differentiate into cardiac cells as well as enhance the inherent regenerative capacities of the heart. Developing therapies that can stimulate heart muscle regeneration in areas of infarction would have enormous medical impact. ... The zebrafish is an excellent model organism to study heart growth and development because there are established genetic approaches that permit visualization of fluorescent beating hearts within transparent embryos. After screening nearly 4,000 compounds, the researchers discovered three structurally related molecules that could selectively enlarge the size of the embryonic heart. The compounds, cardionogen-1, -2, and -3, could promote or inhibit heart formation, depending on when they were administered during development. ... Cardionogen opposes Wnt signaling to induce cardiac muscle cell formation. Importantly, the interaction of cardionogen with Wnt seemed to be restricted to specific cell types. ... Evaluating the potential of cardionogen on human adult and embryonic stem cells is the next logical step. This may ultimately aid in design of therapeutic approaches to enhance repopulation of damaged heart muscle and restore function in diseased hearts."

Link: http://www.eurekalert.org/pub_releases/2011-12/cp-hdy121611.php

A Rejuvenation Research paper: "As mammals age, the rate of neurogenesis in the brain declines with a concomitant reduction in cognitive ability. Recent data suggest that plasma-borne factors are responsible for inhibition of neurogenesis. When the circulatory systems of old and young mice are connected, the old mice experience increased neurogenesis and the young mice exhibit less neurogenesis, suggesting the importance of systemic circulating factors. Chemokine CCL11/eotaxin has been identified as a factor that increases with aging. Injections of CCL11 inhibit neurogenesis in young mice, an effect likely mediated by CCR3 receptors on neural stem cells. Identification of a specific factor that plays a causative role in stem cell dysfunction in aging is consistent with data showing that transforming growth factor-β (TGF-β) inhibits satellite cell-mediated repair. Together, these data suggest that the systemic milieu plays a critical role in the aging of adult stem cells. Because adult stem cells help maintain homeostasis by providing the possibility of replacing metabolically damaged differentiated cells, aging of the systemic milieu and stem cell niches may drive functional decline during aging. The identification of a specific systemic change suggests that aging is more amenable to therapeutic modulation than work on global metabolism-derived damage and cellular senescence implies."

Link: http://dx.doi.org/10.1089/rej.2011.1301

The latest Rejuvenation Research journal issue is available online. Down a way in the contents list, there's one page commentary on gender that can be read in its entirety provided you're fine with small print:

Life span [will be] limited even in biologically immortal individuals. Death can still occur from causes other than aging such as accident, extrinsic disease, murder, suicide, etc. Due to these factors, the statistical probability of extending life by eliminating aging has been estimated to range from as little as 700 years to a few thousand. Because women tend to take fewer risks than men, estimates for their survival are double those for men. Some authors speculate that because of future developments in medicine and technology, the risk for death can be even more significantly reduced, making it possible to extend human life for as much as 50,000 years. This estimate is obviously the extreme, but for argument's sake let's say it may be possible for cautious, biologically immortal individuals living conservative lifestyles to survive for 10,000 years or so before succumbing to a deadly contagion or catastrophic accident.

Which initially suggests that a world of ageless individuals would be largely a world of women - though by the time agelessness is a going concern, I'd imagine that ad hoc gender transformation and selection will also be practical going concerns. Which is not to mention options beyond the traditional male or female duality, or elective alteration of mental traits such as appetite for risk, decoupling the mind from its biological influences. It's entertaining to take narrow slices of the future and ask how things would change is that one slice stood alone, but the future is a monolith - we'll get the potential for all of these outcomes of biotechnology at once, not one at a time.

From where I stand, the technology needed to reduce risk for a standard issue human far enough to enable 50,000 years of life free from fatal occurrences would have to be some fairly advanced stuff - or at least that is so if the individuals in question intend to live free-range and interesting lives. Safety devices and autonomous watchdogs guided by strong artificial intelligences with millisecond reaction times and long planning horizons spring to mind. That sort of thing will be emerging within a hundred years at the present rate of development, but alongside will come the opportunity to stop being a standard issue human - a fragile package of tissue. The most robust way to reduce risk with the foreseeable high technology of the century ahead seems to be, to me at least, to transform the body rather than strive to protect it.

Your risk of fatality for any given activity is a function of your human physiology. Once the research and development community has achieved the goal of practical biotechnologies for the repair and reversal of aging, that will give us all a few hundred years of life in comparative statistical safety. Technological progress will continue across that long period of time, and I can't imagine that much of the toolkit needed for the next step in long-term risk reduction will remain beyond the human civilizations of the 2200s. Your own personal preferences for that next step will no doubt vary, but I would get my neurons replaced - slowly, one at a time over time, to ensure continuity of the self - with some form of much more robust, easily maintained nanoscale machinery.

...

Physical distribution of the self across many disparate locations is in fact the key point when it comes to considering risk over the long term. Locations have much the same issues with time, probability and bad events as people do. Meteorites happen, as do landslides, earthquakes, war, and volcanoes. The way to reduce your location-based risk dramatically is to spread out. You might imagine a wireless brain, using whatever the most robust communications technology of the time happens to be, scattered in a thousand separate machine bodies or vehicles across a continent, or even the whole planet.

Here is an interesting application of guided tissue growth, that focuses on blood vessels. A wide range of work is under way on blood vessel engineering and control of growth, as the ability to incorporate blood vessels into tissue in specific ways is essential to realizing the most important goals of tissue engineering: "A team of engineers has created a bandage that in just one week not only encourages new blood vessel growth but helps guide that growth as well. ... The ability to pattern functional blood vessels at this scale in living tissue has not been demonstrated before. ... The team [calls] the bandage a 'microvascular stamp.' Unlike similar bandages developed to help spur blood vessel growth, the stamp contains living cells that encourage damaged tissue to grow according to the stamp's pattern. At nearly a centimeter across, the stamp is made of porous material that enables small molecules to sneak through in addition to the larger growth factors. The team tested it on a chicken embryo; when they removed it from the surface a week later, a network of new blood vessels appeared in the pattern of the stamp's channels. Future applications could include not only healing wounds, but also redirecting blood vessels to grow around blocked arteries, and even improving the delivery of cancer drugs by repairing blood vessels that feed cancerous cells."

Link: http://news.cnet.com/8301-27083_3-57346717-247/high-tech-bandage-spurs-blood-vessel-growth/

From the New Atlantis, a tour of some of the disturbing views of those who are opposed to enhanced longevity, and in favor of government force used to set limits to life: "Age-retardation technologies are the 'killer app' (so to speak) of enhancements - so deeply and self-evidently appealing that they would seem to sell the whole project of enhancement on their own. Nonetheless, there are those who oppose them. For example, Leon Kass, the former chairman of the President's Council on Bioethics (PCBE) under President Bush, has asserted, 'the finitude of human life is a blessing for every individual, whether he knows it or not.' And Daniel Callahan, co-founder of the Hastings Center, has declared, 'There is no known social good coming from the conquest of death.' Callahan added, 'The worst possible way to resolve [the question of life extension] is to leave it up to individual choice.' When asked if the government has a right to tell its citizens that they have to die, Johns Hopkins University political scientist Francis Fukuyama answered, 'Absolutely.' ... In addition to these concerns, Schaub suggests that 'a nation of ageless individuals could well produce a sclerotic society, petrified in its ways and views.' Daniel Callahan makes a similar argument in a debate with life-extension advocate Gregory Stock, in which he claims, 'I doubt that if you give most people longer lives, even in better health, they are going to find new opportunities and make new initiatives.' Stock goes so far as to help his interlocutor with the hoary example of brain-dead old professors blocking the progress of vibrant young researchers by holding onto tenure. But that seems more of a problem for medieval institutional holdovers like universities than for modern social institutions like corporations. ... In fact, the available evidence cuts against concerns about 'a hardening of the vital social pathways.' Social and technological innovation has been most rapid in those societies with the highest average life expectancies. Yale economist William D. Nordhaus estimates that increases in longevity in the West account for 40 percent of the growth in gross national product for the period 1975-1995. Why? Not only do people work longer, but they work smarter - long lives allow for the accumulation of human capital. ... We do not know what immortality would be like. But should that happy choice become available, we can still decide whether or not we want to enjoy it. Besides, even if the ultimate goal of this technological quest is immortality, what will be immediately available is only longevity. The experience of longer lives will give the human race an opportunity to see how it works out. If immortality is a problem, it is a correctable one. Death always remains an option. Let us turn on its head the notorious argument by Leon Kass that our initial repugnance to biotechnological advances should make us wary of them. Put the other way around, the near-universal human yearning for longer, healthier lives should serve as a preliminary warrant for pursuing age-retardation as a moral good."

Link: http://www.thenewatlantis.com/publications/the-case-for-enhancing-people

It is a truism that, in general, people who look ahead to the future both greatly overestimate predicted progress in the near term of twenty years or less and greatly underestimate predicted progress across longer timeframes. One might argue that this is due in part to most memorable predictions being made about industries and technologies in the early stages of an exponential curve - not much happens for many years as people experiment, persuade, bootstrap support and funding, and then a lot happens in a comparatively short period of time after someone hits the big time, gets it right, and the mainstream wakes up to the latest new new thing. But that's an oversimplification; there are many factors at work here, such as the many variants of hopeful but ultimately self-deluding optimism in the advocacy and technology development communities.

So it is a useful exercise to temper our own predictions of what lies ahead with a look back at earlier well-thought-out and detailed predictions of past progress, to see where they fell down. Here's an example via New Cryonet, written in 1987, and making a set of predictions that, in many cases, have yet to come to pass despite being fairly reasonable - we are not as far along as we'd like to be:

Fairly predictive tests for Alzheimer's disease, schizophrenia, depression, some malignancies, heart disease, and most of the rest of the major killers and disablers will probably be in place by 2000 to 2010. Many if not most of these ailments will be assessable in terms of a very sophisticated genetic risk profile which it will be possible to generate in infancy or childhood (or in utero).

...

Tissue rejection will be amenable to treatment in almost all cases by highly selective destruction or inhibition of certain parts of the immune system without the negative consequences of today's immunosuppressive drugs. Monoclonal and synthetic antibodies carrying toxins or regulatory molecules will be used to turn off or destroy the fraction of immune cells which initially respond and proliferate when a transplant is carried out. More widespread transplantation of tissues will be undertaken, including transplantation of limbs and scalp. Xenografts will be used increasingly in the mid to late 1990's and it will not be uncommon for people to have pancreatic tissue from bovine or porcine sources and perhaps hearts, lungs, and livers from other animals. Expect the first workable transplants to be from great apes (chimps, gorillas, orangutans), with porcine and bovine grafts coming later.

...

By the early decades of 2000, significant rejuvenation and geroprophylaxis of skin, bone, immune, and other "high turn- over" tissues will be possible as the natural regulatory molecules which control these systems are understood and applied. Expect several significant synthetic compounds to be discovered with these kinds of properties as well. There will be the possibility of profound improvement in personal appearance and general health as these agents enter the marketplace. By the early years of the 21st century the first generation of compounds effective at "rejuvenating" (i.e., restoring some degree of normal maintenance and repair to existing brain cells) the central nervous system will be available. These drugs will work by turning on protein synthesis and stimulating natural repair mechanisms.

Many of the specific predictions in the article were in fact demonstrated in the laboratory to some degree, and were technically feasible to develop as commercial products by the year 2000, and in some cases earlier but at much greater expense. Certainly there are partial hits for many of the predictions by 2010, in the sense of it being possible, somewhat demonstrated, or in the early stages of being shown to be a practical goal. Yet the regulatory environment in much of the developed world essentially rules out any form of adventurous, rapid, highly competitive development in clinical medicine - such as exists in the electrical engineering, computing, and other worlds. We are cursed therefore with the passage of many years between a new medical technology being demonstrated possible and then attempted in the marketplace ... if it ever makes it to the marketplace at all. This must change if we are to see significant progress.

A study here shows that calorie restriction reduces levels of mitochondrial damage that accumulates with age - that damage being thought of as a contributing cause of aging - but in different levels in different tissues and different species: "The hypothesis that life-span extension by caloric restriction (CR) is contingent upon the attenuation of macromolecular oxidative damage was tested in two different strains of mice: the C57BL/6, whose life span is extended by CR, and the DBA/2, in which CR has relatively minor or no impact on longevity. Mice were fed ad libitum (AL) or restricted to 40% lesser food, starting at 4 months of age. Protein damage was measured as protein-linked adducts of 4-hydroxy-2-nonenal (HNE) and malondialdehyde (MDA) in skeletal muscle mitochondria at 6 and 23 months of age. Protein-HNE and -MDA content increased with age in C57BL/6 mice and CR significantly attenuated these augmentations. ... DBA/2 mice exhibited little effect of age or CR on protein HNE/MDA content in skeletal muscle mitochondria. In contrast, protein-HNE levels in liver mitochondria showed a significant increase with age in AL-fed mice of both strains, and CR caused significant attenuation of this damage. Overall, results indicated that the age-related increase in protein oxidative damage and its abatement by CR are genotype- and tissue-specific, and not a universal phenomenon."

Link: http://www.ncbi.nlm.nih.gov/pubmed/22182424

An open access paper that suggests that producing therapies for the characteristic loss of muscle mass and strength with age - known as sarcopenia - may be more challenging than we'd like it to be: "Several age-related changes occur in skeletal muscle including a decrease in myofiber size and number and a diminished ability of satellite cells to activate and proliferate upon injury leading to impaired muscle remodeling. Although the molecular mechanisms underlying sarcopenia are unknown, it is tempting to hypothesize that interplay between biological and environmental factors cooperate in a positive feedback cycle contributing to the progression of sarcopenia. Indeed many essential biological mechanisms such as apoptosis and autophagy and critical signaling pathways involved in skeletal muscle homeostasis are altered during aging and have been linked to loss of muscle mass. Moreover, the environmental effects of the sedentary lifestyle of older people further promote and contribute the loss of muscle mass. There are currently no widely accepted therapeutic strategies to halt or reverse the progression of sarcopenia. Caloric restriction has been shown to be beneficial as a sarcopenia and aging antagonist. Such results have made the search for caloric restriction mimetics (CRM) a priority. However given the mechanisms of action, some of the currently investigated CRMs may not combat sarcopenia. Thus, sarcopenia may represent a unique phenotypic feature of aging that requires specific and individually tailored therapeutic strategies."

Link: http://impactaging.com/papers/v3/n12/full/100409.html

Politics, perceptions, and money: these are the guiding trinity of research at the grand scale, the source of determinants for the work of thousands of researchers and the rate and direction of progress in broad fields of medical science - or so says the author of this article on the state of longevity science:

It has been clear for many years that the rate of aging is malleable in diverse species, and the discovery in 2009 that a drug called rapamycin can extend maximum life span in mice suggested that it's now technically feasible to develop anti-aging agents that really work as advertised. Unfortunately, I see no commercial interest in doing so.

The focus here is the mainstream of research, aimed at slowing aging by metabolic manipulation. This, as you all know by now, is the slow boat to nowhere in my view. The only practical way ahead that seems plausible to produce meaningful rejuvenation of the old in our lifetimes is some variant of SENS, the Strategies for Engineered Neligible Senescence: focus on repair and reversal of damage, not on slowing down the rate at which damage accrues. Repair is no harder, and arguably an easier path, and the end result will be far more effective in terms of years gained and suffering quashed. But SENS and other repair strategies yet to emerge into a coherent research program are the minority view in the field, still working to attain recognition and funding - bear that in mind when you read about the hurdles that groups with far more credit in the scientific community are struggling with. It's a long way from here to where we need to be, and there are two battles yet to win: firstly to persuade the research community to adopt the better strategic direction that SENS represents, and secondly to persuade some fraction of the world that reversing aging through biotechnology can and should be achieved within a matter of a few decades.

But back to the article:

Prominent advisors to the National Institute on Aging, as well as some of its officials, are enthusiastic about anti-aging drugs' huge potential to improve public health. In fact, a few years ago the NIA's founding director, the late Robert N. Butler, joined three visionary gerontologists to urge that the federal government mount a major program to accelerate development of such medicines, including funding for clinical trials and the preclinical research needed to make them feasible.

But the idea of investing taxpayer dollars in such a program has proved a very hard sell. As gerontologist Richard A. Miller once put it, "A president who announces a war on cancer wins political points, but a president who publicly committed the government's resources to research on extending people's life span would be deemed certifiable."

Which gets us to the root problem: Few people - including policymakers and medical experts who advise them - appear to realize that the ability to brake aging is now within our grasp, and that even modestly effective anti-aging drugs promise the biggest gains in public health since the advent of vaccines and antibiotics nearly a century ago. Indeed, I suspect most people still regard aging as an inalterable part of the human condition - a view reinforced by the fact that pharmaceutical companies just say no to anti-aging drug development.

An important line item that the author omits is that Big Pharma - and a hundred biotech startups, if there were any justice in the world - don't engage in longevity science because the FDA will not approve therapies for aging, and indeed could not possibly ever approve therapies for aging under its present regulatory regime. There is no way to sell to the clinics in the US marketplace, so there is no potential profit for US-based developers, so there is next to no venture funding for development of promising longevity science. Politics, perceptions, and money - and it's the political and regulatory establishment that is the biggest roadblock here.

Systems biology is the natural evolution of the present mainstream research into metabolism, epigenetics, cellular mechanisms, and aging: tie it all together into one holistic view of how the body works and then fails with age. Here is an example of that sort of viewpoint, and how it reinforces conclusions such as the need to address cellular senescence: "The role of cellular senescence (CS) in age-related diseases (ARDs) is a quickly emerging topic in aging research. Our comprehensive data mining revealed over 250 genes tightly associated with CS. Using systems biology tools, we found that CS is closely interconnected with aging, longevity and ARDs, either by sharing common genes and regulators or by protein-protein interactions and eventually by common signaling pathways. The most enriched pathways across CS, ARDs and aging-associated conditions (oxidative stress and chronic inflammation) are growth-promoting pathways and the pathways responsible for cell-extracellular matrix interactions and stress response. Of note, the patterns of evolutionary conservation of CS and cancer genes showed a high degree of similarity, suggesting the co-evolution of these two phenomena. Moreover, cancer genes and microRNAs seem to stand at the crossroad between CS and ARDs. Our analysis also provides the basis for new predictions: the genes common to both cancer and other ARD(s) are highly likely candidates to be involved in CS and vice versa. Altogether, this study shows that there are multiple links between CS, aging, longevity and ARDs, suggesting a common molecular basis for all these conditions. Modulating CS may represent a potential pro-longevity and anti-ARDs therapeutic strategy."

Link: http://impactaging.com/papers/v3/n12/full/100413.html

An open access review paper: "Cell therapy has been established as an important field of research with considerable progress in the last years. At the same time, the progressive aging of the population has highlighted the importance of discovering therapeutic alternatives for diseases of high incidence and disability, such as stroke. Menstrual blood is a recently discovered source of stem cells with potential relevance for the treatment of stroke. Migration to the infarct site, modulation of the inflammatory reaction, secretion of neurotrophic factors, and possible differentiation warrant these cells as therapeutic tools. We here propose the use of autologous menstrual blood cells in the restorative treatment of the subacute phase of stroke. ... Menstrual blood cell injections are proposed [to] provide functional improvement and, therefore, decrease disability of the affected patients. Migration to the site of injury, immunomodulation, and secretion of neurotrophic factors are their main footholds as therapeutic agents. When compared to bone marrow-derived cells, menstrual blood cells present more immature phenotype and behavior, albeit maintaining the characteristic adult stem cell safety. Experimental studies have demonstrated benefits of menstrual blood cell administration, with tissue repair and functional improvement, not only in the central nervous system, but also in the heart and ischemic limbs."

Link: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3227246/

In the course of exploring mammalian biochemistry, researchers are turning up ways to somewhat enhance the performance and slow the progressive decline of the brain. If pushed through to human therapies, this would all be a matter of poor patches over damage - not addressing the underlying issues at all, which means the performance will be poor and the costs of development still high. But working towards slowing down aging and patching over the end consequences rather than addressing their roots is unfortunately the focus of modern medical science. It's just one of the many things that must change if we are to see significant progress towards engineered human longevity in our lifetimes.

So that said, here are a couple of items for you to look at today relating to ongoing research into the mechanisms of the brain. The first involved CREB1, which if you look back in the archives you'll see is associated with memory and important in calorie restriction - and here researchers are confirming its lynch-pin status in the mechanisms by which calorie restriction produces benefits, in the brain at least:

Eating less keeps the brain young:

A team of Italian researchers at the Catholic University of Sacred Heart in Rome have discovered that this molecule, called CREB1, is triggered by "caloric restriction" (low caloric diet) in the brain of mice. They found that CREB1 activates many genes linked to longevity and to the proper functioning of the brain. ... Many studies suggest that obesity is bad for our brain, slows it down, causes early brain aging, making it susceptible to diseases typical of older people as the Alzheimer's and Parkinson's. In contrast, caloric restriction keeps the brain young. Nevertheless, the precise molecular mechanism behind the positive effects of an hypocaloric diet on the brain remained unknown till now.

The Italian team discovered that CREB1 is the molecule activated by caloric restriction and that it mediates the beneficial effects of the diet on the brain by turning on another group of molecules linked to longevity, the "sirtuins". This finding is consistent with the fact that CREB1 is known to regulate important brain functions as memory, learning and anxiety control, and its activity is reduced or physiologically compromised by aging. Moreover, Italian researchers have discovered that the action of CREB1 can be dramatically increased by simply reducing caloric intake, and have shown that CREB is absolutely essential to make caloric restriction work on the brain. In fact, if mice lack CREB1 the benefits of caloric restriction on the brain (improving memory, etc.) disappear.

The second item touches on an new way of improving memory function in mice. You'll note that this is one of many uncovered in recent years, and there has been quite the boom in finding ways to improve the memory of mammals, and even restore the capacity for memory in old animals.

Neuroscientists boost memory using genetics and a new memory-enhancing drug:

The authors discovered that mice lacking PKR in the brain have a kind of "super" memory. "We found that when we genetically inhibit PKR, we increased the excitability of brain cells and enhanced learning and memory, in a variety of behavioral tests," he said. For instance, when the authors assessed spatial memory (the memory for people, places and events) through a test in which mice use visual cues for finding a hidden platform in a circular pool, they found that normal mice had to repeat the task multiple times over many days in order to remember the platform's location. By contrast, mice lacking PKR learned the task after only one training session.

...

Another key finding made by Costa-Mattioli and his team of researchers was the fact that this process could be mimicked by a PKR inhibitor - a small molecule that blocks PKR activity and thus acts as a "memory-enhancing drug."

"It is indeed quite amazing that we can also enhance both memory and brain activity with a drug that specifically targets PKR". Definitely then, the next step is to use what we have learned in mice and to try to improve brain function in people suffering from memory loss, said Costa-Mattioli.

A look at the role of chronic inflammation in Alzheimer's disease: "Even today, Alzheimer's is still a disease that is definitively diagnosed only after death and autopsy, when it is easy to recognize the disease's cardinal features: a shrunken brain with amyloid plaques dotted among neurons laden with neurofibrillary tangles, and often with inclusions similar to those found in the brains of patients who have died of Parkinson's. These irrefutable histological markers of Alzheimer's led to the logical conclusion by most researchers that plaques are the cause of the problem. Many pharmaceutical companies have taken vigorous aim at amyloid with no clear evidence so far that ridding the brain of plaques in Alzheimer's disease results in cognitive improvement. Lacking a smoking gun that definitively singles out the plaques as the causative agent, amyloid is the scientific equivalent of a culprit assumed guilty until proven innocent. ... Mounting evidence shows that inflammation plays a critical role in causing Alzheimer's disease. Over the last few decades we have gone from a situation where inflammation was generally believed to have no role in the disease to the current picture where chronic activation of IL-1 inflammation has been shown to account for many of the hallmarks of the disease. This review is a personal account of the quest to prove that inflammation plays a critical role in causing Alzheimer's disease."

Link: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3229272/

One part of longevity research is to screen as many as possible existing drugs on cells and lower animals to see what effect they have; it's a first step that may then lead on to finding epigenetic changes to replicate the effect, and then uncover the underlying mechanisms which may point towards novel longevity mutations. This is a long road - consider that researchers still don't fully understand calorie restriction, for example, never mind more recently discovered effects. Here is an open access paper that illustrates how this research process works. Note that the choice of compounds to check is steered by regulation rather than by scientific knowledge - not a good situation: "Screening a library of drugs with known safety profiles in humans yielded 30 drugs that reliably protected mammalian neurons against glucose toxicity. Subsequent screening demonstrated that 6 of these 30 drugs increase lifespan in C. elegans: caffeine, ciclopirox olamine, tannic acid, acetaminophen, bacitracin, and baicalein. Every drug significantly reduced the age-dependent acceleration of mortality rate. These protective effects were blocked by RNAi inhibition of cbp-1 in adults only, which also blocks protective effects of dietary restriction. Only 2 drugs, caffeine and tannic acid, exhibited a similar dependency on DAF-16. Caffeine, tannic acid, and bacitracin also reduced pathology in a transgenic model of proteotoxicity associated with Alzheimer's disease. These results further support a key role for glucose toxicity in driving age-related pathologies and for CBP-1 in protection against age-related pathologies. These results also provide novel lead compounds with known safety profiles in human for treatment of age-related diseases, including Alzheimer's disease and diabetic complications."

Link: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3218048/

Reactive oxygen species (ROS) are damaging molecules that can rip up important cellular machinery; all machinery in a cell is an arrangement of atoms, and promiscuously reactive molecules can gum up the works, pull out important parts of the machinery, and otherwise cause all sorts of issues. In discussions of our biology, the term free radical is often used interchangeably to refer to these reactive molecules. They are produced within our cells as a byproduct of some of the most important mechanisms of metabolism, a fact shared by the vast majority of species, dating back far into evolutionary time. As for all aspects of cellular chemistry with such deep origins, evolution has has a very long time indeed in which to build feedback loops and interlaced machinery that depend upon the existence of ROS, co-opting these molecules for diverse purposes in signaling and regulating the operation of cells and tissues.

Thus ROS generation and damage is not just a harmful side-effect of being alive and having cells that are churning away, but it is also fundamental to the complex processes by which our metabolism maintains cellular homeostasis in the face of day to day challenges. Here are a couple of open access papers that summarize what is known about the more important roles of ROS in the body - in the first paper, section 6 is where you'll find the focus on aging, while the second paper looks at the intersection of muscle, ROS, and exercise.

Mitochondria-Ros Crosstalk in the Control of Cell Death and Aging

ROS are a normal side product of the respiration process, and they react with lipids, protein, and DNA, generating oxidative damage. Indeed, mitochondria are the major site of ROS production, but also the major targets of their detrimental effects, representing the trigger for several mitochondrial dysfunctions. In this review, we will focus on this deadly liaison, with particular attention on ROS production, mitochondrial ROS targets, and their role in apoptosis, autophagy, and aging. ... At physiological levels, ROS function as 'redox messengers' in intracellular signalling and regulation, whereas excess ROS induce cell death by promoting the intrinsic apoptotic pathway. Recent work has pointed to a further role of ROS in activation of autophagy and their importance in the regulation of aging. This review will focus on mitochondria as producers and targets of ROS and will summarize different proteins that modulate the redox state of the cell. Moreover, the involvement of ROS and mitochondria in different molecular pathways controlling lifespan will be reported, pointing out the role of ROS as a 'balance of power,' directing the cell towards life or death.

...

The decline associated with aging is caused by the accumulation of ROS, as supported by cellular and biological data from different model systems and organisms. Indeed defects in antioxidant defense mechanisms fail to protect against oxidative damage, reducing lifespan and causing cardiomyopathy, neurodegeneration, and cancer. ... The relationship between mitochondria dysfunctions observed during aging and ROS production is still debated. However, it is clear that the decline of the integrity of mitochondria as a function of age is implicated in aging and age-related diseases.
Given this wide scientific evidence, many studies were aimed to identify the molecular mechanisms responsible for ROS deleterious effects on the aging process.

Reactive Oxygen Species in Skeletal Muscle Signaling

Up to the 1990s of the past century, ROS have been solely considered as toxic species resulting in oxidative stress, pathogenesis and aging. However, there is now clear evidence that ROS are not merely toxic species but also - within certain concentrations - useful signaling molecules regulating physiological processes. During intense skeletal muscle contractile activity myotubes' mitochondria generate high ROS flows: this renders skeletal muscle a tissue where ROS hold a particular relevance. According to their hormetic nature, in muscles ROS may trigger different signaling pathways leading to diverging responses, from adaptation to cell death.

...

As an example, many studies have concluded that inactivity-induced ROS production in skeletal muscle contributes to disuse muscle atrophy. On the contrary, growing evidence also suggests that intracellular ROS production is a required signal for the normal remodelling that occurs in skeletal muscle in response to repeated bouts of endurance exercise. How can the same trigger promote such opposite effects? Based upon current knowledge, it appears that the mode and the situation characterizing skeletal muscle cells exposure to ROS may account, at least in part, for this apparent paradox. Transiently increased, moderate levels of oxidative stress might represent a potentially health-promoting process, whereas its uncontrolled persistence and/or propagation might result in overwhelming cell damage thus turning into a pathological event: for instance, the role of ROS in inflammation fits well with this model.

...

Supplementation with exogenous antioxidants is being widely studied to attain and maintain an 'ideal titration' of ROS within skeletal muscle: unfortunately, at the present, no clear indication of the benefits arising from supplemental antioxidant intake emerges from literature.

The evolution of knowledge regarding ROS in human metabolism, and the parallel evolution of the market for dietary antioxidant supplements, should be taken as a cautionary tale. Metabolism is complicated, and trying to alter its operation through the use of such blunt tools is probably not the most efficient way to use science to extend human life.

One of the ways in which general health practices - such as exercise and fitness - steer cognitive health is through the state of the blood vessels in your brain: if they are deteriorating more rapidly, then more microinfarcts will occur, destroying more of the function of the brain, one tiny piece at a time. This is a mechanism quite distinct from the root causes of dementias like Alzheimer's disease, as this study illustrates: "This study was untaken to investigate the association of micro brain infarcts (MBIs) with antemortem global cognitive function (CF). ... Subjects were 436 well-characterized male decedents from the Honolulu Asia Aging Autopsy Study. Brain pathology was ascertained with standardized methods, CF was measured by the Cognitive Abilities Screening Instrument, and data were analyzed using formal mediation analyses, adjusted for age at death, time between last CF measure and death, education, and head size. Based on antemortem diagnoses, demented and nondemented subjects were examined together and separately. ... In those with no dementia, MBIs were strongly associated with the last antemortem CF score ... This suggests that microinfarct pathology is a significant and independent factor contributing to brain atrophy and cognitive impairment, particularly before dementia is clinically evident. The role of vascular damage as initiator, stimulator, or additive contributor to neurodegeneration may differ depending on when in the trajectory toward dementia the lesions develop."

Link: http://www.ncbi.nlm.nih.gov/pubmed/22162060

Opposition to enhanced human longevity, which often advocates collectivism and the use of government force to prevent other people from extending their lives through biotechnology, is based on a range of factors: fear of change, the green-eyed monster of envy (who has set up shop in the environmentalist movement these days), and ignorance of basic economics. In the latter case, some folk naively believe all resources to be limited - jobs, wealth, and so forth - rather than growing with population and length of life. But all of these things are made by people, and the more people there are and the longer those people live in good health, the more creation will take place. But there are always naysayers who have convinced themselves that a hundred thousand deaths due to aging every day and the ongoing suffering of hundreds of millions is necessary because of their own vague and unrealized anxieties about the future. Here is one example: "Wolpe's own perspective is that our drive toward immortality is basically selfish. He sees few benefits to society, and a good deal of potential harm, in our living to 200 or beyond. ... There is a natural wisdom in replacing us. There's a natural wisdom in the idea that new people who arise in new circumstances have new perspectives on the world. ... Look at the generations living now from the World War II generation to the Baby Boomers, to Gen-X, all the way down. The young generation today, the people in their teens and 20's today were steeped in a different brine than I was as a Baby Boomer. They were brought up with technology at their fingertips. They move naturally and easily through that world. And the idea that if I got to live to, you know, 150 or 200, that that would be a good thing for anyone other than me, I think is a misguided notion. And there's a deep selfishness in the move towards immortality and these people like Aubrey de Grey and others who are really looking for that Fountain of Youth. ... If we don't change, for example, reproduction, if reproduction stayed between let's say, 20 and 40, that means that you would have another 80 years after reproducing that you'd be around. So there's even the question of how we're going to restructure the human lifespan. Is that a proper dynamic to have your children and then live another hundred years?" As usual, this is airy nonsense when held up against the reality of the vast and pervasive suffering caused by aging - suffering that we can work to address instead of just waffling about intangibles.

Link: http://bigthink.com/ideas/41527?page=all

Below you'll see optimism on the topic of longevity and the future, personal and otherwise, from the establishment political press, which is an unusual enough event to be worthy of remark. These are well-written general interest articles that don't look far beyond a high level overview of economics and exercise, so your mileage may vary - they don't touch on any of the more earnest scientific work on aging and rejuvenation such as SENS, for example. But take a look and see what you think:

Longevity: a Manual

"Genes account for one-fourth to one-third of longevity," estimated Howard Friedman, a professor of psychology at the University of California (Riverside) and the coauthor of The Longevity Project, published this year. "That leaves well over half not accounted for."

Most of the rest, for better or worse, is up to you. "The importance of choices people make is in so many ways responsible for the quality of life in old age," said Charles Reynolds III, a professor of geriatric psychiatry, neurology, and neuroscience at the University of Pittsburgh medical school. "Many people think they should be entitled to a good-quality 25 years after age 60. Well, they're not necessarily entitled, but they can put the odds in their favor."

One way - "the least speculative and the most obvious" - is with exercise, according to Simon Melov, a Buck Institute biochemist. "More activity is better than no activity, and most people are not doing anything. They're just sitting there." Exercise, he said, reduces the risk of cardiovascular disease and perhaps even a decline in cognition. One needn't run a marathon. Gardening, walking, swimming, woodworking - all of these are more active than just sitting.

No, Malthus, No: Living Longer Is a Blessing, Not a Curse

Long life may well be a blessing for the individual. But is it also a blessing for society? The fashionable answer is an increasingly anxious no. Choose your apocalyptic metaphor. The aging of America represents a "financial time bomb," The New York Times has proclaimed - with the solvency of Social Security, Medicare, and Medicaid (the last in line for nursing-home payments for patients who have depleted their assets) all at risk. Foreign Policy magazine has warned that a "gray tsunami is sweeping the planet," the United States included.

And yet the forecast that Americans' increased longevity is a collective downer for the nation ain't necessarily so. The fiscal threat, while real, provides too narrow a prism for understanding a question so complex. History suggests that the size of the total economic pie tends to grow larger as life expectancy rises. From 1950 to 2010, Americans' life expectancy at birth grew by 15 percent and, at age 65, by more than 30 percent - even as household incomes and the gross domestic product increased sixfold.

So, as counterintuitive as this may sound, it is possible, even likely - listen up, worrywarts! - for Americans to live longer and grow richer.

In fact the weight of evidence points strongly towards longevity and wealth moving hand in hand, influencing one another. People with longer time horizons make better decisions for the stewardship of resources, while at the same time increasing wealth means better medicine - more research, improved medicine, greater ability to purchase medical services, and so forth. See these items from the Fight Aging! archives, for example:

• Wealth and Longevity
• Longevity Tends to Change Economic Behavior for the Better
• What is Wealth?
• A Visualization of Wealth and Heath Over Time

Arguing against this view on the basis of the evidence is actually a pretty steep cliff to climb (not that that seems to stop the naysayers). Empires fall and regions become poor for all sorts of reasons, and the US is on the way to a sad end itself, but increasing life expectancy and growth in wealth are not amongst the causes.

A progressive build up of advanced glycation end products (AGEs) is implicated in the aging process; they contribute to skin aging, for example. There are some research programs aimed at producing drugs or other treatments to break down the important AGEs in humans, but far too few of them, and poorly funded. Here, researchers look at AGEs in a mole rat species: "Mole-rat of the genus Fukomys are mammals whose life span is strongly influenced by reproductive status with breeders far outliving nonbreeders. This raises the important question of whether increased longevity of the breeders is reflected in atypical expression of biochemical markers of aging. Here, we measured markers of glycation and advanced glycation end-products formed in insoluble skin collagen of Ansell's mole-rat Fukomys anselli as a function of age and breeding status. Glucosepane, pentosidine, and total advanced glycation end-product content significantly increased with age after correction for breeder status and sex. Unexpectedly, total advanced glycation end-products, glucosepane, and carboxymethyl-lysine (CML) were significantly higher in breeders versus nonbreeders suggesting that breeders have evolved powerful defenses against combined oxidant and carbonyl stress compared with nonbreeders. Most interestingly, when compared with other mammals, pentosidine formation rate was lower in mole-rat compared with other short-lived rodents confirming previous observations of an inverse relationship between longevity and pentosidine formation rates in skin collagen."

Link: http://www.ncbi.nlm.nih.gov/pubmed/22156473

Correlations between character traits and longevity seem to be a growing area of study; interesting results, though of dubious importance, I think: "The relationship between personality and life span is not well understood, and no study to date has examined genetic influences underlying this relationship. The present study aimed to explore the phenotypic and genetic relationship between personality and life span, as well as genetic influences on all-cause mortality. ... Prospective community-based study including 3752 twin individuals older than 50 years. Neuroticism, psychoticism, extraversion, and social desirability and pessimism/optimism were measured at baseline using the Revised Eysenck Personality Questionnaire and the Revised Life Orientation Test, respectively. Information on age at death was obtained 16 years after the initial assessment of personality. ... Extraversion was inversely related to mortality with the risk of death decreasing 3% per unit increase of the extraversion score. Psychoticism and pessimism were positively related to mortality with a 36% and 39% increase in risk of death per unit increase in the respective personality score. Heritability of life span was 7%. ... Extraversion, psychoticism, and optimism/pessimism are significant predictors of longevity; extraversion is associated with a reduction, and pessimism and psychoticism are associated with an increase in mortality risk. Genetic influences on longevity in Australian twins are very low (7%). Our data also suggest a small, albeit nonsignificant, genetic influence on the relationship of pessimism and psychoticism with life span."

Link: http://www.ncbi.nlm.nih.gov/pubmed/22155943

I noticed an easy read of an open access position paper today that asks whether the common wisdom regarding the prevalence of age-related disease today is an open and shut case. Can we definitively say that, in comparison to our ancestors, we are not just living longer and are generally far wealthier, but are also suffering higher rates of cancer, cardiovascular disease, diabetes, and other chronic diseases suffered at the end of life? The general consensus as presented by the media and onlookers is that yes, it's an epidemic - really a terrible misuse of the word, since these age-related conditions are not infectious in nature - and there you have it. But here's a counterpoint:

Over the last 110 years, average global life expectancy has more than doubled from 31 years of age to 65 years of age. This trend is expected to continue, and many of the children born after the year 2000 can expect to live to celebrate their hundredth birthday. In the last 20 years alone, average life expectancy has increased globally by 6 years.

During the same period, doctors have announced a global epidemic of the most common killers: cardiovascular disease, diabetes, chronic kidney, and chronic obstructive pulmonary disease. One of the most important reasons for the more frequent recognition of these diseases is the fact that their diagnostic criteria have changed and become much more acute during the past few years.

These changes in diagnostic criteria have made it difficult, or even impossible, to compare the present statistical data regarding these diseases to historical data for the same illnesses. Due to this difficulty, there is no evidence-based comparison of the prevalence of any disease at present and in the past. Before announcing a global epidemic, a fair epidemiological comparison should be made, based upon the same definitions and using identical diagnostic tools.

In essence this is an argument based on the challenge of distinguishing between the consequences of longevity upon risk and levels of age-related disease and the effects of increasing wealth and improved medical technologies upon diagnosis rates. If you have more money and better medicine, you are more likely to be diagnosed, treated, and entered into the records than otherwise. Following this argument to its conclusion suggests that the effects of increasing wealth and longevity on disease rates are in fact lower than the raw data would imply, and that this effect will always be present in an age of improving technology and increasing wealth.

Via EurekAlert!: [Researchers] have developed a jelly-like material and wound treatment method that, in early experiments on skin damaged by severe burns, appeared to regenerate healthy, scar-free tissue. ... the researchers reported their promising results from mouse tissue tests. The new treatment has not yet been tested on human patients. But the researchers say the procedure, which promotes the formation of new blood vessels and skin, including hair follicles, could lead to greatly improved healing ... the hydrogel is constructed in such a way that it allows tissue regeneration and blood vessel formation to occur very quickly. ... Inflammatory cells are able to easily penetrate and degrade the hydrogel, enabling blood vessels to fill in and support wound healing and the growth of new tissue ... For burns, the faster this process occurs, [the] less there is a chance for scarring. Originally, [the] team intended to load the gel with stem cells and infuse it with growth factors to trigger and direct the tissue development. Instead, they tested the gel alone [and] were surprised to see such complete regeneration in the absence of any added biological signals. ... The hydrogel is mainly made of water with dissolved dextran, a polysaccharide (sugar molecule chains). ... It also could be that the physical structure of the hydrogel guides the repair .. [Researchers speculate] that the hydrogel may recruit circulating bone marrow stem cells in the bloodstream. ... It's possible the gel is somehow signaling the stem cells to become new skin and blood vessels."

Link: http://www.eurekalert.org/pub_releases/2011-12/jhu-itb121311.php

The use of nanoparticles to precisely deliver compounds to cells and specific locations within cells has a far broader application than just cancer therapies. Any existing drug that can be targeted this way can be made far more effective: provided in much smaller doses and with greatly reduced side-effects. For example: "Hitching a ride into the retina on nanoparticles called dendrimers offers a new way to treat age-related macular degeneration and retinitis pigmentosa. A study [shows] that steroids attached to the dendrimers target the damage-causing cells associated with neuroinflammation, leaving the rest of the eye unaffected and preserving vision. ... There is no cure for these diseases. An effective treatment could offer hope to hundreds of millions of patients worldwide. ... [Researchers] tested the dendrimer delivery system in rats that develop neuroinflammation. The target was microglial cells, inflammatory cells in charge of cleaning up dead and dying material in the eye ... When activated as 'trash collectors,' the cells cause damage via neuroinflammation - a hallmark of each disease. The microglial cells gobble up the dendrimers, and the drug then shuts down the cells' activity. ... Surprisingly, the activated microglia in the degenerating retina appeared to eat the dendrimer selectively, and retain them for at least a month. The drug is released from the dendrimer in a sustained fashion inside these cells, offering targeted neuroprotection to the retina. ... The treatment reduced neuroinflammation in the rat model and protected vision by preventing injury to photoreceptors in the retina. Though the steroid offers only temporary protection, the treatment as a whole provides sustained relief from neuroinflammation."

Link: http://www.eurekalert.org/pub_releases/2011-12/mc-nhm121311.php

Parkinson's researchers were among the first to earnestly attempt to create a specific cell type for transplant, and have continued to work at this. The obvious symptoms of Parkinson's are caused by the progressive loss of a thin population of dopamine-producing neurons, and therefore a way of replacing those specialist cells wholesale would be a way to temporarily reverse the course of the disease - perhaps for years or even decades in the best case. Thus these researchers now make up one of the more experienced scientific communities involved in cell therapy research, and can be counted on to rapidly pick up promising new developments in the control and reprogramming of cells. In past years, the focus has been on producing cells for transplant:

• Dopamine Neurons From iPS Cells
• Creating Dopamine Neurons via Transdifferentiation
• Stem Cells Reverse Parkinson's in Rats

Once researchers have demonstrated control over cellular reprogramming, the ability to turn one cell type into another by providing suitable signals, the focus starts to shift away from transplants and on to reprogramming cells in situ: instructing the body - or the brain in this case - to directly produce more of the needed cell type. Here's an example for Parkinson's disease (PD):

In the first step towards a direct cell replacement therapy for Parkinson's, the team reprogrammed astrocytes to dopaminergic neurons using three transcription factors - ASCL1, LMX1B, and NURR1 - delivered with a lentiviral vector. The process is efficient, with about 18 percent of cells expressing markers of dopaminergic neurons after two weeks. The next closest conversion efficiency is approximately 9 percent, which was reported in another study. The dopamine-producing neurons derived from astrocytes showed gene expression patterns and electrophysiolgical properties of midbrain dopaminergic neurons, and released dopamine when their cell membranes were depolarized.

The Penn team is now working to see if the same reprogramming process that converts astrocytes to dopamine-producing neurons in a dish can also work within a living brain - experiments will soon be underway using gene therapy vectors to deliver the reprogramming factors directly to astrocytes in a monkey model of PD.

I'll go out on a limb and suggest that transplants are probably not the be-all and end end-all future of tissue engineering. By the time the 2020s roll around, I'd guess that most of the new therapies moving into US trials and clinical use overseas will be based on delivering increasingly precise and targeted reprogramming instructions into the body rather than introducing new cells or taking the patient's cells and working with them outside the body to produce tissue for transplantation.

Clinical studies in which tissue is grown from a patient's own cells and then implanted to address a medical issue are no longer remarkable; many are currently taking place, with new studies starting all the time. A surprising number of these are focused on pediatric medicine, but the technologies have the prospect of much broader application. Here is an example: "Xeltis, a biomedical technology company developing growing, living and self-healing cardiovascular implants using tissue-engineering technology, has announced conditional approval by the Paul Erlich Institute (PEI) in Germany to commence the first clinical study of its tissue-engineered cardiovascular grafts. The prospective, single-center study will evaluate the safety and efficacy of Xeltis' autologous tissue-engineered vascular grafts in pediatric patients ... Due to their expected longevity, ability to grow and very low risk of thrombosis and infection, these new grafts hold the promise to deliver life-saving therapy for children born with cardiovascular defects. ... Today's grafts are made of artificial material or of animal tissue, both having significant limitations such as potential rejection, limited durability and calcification over time. In contrast, Xeltis implants are 'regrown' from the patients' own cells. The resulting implants are, therefore, designed to behave like native organs, with unlimited durability, no risk of rejection and no need for anticoagulants. In addition, children implanted with today's grafts face the critical problem of outgrowing their implants, requiring them to undergo one or more reoperations, each with an increasing rate of morbidity. Because Xeltis' implants have the ability to grow as the child grows, they may remove the need for reoperations."

Link: http://www.marketwatch.com/story/xeltis-announces-approval-to-begin-first-clinical-study-of-its-tissue-engineered-vascular-grafts-2011-12-06

Via EurekAlert!: researcher have "developed a new method to design antibodies aimed at combating disease. The surprisingly simple process was used to make antibodies that neutralize the harmful protein particles that lead to Alzheimer's disease. ... Antibodies are large proteins produced by the immune system to combat infection and disease. ... Scientists have long sought methods for designing antibodies to combat specific ailments. However, the incredible complexity of designing antibodies that only attached to a target molecule of interest has prevented scientists from realizing this ambitious goal. When trying to design an antibody, the arrangement and sequence of the antibody loops is of utmost importance. Only a very specific combination of antibody loops will bind to and neutralize each target. ... The new antibody design process was used to create antibodies that target a devastating molecule in the body: the Alzheimer's protein. ... We are actually exploiting the same protein interactions that cause the disease in the brain to mediate binding of antibodies to toxic Alzheimer's protein particles ... Alzheimer's disease is due to a specific protein - the Alzheimer's protein - sticking together to form protein particles. These particles then damage the normal, healthy functions of the brain. The formation of similar toxic protein particles is central to diseases such as Parkinson's and mad cow disease. Importantly, the new Alzheimer's antibodies [only] latched on to the harmful clumped proteins and not the harmless monomers or single peptides that are not associated with disease. [Researchers] see the potential for their technique being used to target and better understand similar types of protein particles in disorders such as Parkinson's disease.

Link: http://www.eurekalert.org/pub_releases/2011-12/rpi-rda120911.php

Antioxidants that take the form of pills you buy at the store do nothing beneficial for you, and may even be gently harmful to your long term health. So says the greater weight of evidence, and so the craze for antioxidants begins to look like the present decade's salutary example of magical thinking at work - just because things happen in cell cultures when a given compound is introduced doesn't mean the same thing will happen when you eat that compound. A cell culture and your biochemistry are two very different things.

But wait, you might say, isn't oxidative stress of central importance in aging? All those oxidative, reactive compounds flying around the insides of cells damaging critical things - such as those produced by mitochondria, thought to be an important contribution to aging? Well, sure, but that still doesn't mean that eating things that happen to react in a given way with oxidants in a test tube will do any good.

The body and its cells are a vast city of many roads, a complex system that acts to steer all incoming chemicals into narrow, specific paths. The research of recent years suggests that ingested antioxidants from the store really don't do much because they will never end up face to face with the oxidative compounds that matter, or in the places that matter. This, at least, is the supposition because researchers have demonstrated ways to push antioxidants to where they do matter, and have extended life in mice by doing this. The place that matters is the mitochondria, source of oxidative compounds, and there are two approaches here: firstly, genetic engineering to increase the levels of natural antioxidants such as catalase in the mitochondria, and secondly to carefully construct chemicals that the body will delivery to the mitochondria even if they are ingested.

This latter approach is seeing more interest of late, and a number of different research groups are working on designing and testing mitochondrially targeted antioxidants in rodents. Here is the latest research report from the Russian group led by Vladimir Skulchev:

The effect of the mitochondria-targeted, plastoquinone-containing antioxidant SkQ1 on the lifespan of outbred mice and of three strains of inbred mice was studied. ... For comparison, we also studied mole-voles and dwarf hamsters, two wild species of small rodents kept under simulated natural conditions.

...

SkQ1 prevented age-dependent disappearance of estrous cycles of outbred mice, [while] male BALB/c mice had shorter lifespan than females, and SkQ1 increased their lifespan to the values of the females. In the females, SkQ1 retarded development of such trait of aging as heart mass increase. Male C57Bl/6 mice [lived] as long as females. SkQ1 increased the male lifespan, the longevity of the females being unchanged. SkQ1 did not change food intake by these mice. Dwarf hamsters and mole-voles kept in outdoor cages or under simulated natural conditions lived longer if treated with SkQ1.

The effect of SkQ1 on longevity of females is assumed to mainly be due to retardation of the age-linked decline of the immune system.

For those who are interested, one of the works in slow progress over at Open Cures is a protocol for the laboratory production of SkQ1:

The present protocol is based mainly on the supplementary material provided in a paper by (Antonenko et al, 2008) in which the authors successfully synthesized and used SkQ1 in animal experiments.

In general, the effects of mitochondrially targeted antioxidants of this type on longevity start to look as through they're in the same rough vicinity of everything else that manipulates mitochondrial operation or metabolism in mice - so rather than focusing on this as something to be chased, I think it makes more sense to see this research as a confirmation of the importance of mitochondria in aging. We should be forging ahead far more aggressively on the ways and means to repair mitochondrial damage or otherwise make it irrelevant.

A couple of videos on economics and engineered longevity, by G. Stolyarov II and Aubrey de Grey: "Mr. Stolyarov discusses how indefinite human life extension will bring about numerous economic benefits to human beings and human civilization. He approaches the subject from the standpoint of the idea of time preference and the time horizons that would be greatly expanded for humans who live much longer. Furthermore, indefinite human longevity will enable humans to confront major existential threats - such as the threat of a meteor impact or a new ice age - that are beyond the timeframe of the individual lifespan today. ... Radical life extension would have a huge impact on the economics of society - possibly a dangerous one. Aubrey de Grey explains why he remains optimistic that the economy would adapt well to the drastically new paradigm presented by human immortality." Sadly, there's always someone out there who thinks that extended healthy human life is dangerous, despite the evidence of past centuries and many regions of the world that show greater life expectancy walks hand in hand with economic growth and higher standards of living. This is one of the reasons that advocacy for longevity science is even necessary in the first place. Nonetheless, the two upward trends of longevity and wealth are entwined and drive one another wherever they can start. But despite living in an age of change, so very many people fear change to the point of rejecting it even when it is overwhelmingly positive.

Link: http://www.skepticaleye.com/2011/12/economics-of-immortality.html

You might recall that researchers are making efforts to correlate psychological states, such as character traits and stress, with aging and the biochemistry of aging. Here is another item from that side of the field: researchers "have now shown that sirtuins likely also play a key role in the psychological response to dietary restriction. When sirtuins are elevated in the brain, as occurs when food intake is cut, mice become much more anxious. Furthermore, in two large genetic studies of humans, the team found that mutations that boost production of sirtuins are commonly associated with higher rates of anxiety and panic disorder. The researchers believe that this anxiety may be an evolutionary adaption that makes animals - including humans - more cautious under the stressful condition of having to forage more widely for scarce food. ... It makes sense, because behavior effects would be as adaptive, and as selected by evolution, as physiological effects. I don't think it's surprising that behavior really falls under the umbrella of natural selection." Of course there is uncertainty over whether sirtuins are actually important as drivers of the enhanced longevity produced by calorie restriction.

Link: http://web.mit.edu/newsoffice/2011/anxiety-sirtuins-1209.html

I had been meaning to point out video of Cynthia Kenyon's TEDGlobal presentation recorded earlier this year and posted online last month:

Kenyon, as you might know, leads the Kenyon Lab at UCSF, and was one of the first to demonstrate meaningful life extension in lower animals through single gene mutations back in the 1990s. We've come a long way since then, even if progress towards longevity-enhancing biotechnology and growth in public acceptance of that goal seems painfully slow while you're living through it a day at a time. As Maria Konovalenko of the Science for Life Extension Foundation points out, it is sometimes encouraging to read the public comments on a presentation like this one and see a great many generally positive opinions expressed:

The more TED Talks about ways to intervene in aging processes we have, the faster people all around the world would understand the feasibility of life extension therapies. By the way, I was glad to see that there are quite a lot of folks, advocating for longevity in the comments discussion about the video. I think this is another sign of TED audience becoming more and more educated and open-minded in regard to the idea of radical life extension. I would like to address the TED events organizers and ask them to do more talks on the topic of aging.

A viewpoint from Vladimir Skulachev, whose research group works on mitochondrially targeted antioxidant compounds: "'It is recognized that in exceptional circumstances the possibility exists for selection to favor limiting survival. In acknowledging that at least in theory, aging might occasionally be adaptive, however, the high barriers to validating actual instances of adaptive ageing are made clear' ... A few years ago it was hardly possible to find the latter statement in an article written by the most famous proponents of non-programmed aging. Certainly, this conclusion is accompanied by some reservations. Nevertheless, the balance between concepts of programmed and non-programmed aging seems to be really shifted to the programmed one. ... The idea that programmed death was invented by biological evolution was introduced in the end of nineteenth century by August Weismann, who suggested that such a death is useful for evolution as a mechanism which (i) purifies the population from weak individuals and (ii) promotes succession of generations. For sure, both these roles may be inherent in aging. However, they failed to explain why aging represents slow and concerted decline of many physiological functions (slow phenoptosis) rather than simple fast switching off of a single function of vital importance (acute phenoptosis). ... There is, it must be acknowledged, an instinctive attraction to the idea that aging is programmed. Aging is widespread across species and applies universally to all individuals within a species in which it is observed. There is also reproducibility about changes that occur with aging .... I may only add that, if aging is programmed, it can be retarded, prevented, and perhaps even reversed by treatments interrupting execution of this program, just as we already can interrupt programs of cell death. In other words, programmed aging can be cured like a disease. As for the concept of non-programmed aging, assuming occasional accumulation of stochastic injuries as its reason, it is quite pessimistic for finding any way of successful treatment. Here we simply observe and describe such a process without the possibility of improving the situation." This last viewpoint is exactly the wrong way around - repair of damage is likely to be far easier through SENS and similar programs than safely altering the exceedingly complex systems of metabolism to change the way in which aging happens. We should hope that genetic programs are of limited and narrow influence as a driver of aging - that they are merely reactions to underlying accumulations of damage where they exist at all. Because otherwise we're in for a long, slow road when it comes to extending healthy life.

Link: http://impactaging.com/papers/v3/n11/full/100403.html

A commentary on recent research into the effects of rapamycin on longevity: "Aging is a complex process associated with accumulation of damage, loss of function and increased vulnerability to disease, leading ultimately to death. Despite the complicated etiology of aging, an important discovery of recent years has been that simple genetic alterations can cause a substantial increase in healthy lifespan in laboratory model organisms. Many of these longevity-extending mutations down-regulate the activity of the mTOR/S6K pathway suggesting that reduced Tor/S6K signaling promotes entry into alternative phases normally entered during periods of starvation. In fact, dietary restriction (DR), a reduction in food intake without malnutrition, lowers Tor/S6K signaling and extends the average and maximum life span of a variety of organisms including yeast, flies, worms, fish, and rodents. ... Recently, it has been demonstrated that supplementation with rapamycin (an inhibitor of mTOR) started both at 9 and 20 months of life determines a small but significant extension of average and maximal life span in genetically heterogeneous male and female mice ... More studies are needed to understand benefits and side-effects of rapamycin supplementation in different strains of mice and in monkeys as a candidate cancer-preventive and life-extension pharmacological agent. However, the efficacy of intermittent rapamycin treatment in cancer prevention and life span extension [is] very promising since it is likely to reduce the side effects associated with chronic treatment."

Link: http://impactaging.com/papers/v3/n11/full/100401.html

In addition to funding and coordinating research into rejuvenation biotechnology, the SENS Foundation runs an Academic Initiative program that aims to pull more people into the field at an early stage in their life science careers. We must all bear in mind that turning the vision of ways to repair the biological damage of aging into the reality of suitable therapies will be the work of several decades in the best of circumstances. We have a very clear vision of the path ahead and what needs to be done in detail to repair an old human or prevent a young human from becoming old - but it will still require decades to achieve the end goal. The fastest plausible path to this future starts with a crash program that burns $1 billion in ten years to achieve rejuvenation in mice, but the research community is far from being able to deploy even a fraction of that level of resources and determination. Work proceeds slowly and there is a lot of work to do.

Given that we are looking at 20 to 30 years passing between now and widespread first generation methods of limited age-reversal, it is important to put effort towards ensuring that there will be a growing, enthusiastic research community in the years ahead. Hence the Academic Initiative: building connections, guiding younger life scientists, and encouraging the best to work on the defeat of degenerative aging. In this vein, I see that the SENS Foundation is making a small number of grants for 2012 as a part of the Academic Initiative. Young and interested life scientists in the audience might want to take note:

The SENS Foundation Academic Initiative is pleased to announce that it will be awarding up to $30,000 in materials grants in 2012. These grants are available to undergraduate, graduate, and medical students, and may be used to cover the cost of laboratory materials for aging- and rejuvenation-related research projects. A typical grant will range from $500-$2000, but grants of up to $5000 may be awarded for group projects. These grants are meant to provide students with valuable experience in research and leadership, and to help set recipients on the course to a career in SENS-related research. As such, simple and straightforward "introductory-level" projects will receive full consideration.

The grant application can be found here. You can apply at any time. There may be a high level of competition, so students are encouraged to apply soon.

As the SENS Foundation grows in budget, so too will these long term payoff activities. The primary hurdles within the scientific community that stand in the way of progress towards enhanced human longevity and the reversal of aging are (a) lack of funding, and (b) lack of researchers who are interesting and enthused. Both of these points need fixing, and in both cases that's the long bootstrapped road of incremental progress.

In the next few years were going to see a lot of technology demonstrations in which one very narrow biochemical aspect of aging is reversed in laboratory animals - these are the first few pebbles in what will become an avalanche of rejuvenation biotechnology. You might recall the reversal of lysosomal functional decline in the livers of mice in 2008 as an example of the type. Here is one for the brain: "Drugs that affect the levels of an important brain protein involved in learning and memory reverse cellular changes in the brain seen during aging, according to an animal study. ... [Aging] affects brain cells' ability to alter the strength and structure of their connections for information storage, a process known as synaptic plasticity, which is a cellular signature of memory. ... compared with younger rats, hippocampi from older rats have less brain-derived neurotrophic factor (BDNF) - a protein that promotes synaptic plasticity - and less histone acetylation of the Bdnf gene. By treating the hippocampal tissue from older animals with a drug that increased histone acetylation, they were able to restore BDNF production and synaptic plasticity to levels found in younger animals. ... The researchers also found that treating the hippocampal tissue from older animals with a different drug that activates a BDNF receptor also reversed the synaptic plasticity deficit in the older rats."

Link: http://www.eurekalert.org/pub_releases/2011-12/sfn-dra120711.php

Via MedicalXPress: "researchers [put] forward a theory for the first time based on research evidence that new air sacs, called alveoli, are constantly being formed. This contradicts information in most medical textbooks that explain that the tiny air sacs begin to develop before birth (around the 6th month of pregnancy) and continue to increase in number until the age of about 3 years. ... It was believed that there was no further increase in the number of alveoli beyond that age, and that the existing alveoli just expanded as the lungs grew bigger until final adult size was reached. Our study has challenged this by suggesting that new alveoli continue to be formed as the lungs grow. ... The researchers studied over 100 healthy volunteers aged between 7 and 21 years. Each volunteer [breathed] in hyperpolarised helium and held their breaths. ... The helium [behaves] like a magnetised gas. Within the scanner, we can measure how the magnetism decays, and this in turn depends on the size of the air sacs - alveoli - which contain the helium. ... We studied small children, whose lungs contain approximately one litre of air, and full-grown adults with lung volumes of around four litres. We found very little difference in the size of the alveoli across everyone we studied. If the size of the alveoli are hardly changing, this can only mean one thing - as our lungs increase in size, we must be growing new alveoli. ... This research has important implications. If we can continue to develop new alveoli beyond early childhood, going on through adolescence, there is the potential for lung repair following injury that was never realised before."

Link: http://medicalxpress.com/news/2011-12-fundamentally-lung-growth.html

You may recall the very promising form of cancer immune therapy pioneered by Zheng Cui that involves transplanting granulocytes from suitable donors - it performed very well indeed in mice, superbly in fact, but only the one anemic human trial is underway in the US. You might look back in the Fight Aging! archives for a report last year on where things were with this line of research:

You might recall that people were enthused a few years back over the work of researcher Zheng Cui, who showed that (a) one breed of lab mice shug off cancer because their immune cells are different in ways that enable them to kill cancer dead, (b) transplanting those immune cells into more vulnerable mice also kills cancer dead, and (c) this same state of affairs exists in humans. Somewhere, someone has an immune system that can kill your cancer. If you could find them and undergo a transplant of leukocyte or granulocyte immune cells, the evidence to date suggests that this would be a very effective therapy.

Unfortunately, one anemic trial and a little additional research is where things still stand, more or less. This is a funding and culture of medical development issue: it's not yet completely understood how the therapy works at the biochemical level, and the prevalent incentives are for research groups to strive to fully understand a mechanism so that they can apply for patents, develop drugs that manipulate those mechanisms, and so forth and so on. Fortunately, if work is well publicized and the scientific papers openly published, clinics and medical developers worldwide can get into the game - and not all of them have the same incentives as US-based scientists and other cancer research concerns.

So I see that there is a clinic in Mexico called NCIM that is now offering granulocyte infusion treatment, for example:

Earlier this year we at NCIM approached biomedical theoretician Dr. Anthony G. Payne and asked him for any ideas or suggestions he might have for bettering the lot of a middle-aged male end stage prostate cancer patient. As he had exhausted whatever conventional approaches were available for his particular malignancy this was time for heroic measures. With Dr. Cui's pioneering work in mind Dr. Payne then set to work to develop an experimental protocol that would combine the use of mismatched donor granulocytes from healthy young people with HLA mismatched umbilical cord stem cells from healthy newborns.

Caveat emptor and all that - this looks a great deal more ad-hoc than the Florida clinical trial setup, for example - but this sort of spread in the application of a well-publicized and openly published technique is exactly what I'd like to see happen for the range of nascent biotechnologies in longevity science. When I talk about Open Cures as a long term project for speeding up medical development and implementation, I am talking about helping to make the very early stage biotechnologies for repairing or slowing age-related biotechnology accessible and renowned, just as Zheng Cui's work and its scientific foundations have become. This accessibility helps to spur entrepreneurs, development groups, and clinicians to do what NCIM has done here - pick up where US-based organizations are slacking due to obstructive regulation or a culture of development that rejects implementation of working-but-not-yet-fully-understood therapies. It doesn't matter that the first wave of implementations are likely to include incomplete or incorrect projects - once things get underway in earnest these will be weeded out or improved.

The clinics that service the medical tourism industry are the natural starting point for this sort of spread of practice, but from their experience technologies will spread out into the region's medical and research establishment. This is ever a painfully slow process, but it is much, much faster than the alternative in which it never happens because too few people know of or understand the prospective biotechnology in question. People are only trying to implement granulocyte therapies because there have been years of advocacy and discussion - absent that, I'd wager this would another largely vanished line of research for now.

To what degree can you swing the odds of suffering cancer in your favor? A fair amount, if this article is to be taken at face value, as much or more as other common age-related conditions: "Nearly half of cancers diagnosed in the UK each year - over 130,000 in total - are caused by avoidable life choices including smoking, drinking and eating the wrong things, a review reveals. Tobacco is the biggest culprit, causing 23% of cases in men and 15.6% in women, says the Cancer Research UK report. Next comes a lack of fresh fruit and vegetables in men's diets, while for women it is being overweight. ... Many people believe cancer is down to fate or 'in the genes' and that it is the luck of the draw whether they get it. Looking at all the evidence, it's clear that around 40% of all cancers are caused by things we mostly have the power to change. ... We didn't expect to find that eating fruit and vegetables would prove to be so important in protecting men against cancer. And among women we didn't expect being overweight to be more of a risk factor than alcohol. ... About 100,000 (34%) of the cancers are linked to smoking, diet, alcohol and excess weight. ... The researchers base their calculations on predicted numbers of cases for 18 different types of cancer in 2010, using UK incidence figures for the 15-year period from 1993 to 2007." As usual, excess fat and smoking show up as undesirables - they are there as prominent risk factors for most of the unpleasant things that aging inflicts upon us.

Link: http://www.bbc.co.uk/news/health-16031149

Via EurekAlert!: "Reproductive and somatic aging use different molecular mechanisms that show little overlap between the types of genes required to keep oocytes healthy and the genes that generally extend life span. ... The different genetic pathways help explain why a woman's fertility begins to decline after she is 35 years old, while her other cells do not show significant signs of aging until decades later ... To compare the molecular mechanisms that are switched on or off with the aging of oocytes and somatic cells, Murphy's lab turned to the model organism, Caenorhabditis elegans (C. elegans), the worm-like nematode that set off the whole field of longevity research with the discovery in the 1990s that gene mutations affecting insulin regulation doubled the worm's life span.Using DNA microarrays to measure the expression levels of genes, Dr. Murphy and her colleagues noted a distinctive DNA signature for aging oocytes. They also found that the oocytes of aging insulin and transforming growth factor-beta (TGF-beta) mutant mice had the same DNA profile that characterized young females. The researchers then compared the oocyte gene expression patterns with microarray transcription data on worms carrying the famous long-life mutations. Murphy and her colleagues found that even though somatic and reproductive aging in C. elegans both involve the insulin regulation pathway, the molecular mechanisms to maintain youthful oocyte function and to combat body aging are very different. ... It seems that maintaining protein and cell quality is the most important component of somatic longevity in worms, while chromosomal/DNA integrity and cell cycle control are the most critical factors for oocyte health."

Link: http://www.eurekalert.org/pub_releases/2011-12/asfc-ahb112211.php

There is a great deal of denial floating around when it comes to the excess weight carried by a majority of the people fortunate enough to live in wealthier parts of the world - even more denial than there is for lack of exercise, and there's plenty of that. Wealth is ever a double-edge sword, and brings the opportunity to become overweight and sedentary along with its many benefits - we mammals have evolved to find it hard to turn down large amounts of food that is both cheap and good, and we've succeeded ourselves into a challenging position on that front. Unfortunately indulgence has meaningful costs: a deterioration in health and life expectancy, and the more we overeat the worse that cost becomes. This has always been the folk wisdom of past decades and centuries, but in recent years the life science and medical research communities have brought more rigorous measurement and greater understanding to the costs of excess fat tissue and lack of exercise. Denial is becoming harder - which is a good thing, as the cost of food will continue to head towards zero as technology advances.

Here's an article written by someone who would love to remain upon the boat of denial by the sound of some of the later paragraphs, but it's hard to argue against facts established through good science:

When it comes to lowering our overall risk of death and dying from heart disease, fitness may be just as important, if not more so, than weight. That's what researchers concluded after studying fitness, weight and mortality among 14,345 middle-aged men in an 11-year study. Most studies that have previously linked weight gain, overweight and obesity to higher mortality risk have focused only on BMI, or body mass index, a ratio of height and weight. That's because weight can indirectly affect a number of different metabolic processes that contribute to mortality, such as how we burn calories or process sugars, and how high our blood pressure is. But weight may also be masking the effect of another factor that could protect or propel us to an early death: how efficiently our hearts and lungs are working, or, in other words, how fit we are.

Regular readers here will already know that both exercise and level of body fat go a fair way towards determining the future trajectory of health and life expectancy. Certainly there is no medicine or therapy that a healthy person can obtain at this time that comes even close to the benefits gained by (a) regular exercise, and (b) maintaining an optimal level of body fat. A handful of posts from the archives, for example:

• Exercise, Longevity, and Long Term Medical Costs
• On Aging and Exercise
• Exercise Slows Many of the Consequences of Aging
• There Are Old People and Fat People, But Few Old Fat People
• Don't Get Fat, and Don't Stay Fat
• More Evidence for the Costs of Visceral Fat

A recent paper: "The emergence of longevity in the modern world has brought a sense of urgency to understanding age-related neurodegenerative diseases such as Alzheimer's disease. Unfortunately, there is a lack of consensus regarding the correlation between the pathological substrates of neurodegeneration and dementia status, particularly in the oldest-old. To better understand the pathological correlates of dementia in the oldest-old, we characterized the topographical spread and severity of amyloid-β, tau, TDP-43 and α-synuclein pathologies in the 90+ Study, a prospective longitudinal population-based study of ageing and dementia. ... We used quantitative and/or semi-quantitative measures to assess the burden of amyloid-β, tau, TDP-43 and α-synuclein pathologies as well as hippocampal sclerosis. Amyloid-β and tau were the predominant pathologies in the 90+ Study cohort and both amyloid-β area and tau area occupied measures were strongly associated with the presence of dementia ... Notably, TDP-43 pathology also correlated with dementia, while α-synuclein distribution did not. ... In contrast to previous reports, we found that tau and amyloid-β continue to be robust pathological correlates of dementia, even in the oldest-old."

Link: http://www.ncbi.nlm.nih.gov/pubmed/22120149

If we think of aging as accumulated damage, then we should not be surprised to see a lower rate of mortality associated with later menopause. The timing of menopause is at least partially driven by the degree to which an individual is aging, just like losing hair, degree of skin wrinkling, loss of muscle mass, and so forth - it just happens to be easier to measure as a distinct event: "The reproductive-cell cycle theory of aging posits that reproductive hormone changes associated with menopause and andropause drive senescence via altered cell cycle signaling. Using data from the Wisconsin Longitudinal Study, we analyzed the relationship between longevity and menopause, including other factors that impact 'ovarian lifespan' such as births, oophorectomy, and hormone replacement therapy. We found that later onset of menopause was associated with lower mortality, with and without adjusting for additional factors (years of education, smoking status, body mass index, and marital status). Each year of delayed menopause resulted in a 2.9% reduction in mortality; after including a number of additional controls, the effect was attenuated modestly but remained statistically significant (2.6% reduction in mortality). We also found that no other reproductive parameters assessed added to the prediction of longevity, suggesting that reproductive factors shown to affect longevity elsewhere may be mediated by age of menopause. Thus, surgical and natural menopause at age 40, for example, resulted in identical survival probabilities. These results support the maintenance of the hypothalamic-pituitary-gonadal axis in homeostasis in prolonging human longevity, which provides a coherent framework for understanding the relationship between reproduction and longevity."

Link: http://www.ncbi.nlm.nih.gov/pubmed/22139381

I wanted to draw your attention to an interesting (if not immediately applicable) connection between two pieces of research. We'll start with a method of making oxidative stress glow:

Arterial calcification and coronary heart disease, neurodegenerative diseases such as Parkinson's and Alzheimer's, cancer and even the aging process itself are suspected to be partially caused or accelerated by oxidative stress. Oxidative stress arises in tissues when there is an excess of what are called reactive oxygen species (ROS). "However, up to now, nobody was able to directly observe oxidative changes in a living organism and certainly not how they are connected with disease processes," ... [Researchers] introduced genes for biosensors into the genetic material of fruit flies. These biosensors are specific for various oxidants and indicate the oxidative status of each cell by emitting a light signal - in realtime, in the whole organism and across the entire life span.

...

Up to now, many scientists have assumed that the aging process is associated with a general increase in oxidants throughout the body. However, this was not confirmed by the observations made by the investigators across the entire life span of the adult animals. They were surprised that almost the only age-dependent increase in oxidants was found in the fly's intestine. Moreover, when comparing flies with different life spans, they found out that the accumulation of oxidants in intestinal tissue even accelerated with a longer life span.

This will provide a great deal of grist for various mills, given the central role for oxidative stress in a broad range of aging research - there's nothing quite like finding an extra layer of complexity and a boatload of confounding data to get the grants flowing. Notice that the intestine is the location of rising oxidative stress in the fly, and then glance back at this recent research:

Scientists [found] that tweaking a gene known as PGC-1, which is also found in human DNA, in the intestinal stem cells of fruit flies delayed the aging of their intestine and extended their lifespan by as much as 50 percent.

PGC-1 is involved in regulation of mitochondrial biochemistry, and mitochondria are the go-to source for oxidative stress - they emit damaging oxidative molecules as a side-effect of normal operation. You can speculate on this and how it all hangs together; certainly there's not enough information yet to do more than that. To me, the immediately interesting part of this is the degree to which flies apparently march on their stomachs - but I think we'll be seeing much more of glowing biosensors in the near future. In the long term, similar whole-body biosensor methodologies deployed in mammals have the potential to remove much of the ambiguity that remains in our understanding of metabolism and its relationship to aging.

The structural properties of natural cartilage have proven challenging to recreate in tissue engineering, but researchers are making progress: "A lab discovery is a step toward implantable replacement cartilage, holding promise for knees, shoulders, ears and noses damaged by osteoarthritis, sports injuries and accidents. Self-assembling sheets of mesenchymal stem cells permeated with tiny beads filled with growth factor formed thicker, stiffer cartilage than previous tissue engineering methods. ... We think that the capacity to drive cartilage formation using the patient's own stem cells and the potential to use this approach without lengthy culture time prior to implantation makes this technology attractive ... The team put transforming growth factor beta-1 in biodegradable gelatin microspheres distributed throughout the sheet of stem cells rather than soak the sheet in growth factor. ... The microspheres provide structure, similar to scaffolds, creating space between cells that is maintained after the beads degrade. The spacing results in better water retention - a key to resiliency. The gelatin beads degrade at a controllable rate due to exposure to chemicals released by the cells. As the beads degrade, growth factor is released to cells at the interior and exterior of the sheet, providing more uniform cell differentiation into neocartilage. The rate of microsphere degradation and, therefore, cell differentiation, can be tailored by the degree to which the microsphere are cross-linked. ... After three weeks in a petri dish, all sheets containing microspheres were thicker and more resilient than the control sheet. The sheet with sparsely crosslinked microspheres grew into the thickest and most resilient neocartilage."

Link: http://www.eurekalert.org/pub_releases/2011-12/cwru-ecr120211.php

The Guardian looks at the activities of one Japanese research group: "In the latest of a series of remarkable studies, researchers from the RIKEN Center for Developmental Biology in Kobe, Japan report that embryonic stem cells grown under special conditions can spontaneously organize themselves into a partial pituitary gland that is fully functional when transplanted into mice. ... Over the past four years, Yoshiki Sasai and his colleagues of RIKEN's Organogenesis and Neurogenesis Group have developed a novel cell culture technique for growing embryonic stem (ES) cells in floating three-dimensional aggregates. ... In 2008, Sasai's group showed that ES cells grown in 3D cultures can recapitulate the earliest stages of neural development to self-organize into functional brain tissue, which integrated into existing neural circuits when transplanted into the brains of newborn mice. And earlier this year, they reported ES cells can also generate embryonic eyes with retinas. ... Growing complete, fully functional organs for transplantation is the holy grail of regenerative medicine, one which is being pursued by many groups of researchers around the world. ... Sasai's group is at the forefront of these efforts. Their work shows that ES cells can spontaneously form complex three-dimensional structures when grown under the right conditions, in the absence of a scaffold. With each new study, they demonstrate the generation of increasingly complex structures, and the pituitary gland is the most complex one yet."

Link: http://www.guardian.co.uk/science/neurophilosophy/2011/dec/04/1

Metabolism is complex - very, very complex. In areas that have been well studied for more than a decade, researchers are still pushing back and forth on whether well known genes and pathways are actually important in longevity. In this sort of environment a single study in a few dozen mice isn't worth much, as the results from these various studies are either are all over the map, or prone to being overturned by a more careful, well-funded, and larger research project. That is what seems to have happened here for IGF-1 and longevity:

One of the major discoveries in aging during the past decade has been the observation that mutations in insulin/IGF-1 signaling led to increased longevity in various invertebrate models.

...

The most direct evidence that mutations affecting the insulin/IGF-1 signaling pathway lead to increased longevity in mammals has come from studies with Igf1r+/− mice ... i.e., mice lacking one copy of the gene coding for IGF-1 receptor ... In 2003, Holzenberger et al. reported that female Igf1r+/− mice exhibited a 33% increase in lifespan. ... However, the lifespan data in the Holzenberger study are problematic because of the small sample size and the very short lifespan of both the wild type (WT) and Igf1r+/− mice studied.

...

therefore, we have reassessed the effect of reduced expression of the IGF-1R on lifespan using the rigorous criteria recommended by Ladiges et al., e.g., lifespan and end-of-life pathology were assessed using large sample sizes and husbandry conditions that permitted the control lifespan to approach its full potential, which are necessary if the longevity differences in the experimental group are to be relevant to healthy aging.

In agreement with Holzenberger et al., we found that the female Igf1r+/− mice were more resistant to the oxidative stress than were WT female mice while no difference was observed between the male Igf1r+/− and WT mice. However, there was only a modest increase in the mean lifespan (4.7%) of female Igf1r+/− mice compared to their WT littermates and no significant change in end-of-life pathology. Thus, our data show [that] reduced IGF-1R signaling in mammals does not play the same major role in aging that is observed in invertebrates.

And so it goes - sometimes the early results achieved in small, prospective studies with small budgets don't hold up to closer inspection. Some fundamental processes relating to the link between operation of metabolism and longevity are very similar between lower animals (like worms) and higher animals (like mammals). You might think of the effects of calorie restriction, for example. But clearly other processes are significantly different between species, and this is one more layer of complexity that will increase the cost and slow the progress of efforts to slow aging by manipulating metabolism - such as by altering IGF-1.

From In Search of Enlightenment: "Looking back over our species' history, as told in fossil records, what do we find? ... Prehistoric human remains have never revealed individuals older than about 50 years of age, and humans had a life expectancy at birth of 30 years or less for more than 99.9% of the time that we have inhabited this planet. ... So for most of our species' history there was little progress in terms of increasing life expectancy at birth. But things began to change in the 19th century. Advances in technology (e.g. the sanitation revolution), medical knowledge, material resources and changes in behaviour helped change the future course of our species. ... The fossil records of the 21st century will be unique in our species' history for two reasons. Firstly, there will be more human remains this century than in any other century (because of the size of the human population). Furthermore, the vast majority of these deaths will be caused by chronic disease and will afflict people after the age of 60. Isn't it odd, given how many people are projected to suffer and die from chronic disease and given the rapid progress that is being made in the biomedical sciences, that we don't invest more of our energies into tackling the leading cause of chronic disease? Namely, aging. When future generations look back at the 21st century they will wonder why we didn't act sooner to try to ameliorate the high risks of morbidity and mortality that currently ravage our bodies and minds."

Link: http://colinfarrelly.blogspot.com/2011/12/fossil-records-past-and-present.html

Here is another study showing that rapamycin can extend life in mammals: "The nutrient-sensing TOR (target of rapamycin) pathway is involved in cellular and organismal aging. Rapamycin, an inhibitor of TOR, extends lifespan in yeast, fruit flies and genetically heterogeneous mice. Here, we demonstrate that lifelong administration of rapamycin extends lifespan in female 129/Sv mice characterized by normal mean lifespan of [two years]. Importantly, rapamycin was administrated intermittently (2 weeks per month) starting from the age of [two months]. Rapamycin inhibited age-related weight gain, decreased aging rate, increased lifespan (especially in the last survivors) and delayed spontaneous cancer. 22.9% of rapamycin-treated mice survived the age of death of the last mouse in control group. Thus we demonstrated for the first time in normal inbred mice that lifespan can be extended by rapamycin. This opens an avenue to develop optimal doses and schedules of rapamycin as an anti-aging modality."

Link: http://www.ncbi.nlm.nih.gov/pubmed/22107964

The field of stem cell research is busy indeed, as is the application of new knowledge in regenerative medicine. More and more news that would have been noteworthy five years ago just slips past with a brief mention now - so you might imagine what will be buried in the academic press releases by 2016. By that time, examples of unarguably, demonstrably successful human autologous stem cell therapies will be yesterday's news, offered to hundreds or thousands of patients in many clinics outside the US, and you'll have to do better than repair the ravages of disease or injury in a mouse to gain the attention of the press. But for now, the following items are examples of comparatively buried news - the everyday advances in the field that are no longer written up in glowing editorials. Progress is measured by the increasing degree to which your work has faded into the background hum of science under way.

Newly discovered heart stem cells make muscle and bone:

Researchers have identified a new and relatively abundant pool of stem cells in the heart. ... these heart cells have the capacity for long-term expansion and can form a variety of cell types, including muscle, bone, neural and heart cells. ... While cell-based therapies do have potential for repairing damaged heart tissue, [researchers] ultimately favors the notion of regenerative therapies designed to tap into the natural ability of the heart and other organs to repair themselves. And there is more work to do to understand exactly what role these stem cells play in that repair process. [The] team is now exploring some of the factors that bring those cardiac stem cells out of their dormant state in response to injury and protect their "stemness."

Repairing spinal cord injury with dental pulp stem cells:

Hope that a stem cell population, specifically dental pulp stem cells, might be of benefit to individuals with severe spinal cord injury has now been provided by the work of Akihito Yamamoto and colleagues, at Nagoya University Graduate School of Medicine, Japan, in a rat model of this devastating condition. In the study, when rats with severe spinal cord injury were transplanted with human dental pulp stem cells they showed marked recovery of hind limb function. Detailed analysis revealed that the human dental pulp stem cells mediated their effects in three ways: they inhibited the death of nerve cells and their support cells; they promoted the regeneration of severed nerves; and they replaced lost support cells by generating new ones.

UCLA researchers identify new method for generating stem cell-like cells from human skin:

Researchers from the UCLA School of Dentistry investigating how stem cells can be used to regenerate dental tissue have discovered a way to produce cells with stem cell-like characteristics from the most common type of human skin cell in the epidermis. These skin cells, called keratinocytes, form the outermost layer of skin and can be cultured from discarded skin tissues or biopsy specimens. ... Since [these stem cells] may be obtained by taking a small punch-biopsy of skin tissues from patients, these cells are an easily accessible, patient-specific source of stem cells, which can be used for regenerative purposes.

Adult stem cells use special pathways to repair damaged muscle:

When a muscle is damaged, dormant adult stem cells called satellite cells are signaled to "wake up" and contribute to repairing the muscle. University of Missouri researchers recently found how even distant satellite cells could help with the repair, and are now learning how the stem cells travel within the tissue. This knowledge could ultimately help doctors more effectively treat muscle disorders such as muscular dystrophy, in which the muscle is easily damaged and the patient's satellite cells have lost the ability to repair.

And that was just a random selection of stem cell news grabbed from the top of today's pile. It's a busy time for the life sciences, and we will all benefit from the results ten or twenty or thirty years from now.

Mitochondria are the power plants of the cell, the evolved remnants of what were originally symbiotic bacteria, and which still possess their own fragile DNA distinct from that in the cell nucleus. They churn away producing the adenosine_triphosphate (ATP) used as an energy source in cellular processes, and are clearly of great importance in determining longevity. Scientists have for some years been carefully pulling apart the core mitochondrial machinery to better understand why this is the case, and here is an example of this ongoing research: "A decrease in mitochondrial electron transport chain (ETC) activity results in an extended lifespan in Caenorhabditis elegans. This longevity has only been reported when complexes I, III and IV genes are silenced, but not genes of complex II. We now have suppressed each complex II subunit in turn and have confirmed that in no case is lifespan extended. Animals with impaired complex II function exhibit similar metabolic changes to those observed following suppression of complexes I, III and IV genes, but the magnitude of the changes is smaller. Furthermore, an inverse correlation exists between mitochondrial membrane potential and ATP levels, which strongly suggests that dynamic allocation of energy resources is maintained. In contrast, suppression of genes from complexes I, III and IV, results in a metabolic crisis with an associated stress response and loss of metabolic flexibility. Thus, the maintenance of a normal metabolism at a moderately decreased level does not alter normal lifespan, whereas metabolic crisis and induction of a stress response is linked to lifespan extension."

Link: http://www.ncbi.nlm.nih.gov/pubmed/22122855

As a follow up to an earlier post on why DNA sequencing is of interest to those of us who follow longevity science, here is a look at the present state of the sequencing industry: "BGI, based in China, is the world's largest genomics research institute, with 167 DNA sequencers producing the equivalent of 2,000 human genomes a day. BGI churns out so much data that it often cannot transmit its results to clients or collaborators over the Internet or other communications lines because that would take weeks. Instead, it sends computer disks containing the data, via FedEx. ... the ability to determine DNA sequences is starting to outrun the ability of researchers to store, transmit and especially to analyze the data. ... Data handling is now the bottleneck. It costs more to analyze a genome than to sequence a genome. ... That could delay the day when DNA sequencing is routinely used in medicine. In only a year or two, the cost of determining a person's complete DNA blueprint is expected to fall below $1,000. But that long-awaited threshold excludes the cost of making sense of that data, which is becoming a bigger part of the total cost as sequencing costs themselves decline. ... We believe the field of bioinformatics for genetic analysis will be one of the biggest areas of disruptive innovation in life science tools over the next few years."

Link: http://www.nytimes.com/2011/12/01/business/dna-sequencing-caught-in-deluge-of-data.html