Fight Aging!

As promised, video has been posted of the recent Oxford University Science Society public debate between Aubrey de Grey of the SENS Foundation and Colin Blakemore, former head of the Medical Research Council. Formal debates in science and medicine, sponsored by academic societies, are a long-standing tradition in England: in the history of the sciences many of the important inflection points and transitions between eras of knowledge were marked by public debates held between the worthies of the time. The debates do not in and of themselves determine anything: they are a reflection of ongoing matters of interest and the clash of strategies or theories that currently engage the scientific community. Thus it should be taken as a promising sign that awareness of SENS-style rejuvenation biotechnology is at a level at which such debates are held and well-attended.

Rejuvenation through medical technology is in our future, and factions within the scientific and medical development communities are forming and polarizing around opinions on plausibility, how to construct therapies for aging, and just how urgent it is to take action on this issue. Much of the ongoing debate within the scientific community is invisible to the world at large - but make no mistake, it is taking place, and has been for the better part of a decade. When it comes to aging and what to do about it, the research community of today is a radically different place from the research community of the first years of this century.

The video below is divided into two parts: the debate in the first part, and then the audience question and answer session following in the second part.

Aubrey de Grey will propose the motion 'This house wants to defeat ageing entirely' and Professor Colin Blakemore will be opposing. The debate will be chaired and moderated by Professor Sir Richard Peto. This debate will address whether it is feasible and appropriate to consider ageing as a target of decisive medical intervention, raising the possibility of substantial extension of human lifespan.

Aubrey de Grey is currently Chief Science Officer of SENS Foundation, a biomedical research charity that aims to develop, promote, and ensure widespread access to rejuvenation biotechnologies that address the diseases and disabilities of ageing. SENS Foundation aims to bring ageing under comprehensive medical control. Its research agenda consists of the application of regenerative medicine to ageing - not merely slowing the ageing clock, but resetting it to early adulthood.

Colin Blakemore is Professor of Neuroscience at the University of Oxford Nuffield Department of Clinical Neurosciences. He is an expert in vision, development of the brain and neurodegenerative disease. He is active in communication of science and is president and adviser to several charities concerned with brain disorders. Prof. Blakemore was formerly Chief Executive of the Medical Research Council, the UK's largest public funder of biomedical research.

An interview with a researcher in the field: "the reality is that our brains age throughout life and, in fact, the science tells us that at age 45 we can measure cognitive and memory decline in the average person. There's a steady gradual decline that continues. ... Age is the greatest risk factor. By age 65 or older, your risk is about 10 per cent for Alzheimer's dementia. By 85, it's 40 per cent or more. The implications are that we have a lot more people who have dementia and a lot more people concerned about developing it. ... The studies of successful aging tell us that, when it comes to cognitive success or avoiding dementia or developing it, for the average person only a third of what determines that cognitive outcome results from genetics, from what we inherit. Rarely there are families, less than 2 per cent of cases, with very strong genetic components; they have mutations that cause the disease very early in life. For the vast majority, the genetics are not as strong. They are a factor. About 20 per cent of the population has this risk. It increases the likelihood of getting the disease and the likelihood of getting it at an earlier age but it's not 100 per cent. That means that two-thirds of the formula comes from non-genetic factors: the lifestyle choices we make every day have a major impact on how well our brains age. ... Physical exercise, mental exercise, nutrition, stress management and other behaviours, like avoiding head trauma, not smoking and so forth. ... Exercise seems obvious [but] it may not be completely obvious for people. They know there is a connection between exercise and physical health, exercise and avoiding heart disease. But not everybody is aware of the strong connection between physical exercise and brain health."

Link: http://www.thestar.com/news/insight/article/1169639--a-q-a-with-dr-gary-small-on-aging-and-dementia

Researchers are trying to create new lymph nodes in the body, but tailored to specific needs: "Designer lymph nodes are built with specialized gene-modified cells that are injected into patients and produce a pre-planned immunologic response for cancer patients locally and then throughout their bodies. The researchers are examining a cancer vaccine 'boosting' effect of the manufactured lymph nodes in patients with advanced melanoma. ... Patients with cancer have a dysfunctional immune system either because of the tumor's presence in the body or as a side effect of drugs or radiation used to treat the tumor. The designer lymph nodes, aimed at rebuilding their immune systems, may overcome this dysfunction. ... the researchers are using antigen-presenting cells made from the patient's blood, which are then genetically manipulated to express certain genes before injection into patients. They can inject gene-modified cells at multiple, independent sites throughout the body to create independent lymph nodes that work together. In the trial, the researchers have found early formation of lymph nodes at the vaccine injection sites and are subsequently testing the nature and anti-tumor function of them. [The team] anticipate partnering with [other institutions] to create designer lymph nodes for diseases other than cancer and expand their designer gene immunity boosting research into fighting infectious diseases and even improving the function of immune systems in the elderly."

Link: http://medicalxpress.com/news/2012-04-lymph-nodes.html

I've noted work on correlations between air pollution and reduced life expectancy in past years; the statistical differences are usually very small in comparison to what you can do for yourself via calorie restriction and exercise, as air pollution in wealthier regions of the world is a fraction of what it was a century past. As populations became radically richer in the course of the past three centuries, the luxury of being able to pay for a better environment became possible - either directly or through investment in technologies that cause less pollution in the course of achieving their end goals. It wasn't all that long ago, for example, that there were dead rivers in the US and Western Europe. Those rivers would still be dead if not for the fact that our societies are far wealthier than those of our grandparents; to be able to be an environmentalist is very much a luxury. It requires sufficient surrounding wealth or knowledge to be able to do things a different way.

In any case, here is a recent study on air quality and life expectancy in China - a region of the world that is still largely an expanse of 20th-century styled comparative poverty, scattered with enclaves and belts of modern wealth.

Air Pollution Shortens Life Expectancy and Health Expectancy for Older Adults: The Case of China.

Outdoor air pollution is one of the most worrying environmental threats China faces today. Comprehensive and quantitative analyses of the health consequences of air pollution in China are lacking. This study reports age- and sex-specific life expectancy and health expectancies (HEs) corresponding to different levels of air pollution based on associations between air pollution and individual risks for a host of health conditions and mortality net of individual- and community-level confounders.

...

The main outcome measures in this study include life expectancy estimated from mortality and HEs based on five health conditions including activity of daily living, instrumental activity of daily living, cognitive status, self-rated health, and chronic conditions. Net of the controls, exposure to outdoor air pollution corresponded to subsequent reductions of life expectancy and HEs for all five health conditions. These detrimental pollution effects were stronger for women. The gap in life expectancy between areas with good air quality and moderately heavily polluted areas was 3.78 years for women of age 65 and 0.93 years for men. The differences in HEs at age 65 were also large, ranging from 1.47 years for HE for good self-rated health in men to 5.20 years for activity of daily living disability-free HE in women.

Air quality tends to be mixed up with a range of other confounding factors, however. This requires careful work on the part of researchers to have a chance of teasing out air quality effects independently of other factors that lead people to remain in areas of poor air quality:

I would be willing to wager that the correlation has more to do with the relative wealth of these areas and those who make the economic choice to live there, as well as access to medical technology and lifestyle choices. Things are rarely as simple as a two-parameter study casts them to be.

Still, aging is damage, and there's do great doubt that very polluted air does damage people over the long term, to a degree related to the level of pollution: inflammation, increased risk of age-related disease, outright lung damage, risk of cancer, that sort of thing. But once the air becomes clean enough for effects to be subtle - meaning much less in magnitude that effects of exercise, differences in wealth, intelligence, or even state of mind - then attention should turn to other controllable factors in life.

This seems like an interesting marker of public awareness of aging science; one of the noted researchers in the field recently started on a biweekly column for a local paper. Links to the columns published to date can be found on this page: "In my last column I discussed something we all know intuitively: Generally speaking, larger species of animals live longer than smaller species and this pattern extends even to whales that live more than 200 years. Are there dramatic exceptions to this rule - like people, for instance? Think of other mammals about our size, such as deer or mountain lions or seals. Don't we live longer than they do? The answer is, 'Yes, we do.' Humans live about five times as long as the average mammal of the same size, which makes us pretty special - but not as special as bats. Texas is bat country, as anyone who has watched millions of bats boil out of Bracken Cave or from under Austin's Congress Avenue Bridge can verify. What many people don't realize is how long bats live. For their size, bats are the longest-lived mammals by far, living up to 10 times as long as an average mammal of similar size. ... Think about this for a second. Your dog or cat, eating the best food science can provide, protected from predators and the elements and vaccinated against all sorts of diseases, is doing well to reach 15 to 20 years of age. By comparison, in order for a bat in the wild to survive it must catch its own prey, elude predators, resist climatic extremes, and avoid a wide range of infectious diseases. Yet despite these challenges, bats can live twice as long as your pampered pet." Current thinking on bat longevity looks to be similar to theories on naked mole rat longevity - it has to do with resistance of cell membranes (and especially mitochondria) to oxidative damage, otherwise known as the membrane pacemaker hypothesis of aging. This is thought to have developed in bats, and in birds, in respond to the metabolic demands of flight.

Link: http://barshop.uthscsa.edu/main/newsseminars/news/u50

Damage to mitochondrial DNA contributes to aging, and mitochondrial function is in general influential upon aging - damage causes harm by preventing the production of protein machinery vital to mitochondrial activity, which is the start of a long process that sees cells overtaken by dysfunctional mitochondria, and exporting their dysfunction to surrounding tissue by emitting harmful reactive molecules. There are numerous different sorts of DNA damage, however. Point mutations, for example, have been shown to do little to aging. Deletions, where whole reaches of DNA are knocked out, are a different story, and here researchers are investigating how this form of DNA damage varies between species: "Deletion mutations within mitochondrial DNA (mtDNA) have been implicated in degenerative and aging related conditions, such as sarcopenia and neuro-degeneration. While the precise molecular mechanism of deletion formation in mtDNA is still not completely understood, genome motifs such as direct repeat (DR) and stem-loop (SL) have been observed in the neighborhood of deletion breakpoints and thus have been postulated to take part in mutagenesis. In this study, we have analyzed the mitochondrial genomes from four different mammals: human, rhesus monkey, mouse and rat ... Our analysis revealed that in the four species, DR and SL structures are abundant and that their distributions in mtDNA are not statistically different from randomized sequences. However, the average distance between the reported age associated mtDNA breakpoints and their respective nearest DR motifs is significantly shorter than what is expected of random chance in human and rhesus monkey, but not in mouse and rat, indicating the existence of species specific difference in the relationship between DR motifs and deletion breakpoints. In addition, the frequencies of large DRs tend to decrease with increasing lifespan among the four mammals studied here, further suggesting an evolutionary selection against stable mtDNA misalignments associated with long DRs in long-living animals."

Link: http://dx.doi.org/10.1371/journal.pone.0035271

The latest issue of the open access journal Immunity & Aging includes a number of interesting papers covering the overlap between genetic contributions to natural variations in longevity and the aging of the immune system - which contributes to a range of age-related dysfunction and systems failure. They are very much in the mainstream model of narrow, unambitious, cautious vision: aiming for and expecting only modest, gradual improvements in health and longevity. Even in this time of radical change in biotechnology, the old habits of incrementalism and understatement regarding the bounds of the possible for human longevity are only slowly fading. The future must be one of ambitious, grand visions in medical science and funding for research if we are to benefit fully from the true potential of biotechnology. In any case, these papers remain interesting for what they are, and are available as provisional PDFs at this time - the download links are on the abstract pages below.

"Positive biology": the centenarian lesson:

The extraordinary increase of the elderly in developed countries underscore the importance of studies on ageing and longevity and the need for the prompt spread of knowledge about ageing in order to satisfactorily decrease the medical, economic and social problems associated to advancing years, because of the increased number of individuals not autonomous and affected by invalidating pathologies. Centenarians are equipped to reach the extreme limits of human life span and, most importantly, to show relatively good health, being able to perform their routine daily life and to escape fatal age-related diseases. Thus, they are the best example of extreme longevity, representing selected people in which the appearance of major age-related diseases, such as cancer, and cardiovascular diseases among others, has been consistently delayed or escaped. ... The aim is to realize, through a "positive biology" approach (rather than making diseases the central focus of research, "positive biology" seeks to understand the causes of positive phenotypes, trying to explain the biological mechanisms of health and well-being) how to prevent and/or reduce elderly frailty and disability.

Epidemiological, genetic and epigenetic aspects of the research on healthy ageing and longevity:

In this article we aimed to overview the research on the biological basis of human healthy ageing and longevity, discussing the role of epidemiological, genetic and epigenetic factors in the variation of quality of ageing and lifespan, including the most promising candidate genes investigated so far. Moreover, we reported the methodologies applied for their identification, discussing advantages and disadvantages of the different approaches and possible solutions that can be taken to overcome them.

Genetics of longevity. Data from the studies on Sicilian centenarians:

Scientists have focused their attention on centenarians as optimal model to address the biological mechanisms of "successful and unsuccessful ageing". They are equipped to reach the extreme limits of human life span and, most importantly, to show relatively good health, being able to perform their routine daily life and to escape fatal age-related diseases, such as cardiovascular diseases and cancer. Thus, particular attention has been centered on their genetic background and immune system. In this review, we report our data gathered for over 10 years in Sicilian centenarians. Based on results obtained, we suggest longevity as the result of an optimal performance of immune system and an over-expression of anti-inflammatory sequence variants of immune/inflammatory genes.

Extending healthy ageing: nutrient sensitive pathway and centenarian population:

To increase our understanding of how ageing works, it may be advantageous to analyze the phenotype of centenarians, perhaps one of the best examples of successful ageing. Healthy ageing involves the interaction between genes, the environment, and lifestyle factors, particularly diet. Besides evaluating specific gene-environment interactions in relation to exceptional longevity, it is important to focus attention on modifiable lifestyle factors such as diet and nutrition to achieve extension of health span. Furthermore, a better understanding of human longevity may assist in the design of strategies to extend the duration of optimal human health.

The application of genetics approaches to the study of exceptional longevity in humans: potential and limitations:

The average life-span of the population of industrialized countries has improved enormously over the last decades. Despite evidence pointing to the role of food intake in modulating life-span, exceptional longevity is still considered primarily an inheritable trait, as pointed out by the description of families with centenarian clusters and by the elevated relative probability of siblings of centenarians to become centenarians themselves. However, rather than being two separate concepts, the genetic origin of exceptional longevity and the more recently observed environment-driven increase in the average age of the population could possibly be explained by the same genetic variants and environmentally modulated mechanisms (caloric restriction, specific nutrients). In support of this hypothesis, polymorphisms selected for in the centenarian population as a consequence of demographic pressure have been found to modulate cellular signals controlled also by caloric restriction.

Via ScienceDaily: researchers "have identified a group of 'aging' genes that are switched on and off by natural mechanisms called epigenetic factors, influencing the rate of healthy aging and potential longevity. The study also suggests these epigenetic processes - that can be caused by external factors such as diet, lifestyle and environment - are likely to be initiated from an early age and continue through a person's life. The researchers say that the epigenetic changes they have identified could be used as potential 'markers' of biological aging and in the future could be possible targets for anti-aging therapies. ... the study looked at 172 twins aged 32 to 80 from the TwinsUK cohort. The researchers looked for epigenetic changes in the twins' DNA, and performed epigenome-wide association scans to analyze these changes in relation to chronological age. They identified 490 age related epigenetic changes. They also analysed DNA modifications in age related traits and found that epigenetic changes in four genes relate to cholesterol, lung function and maternal longevity. To try to identify when these epigenetic changes may be triggered, the researchers replicated the study in 44 younger twins, aged 22 to 61, and found that many of the 490 age related epigenetic changes were also present in this younger group. The researchers say these results suggest that while many age related epigenetic changes happen naturally with age throughout a person's life, a proportion of these changes may be initiated early in life."

Link: http://www.sciencedaily.com/releases/2012/04/120419191709.htm

An open access review paper looks at how the study of fly aging has informed the life sciences: "it is likely that not all senescent physiological changes revealed in flies can be simply translated to humans. However, flies and humans often show very similar age-related physiological phenotypes suggesting that at least some of the basic biological properties and mechanisms that regulate longevity are conserved amongst species. ... It is well-known that advances in medicine and health care have significantly contributed to increased longevity in humans over the last 100 years. There is also a clear trend toward increased life expectancy including an increase in the numbers of people living to an advanced age and the number of people with chronic age-related diseases. These trends emphasize the need to understand the genetic and physiological factors underlying biological aging and particularly, those that promote healthy aging. ... there are three ways to extend lifespan: increasing early survival rate, increasing late survival rate, or delaying senescence. Remarkably, the first two do not affect basic aging processes. For example, the first one leads to a significant increase in mean but not maximum lifespan, while the second one leads to change in a maximum but not mean lifespan. Delayed senescence, in turn, leads to a significant increase in both the mean and maximum lifespan. ... This raises the question as to whether healthspan and delayed senescence are inter related. As stated above, while many genes have been shown to extend lifespan, these may have little or no ability to delay physiological senescence. In other words, the period of functional disability before death may increase despite the fact that the total duration of life is increased. Thus, the search for appropriate biomarkers applicable to monitor functional senescence is highly important with regards to healthy aging and age-related diseases." These cautions are very much focused on the mainstream research goals of slowing the rate of aging through genetic and metabolic alterations; they have little relevance to efforts aimed at producing continuous repair of aging.

Link: http://www.frontiersin.org/Integrative_Physiology/10.3389/fphys.2012.00106/full

The employees and appointees of the US Food and Drug Administration have caused an incredible destruction of value and progress over the time that the agency has existed. Their regulatory policies become ever more onerous with each passing year, as unaccountable bureaucrats follow their incentives: nothing good can happen to their careers as a result of approving new technologies, and nothing bad tends to happen to their careers as a result of making it really, really hard to bring new medicine to the clinic. So of course you wind up with an organization whose members collectively pay nothing more than lip service to their declared mission, while working to make sure that medicine stays moribund in a slow-motion stasis. This is most evident in the cancer research community, largely because of its size, but it applies just as evenly across all forms of medicine:

A 2010 study in the Journal of Clinical Oncology by researchers from the M.D. Anderson Cancer Center in Houston, Texas found that the time from drug discovery to marketing increased from eight years in 1960 to 12 to 15 years in 2010. Five years of this increase results from new regulations boosting the lengths and costs of clinical trials. The regulators aim to prevent cancer patients from dying from toxic new drugs. However, the cancer researchers calculate that the delays caused by requirements for lengthier trials have instead resulted in the loss of 300,000 patient life-years while saving only 16 life-years.

To add to this picture, you must also see incumbent Big Pharma entities and their executives and lobbyists - a deeply enmeshed network of regulatory capture. They are far more willing to use the current system as a weapon to suppress disruptive innovation in their industry than to be a source of innovation themselves. So it goes, just as in any other heavily regulated market. The strategic goals of the major players wind up having very little to do with creating beneficial change, and everything to do with keeping things the same as they are now.

As I've said in the past, it is a waste of energy to fight this. That's a money pit, and resources are better spent on creating actual progress than lining the pockets of politicians, their lackeys, and other corrupt cogs in the system. Work around the roadblock instead: start companies and partner for research development outside the US. Deliver services in Asia and take advantage of cheap flights and the growing medical tourism industry. The only way that the FDA will whither away is to make it entirely irrelevant - and as the bureaucrats keep piling on the costs, erecting an ever higher barrier to actually developing any new medicine in the US, that will become a more popular option. You can be sure that the wealthier and more connected individuals who make regulations and advocate for ever greater powers to accrue to the FDA will be amongst the first flying beyond the US to undergo newer therapies - treatments that they have managed to make illegal or too expensive to exist in their own country.

Some more on this topic:

Though the United States urgently needs new treatments for common illnesses such as heart disease, stroke, and diabetes, the nation's system for drug approval discourages innovation and investment, especially for our most pressing public health challenges. In this paper, we find that the main culprit is the high cost of Phase III clinical trials, which are required for FDA approval of most drugs. We examined drug development in four major public health areas and discovered that for any given drug on the market, typically 90 percent or more of that drug's development costs are incurred in Phase III trials. These costs have skyrocketed in recent years, exacerbating an already serious problem.

The enormous cost and risk of Phase III trials create incentives for researchers and investors to avoid work on medications for the chronic conditions and illnesses that pose the greatest threat to Americans, in terms of health spending and in terms of the number of people affected. This avoidance, in turn, harms overall U.S. health outcomes and drives up the cost of health care.

Following on from research into the mechanisms of rapamycin released earlier this month, here is more on the way it might generate its benefits to longevity in laboratory mammals: "Balancing quiescence with proliferation is of paramount importance for adult stem cells in order to avoid hyperproliferation and cell depletion. In some models, stem cell exhaustion may be reversed with the drug rapamycin, which was shown can suppress cellular senescence in vitro and extend lifespan in animals. We hypothesized that rapamycin increases the expression of oxidative stress response genes in adult stem cells, and that these gene activities diminish with age. To test our hypothesis, we exposed mice to rapamycin and then examined the transcriptome of their spermatogonial stem cells (SSCs). Gene expression microarray analysis revealed that numerous oxidative stress response genes were upregulated upon rapamycin treatment ... When we examined the expression of these genes in 55-week-old wild type SSCs, their levels were significantly reduced compared to 3-week-old SSCs, suggesting that their downregulation is coincident with the aging process in adult stem cells. We conclude that rapamycin-induced stimulation of oxidative stress response genes may promote cellular longevity in SSCs, while a decline in gene expression in aged stem cells could reflect the SSCs' diminished potential to alleviate oxidative stress, a hallmark of aging."

Link: http://impactaging.com/papers/v4/n4/full/100451.html

Age-related diseases are among the more visible signs of accumulated biological damage that occurs over time - aging is damage. So we should expect to see less of all such conditions in longer lived populations, and here researchers demonstrate that point for osteoarthritis: "Previous studies have reported that centenarians escape the major age-related diseases. No studies on prevalence and severity of osteoarthritis (OA) in longevity population have previously been reported. Because OA is associated with morbidity and mortality, we hypothesized that radiographic hand OA would generally be less prevalent and would develop at a later age in longevity populations vs non-longevity populations. ... Longevity index was calculated as a ratio of the number of individuals aged [greater than] 90 years vs the number of people aged [greater than] 60, expressed per mil. A population with longevity index [greater than] 40 was considered as a longevity population. ... A significant difference in age standardized prevalence of hand OA was found between each pair of studied samples ... We observed that the pattern of radiographic hand OA in longevity populations differs from the pattern in non-longevity populations. On average, first joints with OA appear at an older age, and progression of hand OA [is] slower."

Link: http://www.ncbi.nlm.nih.gov/pubmed/22526078

The 2nd International Conference on the Genetics of Aging and Longevity is presently underway in Moscow, organized by the active Russian arm of the longevity research community - such as the folk behind the Science for Life Extension Foundation - and well-attended by notable life science researchers from around the world. Earlier this month, the Moscow News ran an interview with Michael Batin, one of the organizers. His views are representative of the Russian community, whose members tend to be forthright and direct when it comes to the end goals of longevity science: to defeat aging entirely, banish the suffering it causes, and usher in an era of ageless humans. More power to them - we could do with a lot more of that sort of outspoken advocacy here in the Anglosphere.

The quoted passages below are run through Google's automated translation engine, which unfortunately still butchers Russian:

Q: What is the real goal that we set ourselves right now? Can you say, talk about extending the life of ten years from now?

MB: In ten years? It is not even present, and yesterday. It has long been proven that reducing caloric intake [and even] just a healthy lifestyle [lead to a longer life]. Our goal is different - a victory over an aging, it is by and large the whole purpose of medical science. After all, if you think about all of the doctors [dedicated to the] prolongation of life, the estrangement of death. A person does not want to die right now, well, anti-aging does not differ fundamentally, it is also the struggle with death.

Q: So you're talking about immortality?

MB: Yes. This is the ultimate goal. In the coming ten years, you can raise the life expectancy [to] 150 years, with adequate [resources and large enough research community]. If, for example, to do research megaproject like the American lunar program. And if we know in ten years that will live more than a hundred years, this will give us more time to find a way to further extend [life].

Q: But how? Are there any pills?

MB: If you're talking about a miracle pill, then, of course not. Aging depends on many factors, and is now the main problem is just that we do not know them all. And the proposed mega-project just involves a systematic search for the causes of aging.

...

Q: And it's all in the mega-project? [It's] going to cost [a] quite impossibly high sum.

MB: But now we are spending huge amounts of money on arms - you've seen defense spending in Russia? - And do not invest in [biogerontology], fundamental research on the causes of aging. Even in the U.S., [where] gerontology takes a billion dollars, [that is] their total spending, of that billion is spent on Alzheimer's disease, [on] geriatrics, and [only a small fraction of it on] the fundamental work on finding the root causes of aging.

Research is always the red-haired stepchild of human endeavors, small and neglected behind the bread, circuses, and cathedrals of destruction. But what can one person do about that? Best not to be too weighed down by the essential insanity of the human condition as we have collectively managed to engineer it. It won't actually require more than a few tens of millions of people to decide they want to make a difference and devote some modest effort towards doing something about aging - a community that large, distributed around the world, could assemble the necessary funds and researchers to, for example, complete the SENS project to demonstrate robust rejuvenation in mice. Everyone else can go on building bombs and monuments if they so desire, but the things that matter will still get done, as they have always done, by a motivated tiny minority.

Long after the time in which anyone can easily recall who was US president in 2011, or what party was in power, or which wars of declining empire were fought, and then long after anyone even cares about that ancient history, and later, long after the whole downward slope of the history of the US is but a footnote of interest to scholars of the transition from second to third millennium, and later still, long after anyone can even find out with any great reliability who was US president in 2011 ... long after all these things are forgotten, the first half of the 21st century will still be clearly recalled as the dawn of the era in which aging was conquered.

Progress in science and technology is really the only thing that matters in the long term.

Cytograft is one of many regenerative science ventures established in the past fifteen years, and a competitor in the space of growing blood vessels: "A lot of people were skeptical when two young California-based researchers set out more than a decade ago to create a completely human-derived alternative to the synthetic blood vessels commonly used in dialysis patients. Since then, they've done that and more. ... First the team created blood vessels from patients' own skin cells. Then, in June, the company announced that three dialysis patients had received the world's first lab-grown blood vessels made from skin cells from donors, which eliminates the long lead time needed for making vessels from a patient's own cells. And now Cytograft has developed a new technique for making human textiles that promises to reduce the production cost of these vessels by half. ... Cytograft's new approach builds on what already has been proved successful. In 2005, the team began extracting fibroblasts from patients' own skin, cultured those cells into thin sheets, rolled up those sheets, cultured them some more so that they would fuse together, and implanted the lab-grown cylindrical vessels. The vessel-growing process was lengthy, at about seven months, but, because the vessels were derived from the patients' own cells, the implants were easily accepted by the patients' bodies, and they held up to the rigors of dialysis, which requires repeated punctures with large-gauge needles. Then the researchers created allogeneic vessels - ones grown from donor cells - with the hope that they were laying the foundation for an off-the-shelf stockpile of 100 percent human replacement parts. ... By combining these two methods we could make something that is allogeneic, cheaper to produce, and that you could store forever, meaning that the clinician can pull it off the shelves whenever they want. If it is frozen and allogeneic, that is kind of the homerun."

Link: http://www.sciencedaily.com/releases/2012/04/120423131512.htm

Via ScienceDaily: researchers "have developed a method of assisting nerves damaged by traumatic accidents to repair naturally, which could improve the chances of restoring sensation and movement in injured limbs. ... the team describes a new method for making medical devices called nerve guidance conduits or NGCs. The method is based on laser direct writing, which enables the fabrication of complex structures from computer files via the use of CAD/CAM (computer aided design/manufacturing), and has allowed the research team to manufacture NGCs with designs that are far more advanced than previously possible. Currently patients with severe traumatic nerve damage suffer a devastating loss of sensation and/or movement in the affected limb. The traditional course of action, where possible, is to surgically suture or graft the nerve endings together. However, reconstructive surgery often does not result in complete recovery. ... When nerves in the arms or legs are injured they have the ability to re-grow, unlike in the spinal cord; however, they need assistance to do this. We are designing scaffold implants that can bridge an injury site and provide a range of physical and chemical cues for stimulating this regrowth. ... Nerves aren't just like one long cable, they're made up of lots of small cables, similar to how an electrical wire is constructed. Using our new technique we can make a conduit with individual strands so the nerve fibres can form a similar structure to an undamaged nerve. ... Once the nerve is fully regrown, the conduit biodegrades naturally. The team hopes that this approach will significantly increase recovery for a wide range of peripheral nerve injuries."

Link: http://www.sciencedaily.com/releases/2012/04/120422232409.htm

There's a lot to be said for aging. The passage of years offers many opportunities to master favored skills, figure out solutions to the issues and upsets of youth, earn the resources and connections needed for true self-sufficiency and confidence, and much more. You can build a great life, given just the time to work on it and a modicum of common sense - and then keep on building atop the foundation of that great life. Humans age like distillates: it can just keep getting better.

But of course there is the matter of degeneration and death, of disease and decrepitude.

The fact that older people are generally happier, more secure, and more confident despite what happens to the body with age is a testament to just how good being aged is. That the majority evaluate their position as far superior to that of earlier years despite the increasing corrosion of the body and the ticking away of time remaining is a powerful statement.

In the 20th century we added an unprecedented number of years to our lifespans, but is the quality of life as good? Surprisingly, yes! At TEDxWomen psychologist Laura Carstensen shows research that demonstrates that as people get older they become happier, more content, and have a more positive outlook on the world.

On this topic, I should note that over the years an unfortunately large number of apologists for aging have become somewhat dazzled by the good parts of the package, to the point at which they are unwilling to talk about picking apart aging and degeneration, or trying to radically change aging through medical technology. To their view, the world is what it is, and we should just focus on the positives and suffer the negatives with dignity. Not that that last point is easy at all - there is no dignity in the failing of the body and mind, only horrors that the dominant voices of this society seem to have chosen to try to close away behind the curtains.

It is both somewhat strange and somewhat understandable to find so many conservatives - in the dictionary definition of the word, not the political definition - in an age of rampant, ongoing, omnipresent change. Those who benefit the most from technological progress, and consequent decade by decade shifts in the minutiae of the human condition, nonetheless adopt positions based on the idea that what presently exists will continue to exist as-is into the future. It's denial, it's letting the ape inside drive - the ape who really, really, doesn't like change or upsets to the present carefully constructed social hierarchy, no matter how beneficial it might be.

Being aged is great, but it's just plain dumb to try to turn that into an argument that being sick, lessened, in agony, and driven mad is also great. Medicine will be able to remove all of these ugly aspects of old age, provided that we work hard enough and fund the right sort of research and development to a sufficient degree. The people who paint on sunny smiles and say that nothing will ever change are only helping to hold back that future.

Oxford University in the UK has a long tradition of formal public debating, and this week the Oxford University Scientific Society will be hosting a debate on longevity science between Aubrey de Grey of the SENS Foundation and Colin Blakemore former head of the Medical Research Council. This will be the first time that a fellow of the British biomedical establishment has risen to the challenge of describing publicly, in a forum where he can be challenged, why intervention against aging is not in fact medicine's most pressing priority - an area of debate in which the UK lags behind the US: "Oxford University Scientific Society is hosting a debate on Wednesday, 25th April, 2012. The debate will begin at 7pm local time (11am Pacific, 2pm Eastern) in the University of Oxford's Sheldonian Theatre; doors open 45 minutes earlier. Dr. Aubrey de Grey will propose the motion 'This house wants to defeat ageing entirely' and Professor Colin Blakemore will be opposing. The debate will be chaired and moderated by Professor Sir Richard Peto. This debate will address whether it is feasible and appropriate to consider ageing as a target of decisive medical intervention, raising the possibility of substantial extension of human lifespan. Aubrey de Grey is currently Chief Science Officer of SENS Foundation, a biomedical research charity that aims to develop, promote, and ensure widespread access to rejuvenation biotechnologies that address the diseases and disabilities of ageing. SENS Foundation aims to bring ageing under comprehensive medical control. Its research agenda consists of the application of regenerative medicine to ageing - not merely slowing the ageing clock, but resetting it to early adulthood. Colin Blakemore is Professor of Neuroscience at the University of Oxford Nuffield Department of Clinical Neurosciences. He is an expert in vision, development of the brain and neurodegenerative disease. He is active in communication of science and is president and adviser to several charities concerned with brain disorders. Prof. Blakemore was formerly Chief Executive of the Medical Research Council, the UK's largest public funder of biomedical research."

Link: http://sens.org/node/2714

From the Daily Mail: "The Elixir of Youth has a terribly bad press. As soon as any scientist mentions that they have discovered a way of making fruit flies or worms or even mice live a bit longer and furthermore states that this might, just might, work in humans (after lots of tests, refinements, clinical trials and so on and anyway it is decades away at best, the caveats will be longer than the original research paper), you can bet a small vat of snake oil that the naysayers will soon weigh in. 'Who wants to live forever? Not me!' one curmudgeonly columnist will opine. 'What would a world be like with all those ancient people walking around, ugh!' will say another writer who, like the first, will have been commissioned mainly on the basis of their own rather advanced years. Because although the bizarre prejudice against anti-ageing research runs deep and wide, it doesn't quite run deep and wide enough for it to be all right for someone the right side of forty, say, to opine that the old really should shuffle off and leave the field clear. Up to now this has been pretty academic as anti-ageing potions have been little more than science fiction but, as an interesting feature in Nature magazine points out, it is beginning to look like a perfect storm of recent serendipitous discoveries and hard-won genetic advanced might - just might - put the holy grail of increasing human lifespan (as opposed to life expectancy, a very different thing) within reach."

Link: http://hanlonblog.dailymail.co.uk/2012/04/its-a-dogs-long-life.html

Here is a large statistical study that claims a correlation between time spent sitting and mortality rate that exists independently of the well known correlations between level of physical activity and mortality rate. More exercise means a longer life expectancy while more sitting means a lower life expectancy even after considering that those who sit more often are most likely exercising less.

Sitting Time and All-Cause Mortality Risk in 222,497 Australian Adults:

We linked prospective questionnaire data from 222,497 individuals 45 years or older from the 45 and Up Study to mortality data from the New South Wales Registry of Births, Deaths, and Marriages (Australia) from February 1, 2006, through December 31, 2010. Cox proportional hazards models examined all-cause mortality in relation to sitting time, adjusting for potential confounders that included sex, age, education, urban/rural residence, physical activity, body mass index, smoking status, self-rated health, and disability.

The association between sitting and all-cause mortality appeared consistent across the sexes, age groups, body mass index categories, and physical activity levels and across healthy participants compared with participants with preexisting cardiovascular disease or diabetes mellitus. ... Prolonged sitting is a risk factor for all-cause mortality, independent of physical activity.

This is not the first study to propose this correlation, of course. There are a range of others from past years. One has to wonder what the mechanism is here, however - my suspicion is that it actually does all come back down to the level of physical activity in the end. In these massive studies the level of exercise and activity is reported by the participants. A person who stands and works is going to be somewhat more active than a person who sits and works, even though that time may not be categorized as physical activity, or reported differently.

Exercise is much like calorie restriction - the effects are so large in comparison to other factors we have easy access to that they are likely to creep into any study.

You might look at a recent study on activity and Alzheimer's disease that was one of the few to use measuring devices rather than reports of activity. One point that emerges is that a fair degree of ongoing low level activity and exercise won't be classified as such by the participants of study without machine measurement. Housework, taking out the trash, the small increase in energy expenditure from standing while waiting versus sitting while waiting, that sort of thing repeated day in and day out. How much you are sitting really does sound a lot like a proxy for how much activity you are undertaking when you are doing things that most people don't really count as activity.

Researchers continue to investigate the genetics of natural variations in aging, such as those that can be generated through diet (e.g. calorie restriction) in mice: "Dietary interventions are effective ways to extend or shorten lifespan. By examining midlife hepatic gene expressions in mice under different dietary conditions, which resulted in different lifespans and aging-related phenotypes, we were able to identify genes and pathways that modulate the aging process. We found that pathways transcriptionally correlated with diet-modulated lifespan and physiological changes were enriched for lifespan-modifying genes. Intriguingly, mitochondrial gene expression correlated with lifespan and anticorrelated with aging-related pathological changes, whereas peroxisomal gene expression showed an opposite trend. Both organelles produce reactive oxygen species, a proposed causative factor of aging. This finding implicates a contribution of peroxisome to aging. Consistent with this hypothesis, lowering the expression levels of peroxisome proliferation genes decreased the cellular peroxide levels and extended the lifespan of Drosophila melanogaster and Caenorhabditis elegans. These findings show that transcriptional changes resulting from dietary interventions can effectively reflect causal factors in aging and identify previously unknown or under-appreciated longevity pathways, such as the peroxisome pathway."

Link: http://www.ncbi.nlm.nih.gov/pubmed/22509016

Another aspect of aging slowed by calorie restriction: "Caloric restriction (CR) retards aging in laboratory rodents. [Little] information is available on the effects of long-term CR on physiologic markers of aging and longevity in humans. Heart rate variability (HRV) is a marker for cardiac autonomic functioning. The progressive decline in HRV with aging and the association of higher HRV with better health outcomes are well established. HRV assessment is a reliable tool by which the effects of CR on autonomic function can be assessed. Time and frequency domain analyses compared 24-hr HRV in 22 CR individuals aged 35-82 yrs and 20 age-matched controls eating Western diets (WD). The CR group was significantly leaner than the WD group. Heart rate was significantly lower, and virtually all HRV significantly higher in the CR than in the WD group. HRV in the CR individuals was comparable to published norms for healthy individuals 20 years younger. In addition, when differences in HR and HRV between CR and WD were compared with previously-published changes in HRV induced in healthy adults given atenolol, percent differences in each measure were generally similar in direction and magnitude and suggested declines in sympathetic and increases in parasympathetic modulation of HR and increased circadian variability associated with CR. These findings provide evidence that CR has direct systemic effects that counter the expected age-associated changes in autonomic function so that HRV indexes in CR individuals are similar to those of individuals 20 years younger eating WDs,"

Link: http://www.ncbi.nlm.nih.gov/pubmed/22510429

If you are around 40 years of age and basically average in terms of genes and health, the odds are good that in your first few decades you gained little in the way of longevity advantages over someone 20 years your senior, living in the same location. Medical science is progressing, but the young in wealthier regions of the world don't really use or need all that much medical technology once past the point of vaccinations and the standard - and diminishing - brace of infectious childhood diseases. The point here is that the bulk of any technology-dependent difference in your life span has yet to be engineered: it depends on how well you take care of the health basics from here on out, and far more on how rapidly medical technology progresses towards working rejuvenation biotechnology. If that medical technology isn't researched, isn't developed, isn't made available in a competitive marketplace, then the life trajectory of your parents is not an unreasonable model for your life.

If medical technology stopped moving forward now, then, sad to say, most people would not live a great deal longer than their parents. Gains due to medical technology are all in the future - they can be seen, discussed, and worked on in detail, but they are not here yet. What does that mean? It means that if you are 40, you're half-way done. You have half of the hour-glass left in which to make a difference - to help build the technologies that will smash this limitation of the human condition. Here are some recently released tables of European demographic data to reinforce the point:

In 2009 men in the European Union (EU27) could expect 61.3 Healthy Life Years (HLY), representing almost 80% of their life expectancy (LE) at birth of 76.7 years. Women could expect 62 HLY, 75% of their life expectancy (LE) at birth of 82.6 years in 2009.

Life expectancy at birth is an artificial construct - it is a measure of quality of health and medical technology, useful for comparisons, not a number that corresponds to what will happen to people born now or who are alive now. It reflects the life expectancy of a person born now if every statistical measure of health and mortality derived from the present population remained the same into the future. So in an age of advancing technology you would expect life expectancy figures to be lower than what will turn out to be the average age attained by your peers.

But still, it should be clear that unless progress in extending healthy life becomes more radical and less incremental, there are fair odds of 40-year-old you not living to see 80. This is not what anyone wants to hear, but it is what it is - the only way to make this different is to work to make it different. Support the work of the SENS Foundation, for example, or other causes that are involved in the science of extended human longevity and repair of aging.

One other item to keep in mind is that the cultural and financial institutions - such as Social Security in the US - that are ostensibly there to provide for you in old age some decades from now won't be around to help you. The money you're presently giving to your local government that is supposedly for that purpose? It's gone. That was nothing but a wealth transfer from you to someone further ahead in the ranks of the Ponzi scheme that you've all been drafted into. The system as it stands is set for collapse, with bailouts and massive devaluation of national currencies along the way, and that's before we consider the likely increases in longevity above and beyond the prediction models presently in use:

An IMF analysis says advanced economies would need to set aside half of their GDP today to pay for a three-year increase in longevity that is actuarially likely by 2050. ... Over the past several decades, governments have consistently underestimated longevity projections and thus have underestimated their pension liabilities. If people live just three years more than expected in 2050, which is in line with the average underestimates of the recent past, the funding gap to pay retirement benefits would be 1% to 2% per year - an amount equal to 50% of 2010 GDP. This gain in longevity will come as a huge shock to public and private pension schemes that are already woefully underfunded.

The point being this: don't look to the future thinking that anyone else is going to pay your way right at the point when it would be peachy keen to have funds for those new medical technologies that will reverse some of the aspects of your age-related degeneration. For one, do you really want to be just another grasping pawn in this vast game of generational theft, and for two, the odds are that the game will be over before you have the chance to do anything other than pay for someone else's increased standard of living. So make your own plans: save, save, save, and invest wisely.

Nature comments on recent advances: "At the turn of the twentieth century, the promise of regenerating damaged tissue was so far-fetched that Thomas Hunt Morgan, despairing that his work on earthworms could ever be applied to humans, abandoned the field to study heredity instead. Though he won the Nobel Prize in 1933 for his work on the role of chromosomes in inheritance, if he lived today, the advances in regenerative medicine may have tempted him to reconsider. Three studies published this week show that introducing new cells into mice can replace diseased cells - whether hair, eye or heart - and help to restore the normal function of those cells. These proof-of-principle studies now have researchers setting their sights on clinical trials to see if the procedures could work in humans. ... You can grow cells in a Petri dish, but that's not regenerative medicine. You have to think about the biology of repair in a living system. ... Japanese researchers grew different types of hair on nude mice, using stem cells from normal mice and balding humans to recreate the follicles from which hair normally emerges. ... A second study using regenerative techniques helped to restore some vision to mice with congenital stationary night blindness, an inherited disease of the retina. ... [Researchers reprogrammed] cardiac fibroblasts into cardiomyocytes - the muscle cells of the heart that are permanently lost after a heart attack. The team used a retrovirus to deliver three transcription factors that induced the reprogramming in adult mice, and improved their cardiac function. ... These three papers are just the tip of the iceberg. By the time we grow old, doctors are going to look back and say, 'Can you believe people used to go bald, go blind or even have their leg cut off from vascular disease?' - and then the doctor will treat the problem with an injection of cells."

Link: http://www.nature.com/news/regenerative-medicine-repairs-mice-from-top-to-toe-1.10472

Via EurekAlert!: "Daily physical exercise may reduce the risk of Alzheimer's disease, even in people over the age of 80 ... The study showed that not only exercise but also activities such as cooking, washing the dishes and cleaning are associated with a reduced risk of Alzheimer's disease. These results provide support for efforts to encourage physical activity in even very old people who might not be able to participate in formal exercise but can still benefit from a more active lifestyle. ... For the study, a group of 716 people with an average age of 82 wore an actigraph, a device that monitors activity, on their non-dominant wrist continuously for 10 days. All exercise and non-exercise was recorded. They also were given annual tests during the four-year study that measured memory and thinking abilities. During the study, 71 people developed Alzheimer's disease. ... The research found that people in the bottom 10 percent of daily physical activity were more than twice as likely to develop Alzheimer's disease as people in the top 10 percent of daily activity. The study also showed that those people in the bottom 10 percent of intensity of physical activity were almost three times as likely to develop Alzheimer's disease as people in the top 10 percent of intensity of physical activity."

Link: http://www.eurekalert.org/pub_releases/2012-04/aaon-gmd041012.php

Researchers have been manipulating stem cells to cause hair follicles to form and hair to grow for a few years now. Consider this research from 2009, for example:

Professor Lin Sung-jan took 10 hair follicles from rodents and cultivated 8 to 10 million dermal papilla cells in vitro in 20 days. Using aggregates of between 3 and 5 million dermal papilla cells, he mixed these with rodent skin cells and transplanted them onto bare rodent skin, which sprouted hair.

Bald skin and haired skin have the same cell populations needed to grow hair, as it turns out, so this sort of cell-based approach has merit. The end of the story will likely be some form of cell signalling treatment to instruct cells already present in the body to form hairs in an area of skin rather than cell transplants - but transplants are first in line for development. The process is not exactly straightforward, unfortunately. Much like the tissue engineering of teeth, some form of guiding technology must be established to ensure that the cells grow as they should - without it, you end up with misshapen or broken structures.

On this subject, the work of a Japanese group on hair regeneration has been in the news of late, and they seem to have established a proof of principle for guiding correct hair growth. You'll find an open access paper and a couple of popular press items to choose from, complete with pictures of a hairless mouse sporting a patch of engineered hair:

Previously, Tsuji and colleagues had bioengineered follicles and hair shafts in the lab using epithelial and mesenchymal cells from mouse embryos. Until now, it was unclear whether these organized clusters of cells would make normal hair if inserted into mouse skin.

In the new work, the team transplanted a group of the engineered follicles into the skin on the backs of hairless mice. After about two weeks, hairs began to sprout. Under the microscope, the hair grown from the bioengineered mouse follicles resembled normal hair, scientists found. And the mouse follicles went through the normal cycle of growing hair, shedding and making new hair.

When researchers injected the region around the bioengineered follicle with acetylcholine, a drug that causes muscles to contract, the hairs perked up. This suggests that the transplanted follicles had integrated with surrounding muscle and nerves like normal hair follicles do.

Importantly, the researchers were able to ensure hair didn't become ingrown or point in the wrong direction by attaching a nylon thread to the engineered follicles and guiding the hair to grow outward.

That guide method doesn't sound very scalable - though given that there is a market for hair restoration techniques that involve moving follicles one by one, I could see it finding use in the clinic. But we can live without our hair and our vanity; a legion of far more serious and life-threatening degenerations accompany aging, and those are where our attention should be directed. The most important long-term effects of this particular line of research will, I think, be the application of the lessons learned to other areas of tissue engineering: guiding the regeneration of small complex structures, of which there are a great many in the body.

The results also mark a step forward in efforts to regenerate organs such as salivary glands that form in a process similar to hair early in their development.

From Queen Mary, University of London, investigation of the mechanisms of periodontitis in aging: "New research [sheds] light on why gum disease can become more common with old age. The study, published in Nature Immunology, reveals that the deterioration in gum health which often occurs with increasing age is associated with a drop in the level of a chemical called Del-1. The researchers say that understanding more about Del-1 and its effects on the body's immune system could help in the treatment or prevention of serious gum disease. ... As people age they are more likely to suffer from inflammatory diseases, including gum disease. The new research investigated gum disease in young and old mice and found that an increase in gum disease in the older animals was accompanied by a drop in the level of Del-1. This protein is known to restrain the immune system by stopping white blood cells from sticking to and attacking mouth tissue. Mice that had no Del-1 developed severe gum disease and elevated bone loss and researchers found unusually high levels of white blood cells in the gum tissue. When they treated the gums of the mice with Del-1, the number of white blood cells dropped, and gum disease and bone loss were reduced. The researchers say their findings could be the basis for a new treatment or prevention of gum disease."

Link: http://www.qmul.ac.uk/media/news/items/smd/71770.html

Researchers are not having as much success as they'd like in finding unambiguous associations between specific genes and human longevity - studies are turning up results, but few are similar between populations, indicating that the genetics of natural variations in longevity are probably very complex: "It has long been thought that related individuals share a familial predisposition to longevity, and for more than a century numerous studies have investigated the degree to which human longevity might be an inherited characteristic. Most studies of this type have reported small (∼10%) to moderate (∼30%) heritability of human longevity, amid differences in definitions of longevity, methods of measuring it, ascertaining individuals who demonstrate it, and in various behavioral and environmental settings. These methodological differences likely account for much of the variation in the resulting estimates of the heritability of longevity. ... We identified individuals from a large multigenerational population database (the Utah Population Database) who exhibited high levels of both familial longevity and individual longevity. This selection identified 325 related 'affected individuals', defined as those in the top quartile for both excess longevity (EL=observed lifespan - expected lifespan) and familial excess longevity (FEL=weighted average EL across all relatives). A whole-genome scan for genetic linkage was performed on this sample using a panel of 1100 microsatellite markers. A strongly suggestive peak was observed in the vicinity of D3S3547 on chromosome 3p24.1, at a point nearly identical to that reported recently by an independent team of researchers from Harvard Medical School (HMS). ... Corroboration of the linkage of exceptional longevity to 3p22-24 greatly strengthens the case that genes in this region affect variation in longevity and suggest, therefore, an important role in the regulation of human lifespan. Future efforts should include intensive study of the 3p22-24 region."

Link: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3323558/

There are many possible forms of therapy that either might be built or are presently being built atop of a greater knowledge of stem cells and cell biotechnologies. Cultured populations of stem cells can be let loose into the body to do their work, or existing cells can be directed to take action where they would normally stand aside, or tissues can be constructed for transplant, and many more variants upon these themes. As explained in a recent open access paper, stem cells can also stand duty as a method of delivering a therapy rather than being a form of therapy themselves: they can move around the body largely unhindered, and different types of stem cells have quite strong opinions as to which part of the body they would like to migrate towards. Given the right signals, stem cells can even be directed to quite specific locations - consider the way in which cells respond to injury, for example. This is but one of countless signals that cause stem cells to travel or take specific actions: a great deal of future medicine will be based on better understanding and control over stem cells in the body.

So let us say that you want to move a dose of a fragile therapeutic molecule into the brain, past the blood-brain barrier - and, further, to quite specific locations within the brain. Why not enlist stem cells to carry it in? Unfortunately it's not completely straightforward - stem cells have their own ideas as to where they would like to go, and if that isn't suited to the need at hand, then further improvement in control is needed. The basic concept still looks promising, however, even though early attempts are not achieving great results:

Transplantation of neural stems cells (NSCs) could be a useful means to deliver biologic therapeutics for late-stage Alzheimer's disease (AD). In this study, we conducted a small preclinical investigation of whether NSCs could be modified to express metalloproteinase 9 (MMP9), a secreted protease reported to degrade aggregated Aβ peptides that are the major constituents of the senile plaques.

Our findings illuminated three issues with using NSCs as delivery vehicles for this particular application. First, transplanted NSCs generally failed to migrate to amyloid plaques, instead tending to colonize white matter tracts. Second, the final destination of these cells was highly influenced by how they were delivered.

...

Overall, we observed long-term survival of NSCs in the brains of mice with high amyloid burden. Therefore, we conclude that such cells may have potential in therapeutic applications in AD but improved targeting of these cells to disease-specific lesions may be required to enhance efficacy.

The medicine of the 2040s may involve more cell therapies than any other area at the present pace: cells ordered around, changed in situ into augmented bioartifical machinery to conduct repairs or deliver compounds to needed locations, or even joined by artificial cells that carry out similar duties but more effectively. We are built of cells, so it makes some sense that our medical technology might eventually also be largely built of cells, act through cells, or otherwise be based on the direct control and repair of cells.

Breakout Labs is a part of Peter Thiel's vision of radical philanthropy in science and technology funding, modeled on the venture capital industry and aiming to invest in high risk, high reward programs: "The Thiel Foundation announced today the first grants awarded through Breakout Labs, its revolutionary revolving fund to promote innovation in science and technology. ... it provides teams of researchers in very early-stage companies with the means to pursue their most radical goals in science and technology. Breakout Labs has awarded six grants, of up to $350,000 each, to the following recipients: ... 3Scan, to develop 3-D digital reconstruction of brain tissue, using a novel, faster, less expensive microscope technology. Building a map of connections in the brain-the connectome-is a critical step to understanding what makes the human brain unique. ... Arigos Biomedical, to develop methods of cooling organs for long-term storage. When combined with emerging advances in cryopreservation, tissue engineering, and stem cell therapies to eliminate graft rejection, this technology would make banked organs immediately available to anyone needing a transplant. ... Immusoft, to re-program human immune cells to produce therapeutics in the body. This technology could dramatically improve the ability to treat a range of diseases, as well as enhance human health and longevity. ... Longevity Biotech, to develop an entirely new class of therapeutics via artificial protein technology ("Hybridtides"). Hybridtides are targeted biologic-like molecules which are highly-resistant to breakdown by natural digestive enzymes and tunable to very stable molecular structures. These features have demonstrated potent therapeutic activity with the possibility of oral biologic delivery. ... In the past, people dreamed of the future as a radically better, more technologically advanced place: you might live for centuries, delegate work to your robots, and take your vacations on the moon. Now, many people expect their children to inherit a world worse than today's. With Breakout Labs, we want to rekindle dreams of an amazing future. That's why we're supporting researchers who dream big and want to build a tomorrow in which we all want to live."

Link: http://www.breakoutlabs.org/news-events/news-event-item/article/breakout-labs-announces-first-grantees.html

A research group is claiming that fullerenes (C60, ingested and injected) greatly extend life span in rats; this is meeting with some considerable skepticism, given the degree of life extension and the lack of a plausible mechanism. "In the current study researchers fed the molecule dissolved in olive oil to rats and compared outcomes to a control group of rats who got plain olive oil. The main question they wanted to answer was whether chronic C60 administration had any toxicity, what they discovered actually surprised them. ... Here we show that oral administration of C60 dissolved in olive oil (0.8 mg/ml) at reiterated doses (1.7 mg/kg of body weight) to rats not only does not entail chronic toxicity, but it almost doubles their lifespan. ... The estimated median lifespan (EML) for the C60-treated rats was 42 months while the EMLs for control rats and olive oil-treated rats were 22 and 26 months, respectively. Using a toxicity model the researchers demonstrated that the effect on lifespan seems to be mediated by 'attenuation of age-associated increases in oxidative stress'." So what might be going on here? The average life span of the Wistar rats used is 2-3 years (24 - 36 months). This was a small study size, but that's not so important in determining whether you have an actual means of life extension if you can show that any of your study group lived much longer than usual - but it is important when it comes to the degree of life extension. If the study group is small, as it is here, using only a handful of rats, then the size of the effect can be much more readily distorted by chance. This line in the paper jumped out at me: "Before C60 administration, the rats were fasted overnight but with access to water." If they failed to fast the control group, then we're looking at yet another study that failed to control for calorie restriction, and this is actually largely an intermittent fasting study - which has certainly been shown to extend life in rats.

Link: http://extremelongevity.net/2012/04/16/chronic-buckyball-administration-doubles-rat-lifespan/

This hour-long video presentation from the SENS5 conference features research Caleb Finch, one of the leading figures in the mainstream of aging research:

Since the 18th C, human life spans have increased globally from a life expectancy at birth (LE0) of 25-40y, to over 80y in healthy countries; the LE70 has also more than doubled. ... These remarkable changes are attributable to reduced loads of infections from public health and improved nutrition, starting long before immunization and antibiotics. Reduced inflammatory and infections loads are hypothesized to retard a broad suite of age-related degenerative conditions. Even brief exposure to infections in a well nourished population can have long-term consequences, as illustrated by the 1918 Influenza which increased later-life heart disease by 25% in the cohort that was prenatally exposed.

The historical improvements in life expectancy that accompany lower levels of chronic disease are an excellent illustration of aging as an accumulation of damage - that data fits well with the application of reliability theory to aging, for example. Find a way to reduce exposure to damage at the level of cells and molecular machinery and life will lengthen.

Researchers like Finch - epidemiologist S. Jay Olshansky being another with similar views - see the most plausible future as an extension of this gradual improvement from the past. It won't be the same processes at work, because the easy gains accruing from control over infectious disease have been achieved, but it will be another gradual shifting of the chart of life expectancy, just a little progress achieved with each passing year of modestly longer lives. In this view of the world, growing levels of obesity form a very serious threat that may reduce life expectancy by causing more harm than incremental medical progress will prevent.

This sort of viewpoint is, I think, harmful to the prospects for significant advances to arise from initiatives like the Strategies for Engineered Negligible Senescence. When gradualism is institutionally entrenched, radical investigations with radical goals are discouraged at every level, from student education through to the funding rat race, and cautious predictions in public do not attract the sort of supporters and researchers who can make bold strides. This is why we need philanthropists willing to back those who can credibly think outside the box and shoot for the moon. Big risks and potentially very large payoffs. In this time of revolution and progress in biotechnology, when better to break out of the straightjacket vision of incremental progress and tinkering with metabolism?

Following on from a recent presentation on cost-effectiveness in longevity research, here's an interview with Aubrey de Grey of the SENS Foundation at 80,000 hours: "ZR: Back to matters financial... How much funding would your programme actually need to complete its goals? Paraphrasing your talk again, you guesstimated '$50,000,000 allocated appropriately would be 'enough for the next while''. Can you be a bit specific about what 'the next while' means? ... AdG: I think I said $50M per year. 20M/year would be a good start, and I think above $100M/year we'd be reaching diminishing returns. This is tiny compared to (for instance) the NIH budget, but that's because it's only the budget for the next several years, when the key work will be on mice rather than humans. ... It's pretty clear that a dollar makes more difference when spent on early-stage biomedical research (which is what we'd spend it on) than on the delivery of existing therapies. ... ZR: How confident are you about the success of your program? I'll paraphrase a couple of off-the-cuff remarks on the subject you made in your 80K talk: 'We'll get to robust human rejuvenation - within the next 25 years with 50% probability.' 'I'd give a 10% chance we won't get there for 100 years.' Would you modify these now you're not on the spot? What exactly do you mean by robust human rejuvenation? Is that the same thing as reaching what you call the ageing escape velocity? (for the benefit of readers: the point at which progress in our ability to extend our lifespans surpasses the rate at which we age, effectively making us immune to age-related death) ... AdG: I still stand by both those statements, but please note that I always add the caveat that the former depends on adequate funding, especially in the coming decade. I define 'robust human rejuvenation' (RHR) as the addition of 30 years of extra healthy life to those who are already 60 when the therapies are first given. Longevity escape velocity is different - it's the postponement of aging faster than time is passing, which results from continued progress in improving the comprehensiveness of the therapies. The moment at which we reach LEV, which we call the Methuselarity (and we're pretty sure there will be inly one such moment, i.e. that once we exceed LEV we will never fall below it again), will probably occur at around the same time when we achieve RHR - maybe a little sooner, maybe a little later."

Link: http://80000hours.org/blog/42-living-to-1000-an-interview-with-aubrey-de-grey

Researchers manage to make an immunotherapy work well in aged immune systems - which is important, as most of the potential uses for immune therapies will target older people: "a new study [shows] that some types of immunotherapy previously thought to work only in younger patients can be used to help the elderly, with less toxic effects than many common therapies, if combined in ways that account for age-related changes in the immune system. ... We've shown that immunotherapy for cancer not only works in aged mice, but actually can work better in aged hosts than in young counterparts by capitalizing on the immune changes that happen with age ... As you age, most parts of your body begin to wear out. They keep doing what they're made to do [but] over time, they don't do it as well. The general perception is that the immune system also simply declines with age. ... That's really too simplistic. That's really not the full picture of what's happening. ... The body's immune system does weaken with age, but it also changes, and that changes the rules for fighting disease within the body. [The researchers] started by examining an immune therapy that they previously had shown to work in younger hosts, including cancer patients. It's designed to eliminate regulatory T cells (called Tregs), which are cells that turn off immune responses, allowing cancer to progress. Tregs increase in cancer. In young hosts, the drug turns off Treg activity, allowing the immune system to function better. In older hosts, even though the drug turns off the Tregs, it has no clinical benefit. ... In older mice, when the drug turned off the Tregs, the researchers found that another type of immune suppressor cell (a myeloid-derived suppressor cell or MDSC) exploded in number to take the Tregs' place, hampering clinical efficacy. That did not happen in young mice. The team added a second drug that targets the MDSC, and found that with those tools to help immunity, the older hosts can combat cancer just as well as the younger hosts."

Link: http://www.eurekalert.org/pub_releases/2012-04/uoth-ife041012.php

Daniel Perry of the Alliance for Aging Research was kind enough to send over an article written in conjunction with Brian Kennedy of the Buck Institute for Research on Aging. I take this as a sign that various conjunctions are imminent in the moving spheres of government funding of aging research and the broader pressures on the economy. Organizations like these two have their own cycles of publicity and outreach that ebb and flow in time with potential shifts in public funding:

Bette Davis was right - old age is not for sissies.

One hundred years ago most of us didn't have the luxury of old age. Today, life expectancy is almost 80 years. But while we've gotten very good at adding life-years, we've yet to master how to keep those years healthy and vigorous. Eighty percent of seniors have at least one major chronic condition and half have two or more. Chronic diseases of later life are costing the nation more than $1 trillion per year - a figure expected to increase to $6 trillion by the middle of this century.

Scientists who study aging are in general agreement that the process isn't set in stone - the aging process can be sped up by genetics or poor lifestyle choices, but it can also be slowed down. With sufficient funding and focus, research that slows aging has the potential to do what no drug, surgical procedure, or behavior modification can do - add healthy years of life, and simultaneously postpone the costly and harmful conditions of old age.

Age is the common denominator and number one risk factor to virtually every chronic disease we face. Scientists know that alterations in cell replacement and repair, stress response, and inflammation are the key influencers to the development of cancer, heart disease, diabetes, and other debilitating (and costly) conditions later in life. These are also the essential changes taking place in our aging bodies.

There are currently 10,000 Americans a day turning 65; by 2030, about one in five Americans will be past that age. To afford the eldercare costs that lay ahead our country must invest now in the prevention and postponement of age-related illness. New realities of population aging and chronic disease call for new thinking how we fund biomedical research. The great majority of federal medical research funds goes to studies of diseases of aging such as cancer, heart ailments and diabetes in isolation from each other and largely divorced from the underlying aging processes that lead to all of them. Less than one percent of the National Institutes of Health's (NIH) annual budget funds research into the underlying biology of aging and its role in age-related disease.

Meanwhile privately funded research centers such as the Buck Institute for Research on Aging in California and other centers in universities across the U.S. are probing new understanding of aging in order to defeat diseases from cancer to Alzheimer's. And the private non-profit Alliance for Aging Research is pressing a 'Healthspan Campaign' pointing out the large social and economic rewards to be gained by increasing the federal investment in medical research with a greater focus on the underlying biology of aging.

Already the National Institutes of Health, which is mostly organized by various disease research programs, has initiated a cross-cutting interest group involving 17 separate NIH Institutes to pursue "geroscience," a new term for understanding our aging bodies so we might experience more healthy years of life. At a time when even medical research is feeling a funding squeeze, for multiple research institutes to pool expertise and resources in order to confront the mammoth health challenge of an aging population, this is a prudent course and a sound public investment for America's future.

Recently, the Director of the NIH, Dr. Francis Collins, testified before the Senate subcommittee that determines future appropriations. We were encouraged that the promise of more coordinated research into aging was set before important members of Congress who help determine research priorities. As we have learned from the experience with polio and HIV/AIDS, significant federal investment in biomedical research can have a profound impact on not only reducing mortality and morbidity, but on reducing healthcare costs.

The evidence is strong that the single most effective strategy in "bending the cost curve" on health care is preventing age-related chronic diseases in the first place. It will require courageous and innovative policy-making to step outside the traditional way medical research priorities have been established. Just as old age is not for sissies, neither is forward-looking public policy.

---

Daniel P. Perry is President and CEO of the Alliance for Aging Research.
Brian K. Kennedy, Ph.D. is President and CEO of the Buck Institute for Research on Aging.

It's possible to agree with everything said above about aging and the need for action, and then completely disagree that a wise use of time is chasing tax dollars and playing the lobbying game - putting money into the pockets of politicians and their cronies rather than research institutions. Government funding comes with government regulation and government values: it corrodes everything it touches, destroys the incentives to create progress, blocks clinical applications of research, and turns even the most ambitious ideals into staid jobs programs for the connected that win ever more money by failing to achieve any of their goals.

My view of the ideal future for the funding of medical research is closer to that of Peter Thiel - venture philanthropy, crowdsourcing for research, radical distribution of research collaboration between regions of the world, open biotechnology and science, and big financial risks put on programs like the Strategies for Negligible Engineered Senescence that have massive payoffs on achieving success. This is a future in which the connectivity of the Internet, dirt-cheap biotechnology, crowdsourcing, cheap air travel, and medical tourism combine to make every present institution in medical research irrelevant.

So avoid like the plague the incremental, aim-for-one-little-bit-better, money-chewing philosophy of government expenditures and near-sighted goals, that's what I say. Political culture is unable to look past the present and unable to avoid corruption. If you leave progress up to politicians and the regulatory capture collective that is Big Pharma, all you'll get is waste, "progress" that is one step short of stasis, and the building of institutions that - like the FDA - are incentivized to prevent the future, not unleash it.

So in conclusion, I see folk like the authors above to be in some ways rather like the A4M business leaders, for all that their politics couldn't be any more different. By that I mean that their hearts are in the right place, they have an enthusiasm for the cause of really, actually doing something about aging, but are heading down the wrong road when it comes to achieving significant, game-changing progress in longevity science by the only metric that matters - how long we all live.

Transdifferentiation is showing up more often of late - the ability to switch somatic cells directly between types without having to go through an intermediate stage of reprogramming into stem cells. It should in theory make obtaining specific cells for research and therapy a cheaper and more reliable process in the future: "it has become possible to directly convert cells of the body into one another - without the time-consuming detour via a pluripotent intermediate stage. However, this method has so far been rather inefficient. [Scientists] have now developed the method to the point that it can be used for biomedical applications. ... [Researchers] are interested in the biomedical utilization of artificially produced human nerve cells for disease research, cell replacement, and the development of active substances. ... By blocking the so-called SMAD signaling pathway and inhibiting glycogen synthase kinase 3 beta (GSK3ß), they increased the transformational efficiency [of skin cells to neurons] by several times - and were thus able to even simplify the means of extraction. Using only two instead of previously three transcription factors and three active substances, [the] researchers were able to convert a majority [of] skin cells into neurons. In the end, their cell cultures contained up to more than 80% human neurons. ... We were able to demonstrate how the genes typical for skin fibroblast were gradually down-regulated and nerve-cell-specific genes were activated during the cell transformation. In addition, the nerve cells thus obtained were functionally active, which also makes them interesting as a source for cell replacement."

Link: http://www.sciencedaily.com/releases/2012/04/120411084044.htm

As time progresses, researchers are increasingly able to correlate changing mental characteristics in aging with changing structure in the brain. Here is one example: "A brain-mapping study [has] found that people's ability to make decisions in novel situations decreases with age and is associated with a reduction in the integrity of two specific white-matter pathways that connect an area in the cerebral cortex called the medial prefrontal cortex with two other areas deeper in the brain. Grey matter is the part of the brain that contains the bodies of the neurons while white matter contains the cable-like axons that carry signals from one part of the brain to another. In the past, most brain-imaging research has concentrated on the grey matter. Recently, however, neuroscientists have begun looking more closely at white matter. It has been linked to the brain's processing speed and attention span, among other things, but this is the first study to link white matter to learning and decision making. ... The evidence that this decline in decision-making is associated with white-matter integrity suggests that there may be effective ways to intervene. Several studies have shown that white-matter connections can be strengthened by specific forms of cognitive training. ... The critical white-matter connections that the experiment identified run from the thalamus, a highly connected relay center in the brain, to the medial prefrontal cortex, an area of the brain involved with decision making, and from the medial prefrontal cortex to the ventral striatum, which is associated with the emotional and motivational aspects of behavior." You might also look at past research on age-related damage to white matter and its consequences on metal capacity.

Link: http://www.sciencedaily.com/releases/2012/04/120411131917.htm

Resistance to cancer and increased longevity are thought to be flip sides of the coin when it comes to variations in metabolism and the controlling mechanisms of stem cell action. Either your cells are more ready to divide and repair your tissues, in which case you have increased longevity coupled with increased risk of cancer, or your cells are less ready to divide and repair your tissues and as a consequence you are less likely to suffer cancer, but also less likely to live for as long as your contemporaries in the scenario under which you do evade cancer. The decline of stem cell capacity with age is thought to be an adaptation to resist the increasing risk of cancer due to rising levels of cellular and molecular damage - the less that your stem cells take action, the less likely it is that a cancerous mutation will occur and take hold.

Cancer is a game of odds, in other words. We're all rolling those dice, day in and day out - regardless of how indifferent we are or pretend to be. It's a sobering thought.

On this topic, I noticed an intriguing twin study today that suggests the naturally longer-lived humans amongst us are having their cake and eating it too when it comes to the supposed cancer-longevity balance. There's no balance here at all, just benefits all round from happening to be naturally longer-lived:

BACKGROUND: Animal models and a few human studies have suggested a complex interaction between cancer risk and longevity indicating a trade-off where low cancer risk is associated with accelerating aging phenotypes and, vice versa, that longevity potential comes with the cost of increased cancer risk. This hypothesis predicts that longevity in one twin is associated with increased cancer risk in the cotwin.

METHODS: A total of 4,354 twin pairs born 1900-1918 in Denmark were followed for mortality in the Danish Civil Registration System through 2008 and for cancer incidence in the period 1943-2008 through the Danish Cancer Registry.

RESULTS: The 8,139 twins who provided risk time for cancer occurrence entered the study between ages 24 and 43 (mean 33 years), and each participant was followed up to death, emigration, or at least 90 years of age. The total follow-up time was 353,410 person-years and 2,524 cancers were diagnosed. A negative association between age at death of a twin and cancer incidence in the cotwin was found in the overall analyses as well as in the subanalysis stratified on sex, zygosity, and random selection of one twin from each twin pair.

CONCLUSIONS: This study did not find evidence of a cancer-longevity trade-off in humans. On the contrary, it suggested that longevity in one twin is associated with lower cancer incidence in the cotwin, indicating familial factors associated with both low cancer occurrence and longevity.

It's worth remarking that the ultimate goal for longevity science is to make this and all similarly interesting discoveries absolutely irrelevant - to create a world in which it no longer matters in the slightest which genes we are born with. Sufficiently advanced medical technology - such as that envisaged in the Strategies for Engineered Negligible Senescence, which could be produced within the next twenty to thirty years given the funding - will enable all people to live extremely long lives in good health regardless of their genetic heritage. This is all the more reason to support that research; doing something about the limitations of the human condition beats sitting around listening to the dice roll and your chances of cancer inch upward year by year.

An article from the Scientist: "Based on new intelligence, oncologists are making informed battle plans to attack a particularly pernicious enemy - the cancer stem cell (CSC). Controversial though they are, cancer stem cells are an incredibly promising target. If treatment-resistant cancer, and the metastases that transplant the cancer throughout the body, could be attributed to the actions of a single cell type, it could explain many of the treatment failures and provide a novel way to attack the disease. The idea that cancers are driven by cells with 'embryonic features' is an old one. Many cancers regress to a less differentiated state, expressing proteins that are usually expressed only in the embryo or during early development. It is only in the past 20 years or so, however, that additional observations led to the hypothesis that these embryonic-like cells were a separate subpopulation that fueled tumor expansion, much the same way that stem cells churn out the cells that make up a particular organ. ... In the past 5 years there has been an exponential increase in CSC research. This research has helped to resolve a number of controversies regarding identification of these cells and their role in driving tumor growth and mediating treatment resistance. Despite these advances, the CSC field is still in its relative infancy, and many questions and challenges remain. More than a dozen biotechnology and pharmaceutical companies are now vigorously pursuing CSC research. As a result, a number of early-phase clinical trials targeting CSCs are in progress. These studies and the later-stage efficacy trials that follow them should indicate whether successful targeting of CSCs significantly improves outcomes in cancer patients. If this is found to be the case, it may usher in the beginning of a new era of cancer therapy."

Link: http://the-scientist.com/2012/04/01/are-cancer-stem-cells-ready-for-prime-time/

A look at why, in this age of biotechnology and great uncertainty over the degree to which life spans will be extended in the next few decades, it is unwise to trust your financial future to large pension and welfare institutions. Any significant progress over the present very modest baseline of incidental life extension through general advances in medicine will likely bring down much of the existing system in the years ahead - which of course suggests that big centralized pension systems should be avoided like the plague, but that won't happen. If today's politics are any guide, politicians will continue to aggressively devalue their national currencies, taking wealth from their broader population to pay for what cannot be afforded until such time as the house of cards cannot be propped up any longer. The lesson to be taken away here: expect to provide for your own financial security in later life, and act accordingly now: "Here's the issue: governments have done their analysis of the aging issue largely based on best guesses of population developments in the future. These developments include further drops in fertility and some further increase in longevity. The trouble is that in the past, longevity has been consistently and substantially underestimated. We all live much longer now than had been expected 30, 20, and even just 10 years ago. So there is a good chance in the future people will live longer than we expect now. We call this longevity risk - the risk we all live longer than anticipated. ... Why is that a risk, you may ask. We all like to live longer, healthy lives. Sure, but let's now return to those pension worries. If you retire at 65 and plan your retirement finances expecting to live another 20 years (assuming you have enough savings for at least that period), you would face a serious personal financial crisis if you actually live to 95, or - well in your 100s. You could rely on your social security system at that point, but the program is also counting on people not living much beyond their mid-80s in most countries. Your personal financial problem multiplies by the size of the population, and, for society as a whole, becomes a very large problem." An example of how the present politics and systems of wealth transfer reward irresponsibility at all levels until such time as growth in collective irresponsibility sinks the whole venture.

Link: http://www.huffingtonpost.com/erik-oppers/seven-billion-reasons-to-_b_1417749.html

By way of a follow-up to an interview last month on what are termed very small embryonic-like stem cells (VSELs), here is a recent open access review paper that outlines the present state of knowledge on this topic - which has some relevance to studies of longevity in addition to the broader field of regenerative medicine:

Very small embryonic/epiblast-like stem cells (VSELs) and their potential role in aging and organ rejuvenation - an update and comparison to other primitive small stem cells isolated from adult tissues:

One of the most intriguing questions in stem cell biology is whether pluripotent stem cells (PSCs) exist in adult tissues. Several groups of investigators employing i) various isolation protocols, ii) detection of surface markers, and iii) experimental in vitro and in vivo models, have reported the presence of cells that possess a pluripotent character in adult tissues. Such cells were assigned various operational abbreviations and names in the literature that added confusion to the field and raised the basic question of whether these are truly distinct or overlapping populations of the same primitive stem cells. Unfortunately, these cells were never characterized side-by-side to address this important issue. Nevertheless, taking into consideration their common features described in the literature, it is very likely that various investigators have described overlapping populations of developmentally early stem cells that are closely related.

...

[We believe that] during embryogenesis, some PSCs give rise to [populations of less potent tissue-committed stem cells (TCSC)s] but some survive in adult tissues as a backup population of PSCs that renews the pool of TCSCs over time. In this scenario, PSCs are precursors of TCSCs during organ/tissue rejuvenation and a source of these cells in emergency situations when organs are damaged (e.g., heart infarct or stroke).

...

a main goal of the molecular analysis studies was to explain why VSELs do not fulfill the in vivo gold-standard criteria expected for PSCs (complementation of blastocyst development and teratoma formation in immunodeficient animals), which are seen with [embryonic stem cells] and [induced pluripotent stem cells]. To explain this discrepancy, we observed that VSELs, in a similar manner as late migratory primordial germ cells (PGCs), modify the methylation of imprinted genes, preventing them from uncontrolled proliferation and explaining their quiescent state in adult tissues

...

we proposed a hypothesis that relates aging, longevity, and insulin/insulin-like growth factors signaling (IIS) to the abundance and function of pluripotent VSELs deposited in adult murine tissues. We postulate that a decrease in the number of these cells due to prolonged IIS negatively affects the pools of TCSCs in various organs and has an impact on tissue rejuvenation and life span. In support of this notion, we observed a significantly higher number of VSELs in long-living murine strains (e.g., Laron dwarfs and Ames dwarfs), whose longevity is explained by low levels of circulating IGF1 and a decrease in IIS. By contrast, the number of VSELs is reduced in mice with high levels of circulating IGF1 and enhanced IIS (e.g., growth hormone-overexpressing transgenic mice) compared to normally aging littermates.

...

a chronic increase in caloric uptake that elevates circulating levels of IGF1 and [insulin] may contribute over time to depletion of [VSELs] from adult tissues, affect the generation of VSEL-derived TCSCs, and thus negatively affect life span. This explains why mice that have high levels of circulating blood plasma IGF1 and enhanced IIS display accelerated depletion of VSELs and have a shorter lifespan than age-matched littermates.

Interestingly, it is often the case that life science researchers spend years investigating the same entity within the body from different directions, working in comparative isolation from one another and developing quite divergent nomenclature. It is only later on that lines are drawn between the dots and some unity imposed on that area of research - this is more or less what happened for lipofuscin, for example, the build up of many mixed harmful chemicals inside cells that occurs with aging. Lipofuscin contributes to many different age-related conditions, and for years went by many different names in different subfields of medical and biological science, and few of the researchers were picking up on parallel and useful research outside their specialty.

So, even aside from the evidence amassed, it is entirely plausible that there is a great deal of this unification and synthesis yet to happen for portions of stem cell research - but on the other hand cells are very complicated beasts. To a certain degree calling something a stem cell or a particular type of stem cell at this time is a form of pidgeonholing in the face of complexity: a cell is quite capable of being sort of a stem cell or somewhat stem cell-like, and different types of stem cell might be as different from each other as they are from non-stem cells - and their categories all blur at the edges. Stemness isn't the result of a single switch, and is rather much more like a collection of linked controlling mechanisms.

Insofar as this all touches upon calorie restriction (CR) and its effects on health and longevity, we should absolutely expect that calorie restriction in some way affects stem cell populations for the better. Stem cells are an integral mechanism of health, and it would be hard to explain how CR improves near every measure of health, slows aging, and extends life in diverse animal species without it causing some improvement in stem cell capacity and operation in addition to its other lower level mechanical effects.

Signs of progress in understanding the mechanisms of induced longevity through altered insulin/IGF-1 signaling are shown in this paper. This is one of the most-studied class of longevity mutations in lower animals, despite there being some debate over whether it is relevant to mammal biochemistry. Here, the basic mechanism is explained as being hormetic, centering on the mitochondria: researchers "elucidate a conserved mechanism through which reduced insulin-IGF1 signaling activates an AMP-kinase-driven metabolic shift toward oxidative proline metabolism. This, in turn, produces an adaptive mitochondrial [reactive oxygen species (ROS)] signal that extends worm life span. These findings further bolster the concept of mitohormesis as a critical component of conserved aging and longevity pathways. ... Impaired insulin and IGF-1 signaling (iIIS) in C. elegans daf-2 mutants extends life span more than 2-fold. Constitutively, iIIS increases mitochondrial activity and reduces reactive oxygen species (ROS) levels. By contrast, acute impairment of daf-2 in adult C. elegans reduces glucose uptake and transiently increases ROS. Consistent with the concept of mitohormesis, this ROS signal causes an adaptive response by inducing ROS defense enzymes, culminating in ultimately reduced ROS levels despite increased mitochondrial activity. Inhibition of this ROS signal by antioxidants reduces iIIS-mediated longevity by up to 60%. ... IIIS upregulates mitochondrial L-proline catabolism, and impairment of the latter impairs the life span-extending capacity of iIIS while L-proline supplementation extends C. elegans life span. Taken together, iIIS promotes L-proline metabolism to generate a ROS signal for the adaptive induction of endogenous stress defense to extend life span."

Link: http://www.ncbi.nlm.nih.gov/pubmed/22482728

Researchers are comparing the biochemistry of long-lived species to better understand the roots of large differences in life span: "The team looked at the genome of more than 30 mammalian species to identify proteins that evolve in connection with the longevity of a species. They found that a protein, important in responding to DNA damage, evolves and mutates in a non-random way in species that are longer-lived, suggesting that it is changing for a specific purpose. They found a similar pattern in proteins associated with metabolism, cholesterol and pathways involved in the recycling of proteins. Findings show that if certain proteins are being selected by evolution to change in long-lived mammals like humans and elephants, then it is possible that these species have optimized pathways that repair molecular damage, compared to shorter-lived animals, such as mice. ... The genetic basis for longevity differences between species remains a major puzzle of biology. A mouse lives less than five years and yet humans can live to over 100 for example. If we can identify the proteins that allow some species to live longer than others we could use this knowledge to improve human health and slow the aging process."

Link: http://esciencenews.com/articles/2012/03/29/study.suggests.why.some.animals.live.longer

Back in 2006 I had this to say on the topic of what was then the first flush of popular interest in resveratrol, back when far less was known about it:

Our metabolic biochemistry looks like a big wall full of levers. Some of them are painted red, and we think we understand what the instructions beneath these red levers say. Maybe. How much information do you feel you would like before you pull the big red levers in your own personal metabolism? What level of risk due to disease would you presently need to be suffering in order to take the risk represented by a new compound? How do you evaluate these levels of risk?

Resveratrol has turned out, almost predictably, to be another heaped mound of hype that buries a modest kernel of interesting-but-not-terribly-applicable metabolic research. At this stage it seems fairly certain that resveratrol does not extend life in mammals to any great degree - when you find compounds that can do that, there is little uncertainty once the life span studies are in and replicated. See the past couple of years of work on rapamycin in mice as a contrasting example to the uncertainty and lack of verifiable effects for resveratrol and its derived compounds.

In any case, I was reminded of the topic by a recent post at In the Pipeline that echoes many of the same sentiments in my 2006 post:

I've written many times here about sirtuins, and their most famous associated small molecule, resveratrol. And I've been asked more than once by people outside the med-chem field if I take (or would take) resveratrol, given the available evidence. My reply has been the same for several years: no, not yet. Why so cautious, for a compound that's found in red grapes and other foods, and to which I've presumably been exposed many times? Several reasons - I'll lay them out and let readers decide how valid they are and how they'd weight these factors themselves.

...

So what do we know about what resveratrol does? A lot, and not nearly enough. Its pharmacology is very complex indeed, and the one thing that you can clearly draw from the (large) scientific literature is that its (a) a very biochemically active compound and (b) we haven't figured out many of those actions yet. Not even close. Even if all it did was act as on one or more sirtuins, that would be enough to tell us that we didn't understand it.

...

There's room to wonder about the mechanisms of a number of drugs. Indeed, there have been many that have made it to market (and stayed there for many years) without anyone knowing their mechanisms at all. We're still finding things out about aspirin; how much can one expect? Well, one response to that is that aspirin has been used widely in the human population for quite a long time now, and resveratrol hasn't. So the question is, what do we know about what resveratrol actually does in living creatures? If it has beneficial effects, why not go ahead and take advantage of them?

Unfortunately, the situation is wildly confusing (for an overview, see here). The first thing that brought resveratrol into the spotlight was life extension in animal models, so you'd think that that would be well worked out by now, but boy, would you be wrong. The confusion extends up to mouse models, where some of the conclusions - all from respectable groups in respectable publications - seem to flatly contradict each other. No, the animal-model work on resveratrol is such a bubbling swamp that I don't see how anyone can safely draw conclusions from it.

We can conclude that it doesn't straightforwardly extend life at this point. So you have on the one hand a distinct lack of knowledge as to long term effects and on the other hand it clearly isn't doing anything spectacular in laboratory animals. That looks like the worst of both worlds from where I stand.

The sensible thing to do whenever another of these oral-fixation ingested substance hype machines emerges from the juncture of the scientific and business worlds is to balance the purported results against the clear, proven, and solid benefits of exercise and calorie restriction. The risks in moderate exercise and calorie restriction are minimal, while the evidence for great benefit to long-term health is gold-plated and voluminous. When someone is trying to convince you to spend money on something that seems unlikely to produce even a pale shadow of the health benefits of either exercise or calorie restriction, and has largely unknown long term risks - then why even try? It just doesn't make sense.

The research community, and just as importantly the public at large, needs to move beyond their enthusiasm for metabolic manipulation through ingested substances as a path to extending healthy life. It's a grand example of looking for the lost keys under the lamp post - doing something just because it's easier and the path of least resistance, regardless of the likelihood of significant results at the end of the day. Real progress towards longer lives is only going to come through building medical technology capable of repair and rejuvenation at the level cells, organs, and systems within the body: very specific biotechnologies engineered to perform very specific jobs within and around cell structures, and aim to exactly reverse aging by doing so. That couldn't possibly be further removed from the present dominant strategy of mining the natural world for compounds that might or might not cause more minor benefits than minor disadvantages.

It's a common refrain here, but no less true for it: work on rejuvenation biotechnology must displace the present longevity science mainstream if we want to see significant progress towards radical life extension occur before we run out of time, aged to death on the very verge of success.

This is work performed on cells rather than organisms, but it still might be added to the great weight of existing evidence to suggest that calorie restriction improves most aspects of health: "Heart cells starved of nutrients are less likely to be damaged during periods of decreased blood flow and sudden influxes of blood, known as ischemia and reperfusion, and are also less likely to get out of synch with their cellular neighbors, the damaging phenomenon called arrhythmia. ... scientists learned that starved heart cells maintain normal calcium cycling and basic mitochondrial function far longer than non-starved cells during periods of extreme stress. The findings [add] to a growing body of scientific evidence that suggests the consumption of less energy - while maintaining balanced nutrition - can benefit tissues by enhancing cell performance and reducing DNA damage associated with the aging process. ... We are connecting several loose facts about calorie restriction and heart function, in particular, arrhythmias. We have shown why nutrient restriction protects the cells from ischemia and reperfusion. Normal function means less risk of arrhythmias, during which heart cells stop communicating properly with each other, and which can cause further damage, even sudden cardiac death. ... The scientists studied cultured heart cells originally derived from young rats. The cells were grown in a 2 cm-by-2 cm monolayer, to allow ease of study. The researchers mapped intracellular calcium ions and mitochondrial membrane potential with the help of fluorescent tags. Ischemia was simulated by placing a 1.8 cm-by-1.8 cm cover slip over the center of the cell culture, which limited oxygen and nutrient flow to that portion of the culture. Reperfusion was simulated by the removal of the cover slip. ... These experiments are not yet telling us whether we can emulate the effects of nutrient restriction in humans to lessen the damage of ischemia-reperfusion. But we have shown one way nutrient restriction may be acting to reduce heart tissue damage, a subject of interest to many laboratories."

Link: http://www.newswise.com/articles/could-starving-the-heart-make-it-resistant-to-damage

A review paper: "With the improvement of medical care and hygienic conditions, there has been a tremendous increment in human lifespan. However, many of the elderly (older than 65 years) display chronic illnesses, and a majority requires frequent and longer hospitalization. The robustness of the immune system to eliminate or control infections is often eroded with advancing age. Nevertheless, some elderly individuals do cope better than others. The origin of these inter-individual differences may come from genetic, lifestyle conditions (nutrition, socio-economic parameters), as well as the type, number and recurrence of pathogens encountered during life. The theory we are supporting is that chronic infections, through life, will induce profound changes in the immune system probably due to unbalanced inflammatory profiles. Persistent viruses such as cytomegalovirus are not eliminated and are a driven force to immune exhaustion. Because of their age, elderly individuals may have seen more of these chronic stimulators and have experienced more reactivation episodes ultimately leading to shrinkage of their repertoire and overall immune robustness." Evidence in recent years suggests that this issue can be addressed by selectively destroying immune cells devoted to largely useless causes such cytomegalovirus - a goal that becomes ever more practical as targeted cell-killing therapies move closer to the clinic.

Link: http://www.ncbi.nlm.nih.gov/pubmed/22477521

At its simplest, aging is nothing more than damage and the flailing of adaptive systems that try and fail to cope with operating while damaged. The damage of aging comes in a variety of forms, but much of it involves broken proteins. Proteins are the cogs and wheels of cellular machinery, intricate assemblies of atoms encoded in your DNA and tailored by evolution to specific roles. The inside of any cell is a madhouse of flowing material and chemical reactions, however, not all of them benign. There is constant turnover as proteins are damaged, recycled, and replaced, some more often than others. In this dynamic environment of wear and repair, it takes decades for forms of damage to begin to overwhelm the recycling machinery, but the downward slide only gets faster with time.

Here is a recently posted video from last year's SENS5 conference that looks at research into this contribution to degenerative aging:

Proteins undergo continual spontaneous modifications in physiological systems leading to change in their structure and function. This increases with age. ... Data of protein damage is now being combined to produce refined dynamic, multi-compartmental mathematical models of in-life protein damage. Accumulation of protein damage in ageing, that is, increased steady-state levels of damaged proteins occurs as a consequence of: (i) increased rates of protein damage -- linked to increased rate of damaging agent formation and decreased anti-glycation and oxidant defences, (ii) decreased rates of repair of damaged proteins, and (iii) decreased rates of proteolysis of damaged proteins.

...

Antistress gene transcriptional responses also decline with age leaving the proteome particularly vulnerable in periods of oxidative, metabolic and lipogenic stress. Healthy ageing has been achieved in transgenic animals through manipulation of oxidative and non-oxidative mechanisms. Healthy ageing may be available for people through dietary supplements which prevent decline in expression in adulthood of a battery of genes protective against multi-modal stresses. Such interventions are designed to maintain vascular, metabolic, skeleto-muscular and other aspects of health, in part, through preventing increased flux of damage to proteins and increased steady-state levels of damaged proteins.

There are a fair number of researchers interested in protein homeostasis in this way - that is the maintenance of relative protein abundances and low damage levels over time. Aging manifests as an accelerating disruption of homeostasis, and the thinking is that there may be something to be learned from the details of how this disruption proceeds.

Some species of sea urchin, you may recall, age so slowly that it is hard to talk about life expectancy or pin down the likely age of a particular specimen with any ease. As for lobsters, another near-ageless collection of species, there isn't actually all that much research taking place into the biology of aging and longevity in these animals. Here is an example, however: "The life history of sea urchins is fundamentally different from that of traditional models of aging and therefore they provide the opportunity to gain new insight into this complex process. Sea urchins grow indeterminately, reproduce throughout their life span and some species exhibit negligible senescence. Using a microarray and qRT-PCR, age-related changes in gene expression were examined in three tissues (muscle, esophagus and nerve) of the sea urchin species Strongylocentrotus purpuratus. The results indicate age-related changes in gene expression involving many key cellular functions such as the ubiquitin-proteasome pathway, DNA metabolism, signaling pathways and apoptosis. Although there are tissue-specific differences in the gene expression profiles, there are some characteristics that are shared between tissues providing insight into potential mechanisms that promote lack of senescence in these animals. As an example, there is an increase in expression of genes encoding components of the Notch signaling pathway with age in all three tissues and a decrease in expression of the Wnt1 gene in both muscle and nerve. The interplay between the Notch and Wnt pathways may be one mechanism that ensures continued regeneration of tissues with advancing age contributing to the general lack of age-related decline in these animals."

Link: http://www.ncbi.nlm.nih.gov/pubmed/22475988

The assemblies of molecules designed as a part of targeted therapies presently under development - such as those used to attack cancer cells without harming normal cells - are increasing in sophistication. It won't be too much longer before we can call them robots, and either way this field is the basis for a wide range of medicine that is far more effective and far more safe than anything available today: researchers "have developed a robotic device made from DNA that potentially could seek out specific cell targets within a complex mixture of cell types and deliver important molecular instructions, such as telling cancer cells to self-destruct. Inspired by the mechanics of the body's own immune system, the technology might one day be used to program immune responses to treat various diseases. ... A research team [used] what they call the DNA origami method, in which complex three-dimensional shapes and objects are constructed by folding strands of DNA. In this case, the researchers created a nanosized robot in the form of an open barrel whose two halves are connected by a hinge. The DNA barrel, which acts as a container, is held shut by special DNA latches that can recognize and seek out combinations of cell-surface proteins, including disease markers. When the latches find their targets they reconfigure, causing the two halves of the barrel to swing open and expose its payload. The container can hold various types of payloads, including specific molecules with encoded instructions that can interact with specific cell surface signaling receptors. The investigators used this system to deliver instructions, which were encoded in antibody fragments, to two different types of cancer cells - leukemia and lymphoma. In each case, the message to the cell was to activate its 'suicide switch' - a standard feature that allows aging or abnormal cells to be eliminated. And since leukemia and lymphoma cells speak different languages, the messages were written in different antibody combinations. ... We can finally integrate sensing and logical computing functions via complex, yet predictable, nanostructures - some of the first hybrids of structural DNA, antibodies, aptamers, and metal atomic clusters - aimed at useful, very specific targeting of human cancers."

Link: http://nano.cancer.gov/action/news/2012/apr/nanotech_news_2012-4-2e.asp

Researchers have demonstrated modest progress towards the goal of making the body's existing cell populations rebuild damaged cartilage in situ:

A small molecule dubbed kartogenin encourages stem cells to take on the characteristics of cells that make cartilage, a new study shows. And treatment with kartogenin allowed many mice with arthritis-like cartilage damage in a knee to regain the ability to use the joint without pain. ... The new approach taps into mesenchymal stem cells, which naturally reside in cartilage and give rise to cells that make connective tissue. These include chondrocytes, the only cells in the body that manufacture cartilage.

...

"In the blue-sky scenario, this would be a locally delivered therapy that would target stem cells already there," says study coauthor Kristen Johnson, a molecular biologist at the Genomics Institute of the Novartis Research Foundation in San Diego. Johnson and her colleagues screened 22,000 compounds in cartilage and found that one, kartogenin, induced stem cells to take on the characteristics of chondrocytes. The molecule turned on genes that make cartilage components called aggrecan and collagen II. Tests of mice with cartilage damage similar to osteoarthritis showed that kartogenin injections lowered levels of a protein called cartilage oligomeric matrix protein. People with osteoarthritis have an excess of the protein, which is considered a marker of disease severity. Kartogenin also enabled mice with knee injuries to regain weight-bearing capacity on the joint within 42 days.

As a long term goal for tissue engineering, controlling existing cell populations sufficiently well to rebuild lost or damaged structures in the body is preferable to strategies that involve surgery - such as, for example, building cartilage outside the body and then implanting it. Both avenues are under development at this time.

One consequence of an increased focus on controlling stem cells in the body is that researchers must find ways to reverse the stem cell decline that comes with aging. If stem cell populations are generally less effective, then therapies based on directing those cells may be of limited benefit. Given that most of the regenerative therapies we can envisage will be of greatest use to the elderly, the people who bear the most damage and bodily dysfunction, and who are generally the wealthiest portion of the population, there is a strong financial incentive to find ways to build working therapies for that market. This is why I see the regenerative medicine community blending in at the edges with the longevity science community in the years to come - many of the goals are much the same.

An interesting experiment, especially when compared with work on brain aging that focuses on levels of cell proliferation: "During the past decade, it has become increasingly clear that consistent changes in the levels of expression of a small cohort of genes accompany the aging of mammalian tissues. In many cases, these changes have been shown to generate features that are characteristic of the senescent phenotype. Previously, a small pilot study indicated that some of these changes might be reversed in rat liver, if the liver cells became malignant and were proliferating. The present study has tested the hypothesis that inducing proliferation in old rat liver can reset the levels of expression of these age-related genes to that observed in young tissue. A microarray approach was used to identify genes that exhibited the greatest changes in their expression during aging. The levels of expression of these markers were then examined in transcriptomes of both proliferating hepatomas from old animals and old rat liver lobes that had regenerated after partial hepatectomy but were again quiescent. We have found evidence that over 20% of the aging-related genes had their levels of expression reset to young levels by stimulating proliferation, even in cells that had undergone a limited number of cell cycles and then become quiescent again. Moreover, our network analysis [may] provide insights into mechanisms involved in longevity and regeneration that are distinct from cancer."

Link: http://www.ncbi.nlm.nih.gov/pubmed/22477361

An example of work that lays the foundations for lung tissue engineering, which has been lagging behind advances for other organs: "How do you grow stem cells into lungs? The question has puzzled scientists for years. First you need the right recipe, and it took [researchers] seven years of trial and error and painstaking science to come up with it. ... Some tissues, like muscle and nerves, are relatively easy to grow, but others, including liver, lung, thyroid, and pancreas, have been much more difficult. These troublesome tissues all spring from the endoderm, the innermost layer of an early embryo. The endoderm forms when an embryo is about three weeks old and differentiates into organs as early as five weeks. Somehow, in these two weeks the endoderm transforms into differentiated organs as diverse as the lungs and the stomach. ... [Researchers] decided to create a knock-in reporter gene that would glow green during the 'fate decision' - the moment when the stem cells expressed a gene called Nkx2-1 and thereby took a step toward becoming lungs. This allowed the team to track the cells as they developed, mapping each of the six critical decisions on the path to lung tissue. ... Once [the] team had grown what appeared to be lung cells, they had to make sure they had the recipe right. They took samples of mouse lungs and rinsed them with detergent until they became cell-free lung-shaped scaffolds. They seeded one lung with 15-day-old homegrown lung cells that they had purified from stem cells. As a control, they seeded another lung with undifferentiated embryonic stem cells. Within 10 days after seeding, the lung cells organized themselves and populated the lung, creating a pattern recognizable [as] lung tissue. ... A happy side effect of the discovery was that the scientists also mapped out the road from stem cell to thyroid. [The] thyroid, it turns out, also comes from the endoderm layer, deriving from a progenitor that expresses the same key gene as lung progenitors. [The] work will likely have a huge impact on lung stem cell researchers, who have been waiting for a discovery like this to propel their research on inherited lung disease."

Link: http://www.bu.edu/today/2012/from-stem-cells-to-lung-cells/

Much like the practice of calorie restriction, exercise changes everything for the better in most people - it is far more effective in improving and sustaining long term health for the majority of us than any presently available medical technology. We need the future of better medicines that will achieve what good living cannot, such as rejuvenation of the elderly, absolute prevention of age-related disease, and radical life extension, but in the meanwhile it makes sense to make the most of present and proven methodologies to better out position as much as possible. People in the middle of life today will be cutting it fine under the most optimistic estimates for the development of working rejuvenation biotechnology - every year counts when it comes to either making future technology arrive more rapidly or being able to wait for longer.

The present phase of rapid development in biotechnology is uncovering a great deal of new knowledge when it comes to the workings of exercise: how exactly, down to the level of cells and signals, it improves health and life expectancy. For example, here is a paper on exercise and the brain:

The benefits of exercise and physical fitness on mental health and cognitive performance are well documented ... Animal studies have also demonstrated that exercise or physical activity produces very specific changes in the brain that are distinct from those produced by learning or novel experiences. ... Recently, studies have been carried out in humans using non-invasive brain imaging techniques to investigate exercise-related changes in brain structure. Such studies provide compelling evidence for the powerful effects of exercise on the brain, but also raise several questions. For example, do structural changes occur throughout the brain or are they limited to specific brain regions? What aspects of brain architecture are specifically modified by physical activity? On what time scale do these changes occur, and how persistent are they when exercise is discontinued? Do specific preconditions such as aging, disease, or genetic phenotypes make individuals more or less susceptible to activity-based brain changes?

...

Although relatively few studies exist on the effects of aerobic activity on the brain structure of healthy, younger individuals, there is a wealth of data demonstrating the cognitive benefits of frequent aerobic exercise throughout the lifespan - perhaps none more convincing than a recent study of 1.2 million Swedish military conscripts that showed a strong correlation between fitness and intelligence. Much work remains to be done to determine what level of aerobic activity is required for cognitive and brain health to be maximized, but it seems likely this level is well above that of the average individual.

You might compare that conclusion with data on life expectancy in athletes:

• Atheletes Live Longer, Probably the Exercise
• Putting Upper Bounds on Longevity Derived From Exercise

But equally, it seems clear that even moderate regular exercise has great benefits - the 80/20 point is probably somewhere in the vicinity of the venerable recommendation of 30 minutes of some aerobic activity. Sadly, even that level of exercise is probably "well above that of the average individual" in the wealthier nations.

Progress in the tissue engineering of cell structures for use as research tools, and later as the basis for therapies: "Three-dimensional clusters of pancreatic beta-cells that live much longer and secrete more insulin than single cells grown in the laboratory are valuable new tools for studying pancreatic diseases such as diabetes and for testing novel therapies. This cutting-edge advance is described in [an open access paper] ... Finding a solution for the culturing and final transplantation of pancreatic cells will be an enormous breakthrough for the treatment of diabetes ... Growing pancreatic cells in the laboratory is challenging, in part because to survive and function normally they require cell-cell contact. [Researchers] developed an innovative method that uses photolithography to create microwell cell culture environments that support the formation of 3-D pancreatic beta-cell clusters and control the size of the cell aggregates. They describe the ability to remove these cell clusters from the microwells and encapsulate them in hydrogels for subsequent testing or implantation."

Link: http://www.sciencecodex.com/new_method_yields_insulinproducing_pancreatic_cell_clusters-89204

Via ScienceDaily: "Individuals who suffer from autoimmune diseases also display a tendency to develop atherosclerosis - the condition popularly known as hardening of the arteries. Clinical researchers [have] now discovered a mechanism which helps to explain the connection between the two types of disorder. The link is provided by a specific class of immune cells called plasmacytoid dendritic cells (pDCs). ... Using laboratory mice as an experimental model, the researchers were able to show that pDCs contribute to early steps in the formation of athersclerotic lesions in the blood vessels. Stimulation of pDCs causes them to secrete large amounts of interferons, proteins that strongly stimulate inflammatory processes. The protein that induces the release of interferons is produced by immune cells that accumulate specifically at sites of inflammation, and mice that are unable to produce this protein also have fewer plaques. Stimulation of pDCs in turn leads to an increase in the numbers of macrophages present in plaques. Macrophages normally act as a clean-up crew, removing cell debris and fatty deposits by ingesting and degrading them. However, they can also 'overindulge,' taking up more fat than they can digest. When this happens, they turn into so-called foam cells that promote rather than combat atherosclerosis. In addition, activated, mature pDCs can initiate an immune response against certain molecules found in atherosclerotic lesions, which further exacerbates the whole process. ... The newly discovered involvement of pDCs in the development of atherosclerosis [reveals] why the stimulation of pDC that is characteristic of autoimmune diseases contributes to the progression of atherosclerosis. The findings also suggest new approaches to the treatment of chronic inflammation that could be useful for a whole range of diseases."

Link: http://www.sciencedaily.com/releases/2012/04/120404102943.htm

The SENS Foundation research community is steadily gathering momentum in their work on biotechnologies that, once fully realized, will be capable of rejuvenating the old - restoring youthful health, vigor, and function to the formerly declining organs and biological systems in the body. Even before then, the first applications resulting from SENS research will have a significant impact on health and age-related disease, achieved by partially reversing some of the root causes of aging. To go along with the recently released 2011 annual report, the SENS Foundation staff have also published their 2011 research report (in PDF format):

The subtitle on our logo banner reads "advancing rejuvenation biotechnologies", and in keeping with the dynamic connotations of that statement, we've spent 2011 engaged in focused, concrete actions toward embodying it. ... We're excited to be a part of this revolution in scientific innovation, grateful to everyone who has supported us through their generous gifts of time and funding, and delighted to have multiple exciting developments to report on the research front.

There is a lot of material in the report, and I encourage you to read the whole thing - it's very approachable for the layperson, and a good way to obtain a top to bottom view of the Foundation's research strategy at present. That more or less encompasses these questions: what exactly causes aging, and what can be done here and now to make progress towards preventing it and reversing it? For example, here's an excerpt from the GlycoSENS category, research with the potential to reverse the cause of much of the chemical and structural aging of skin, blood vessel walls, and many forms of connective tissue:

The elasticity of the artery wall, the flexibility of the lens of the eye, and the high tensile strength of the ligaments are examples of tissues that rely on maintaining their proper structure. But chemical reactions with other molecules in the extracellular space occasionally result in a chemical bond (a so-called crosslink) between two nearby proteins that were previously free-moving, impairing their ability to slide across or along each other and thereby impairing function. It is the goal of this project to identify chemicals that can react with these crosslinks and break them without reacting with anything that we don't want to break.

...

In 2011, we established a Center of Excellence for GlycoSENS and other rejuvenation research at Cambridge University and hired postdoctoral student Rhian Grainger to design and perform experiments to develop reagents that can detect proteins bearing glucosepane crosslinks, facilitating further studies on its structure, abundance, and cleavage by small molecules. We also established a collaboration with researchers at Yale University, who will lend their expertise in generating advanced glycation end-products and lead efforts in developing agents which may be able to cleave glucosepane.

There are other projects recently started by the Foundation in other areas of the SENS program. You'll also find progress reports for the work that has been ongoing for some years: the MitoSENS project to block the contribution of mitochondrial DNA damage to aging, and the LysoSENS biomedical remediation work that is a search for enzymes to safely remove the build up of damaging compounds that the body's recycling mechanisms cannot cope with on their own.

An introduction to calorie restriction at h+ Magazine: "In the early twentieth century nutrition researchers found that rats maintained on reduced caloric intake showed lower spontaneous tumors compared to rats fed ad libitum (allowed to eat as much as they chose). Although this work did not address caloric restriction (CR) and aging, it suggested that CR might slow the onset of age-associated disease in rodents. ... Numerous follow-up studies demonstrated that a micronutrient adequate CR diet significantly increased the lifespan of many species, largely crossing species boundaries. ... While CR increases the lifespans of most species examined, it also suppresses many of the diseases associated with human aging, thus increasing the 'health-span.' Over short periods, CR lowers blood pressure, heart rate, and glucose levels, and improves memory in older individuals and measures of cognitive performance in animals. Over longer periods CR significantly reduces the risk for many different types of cancer, age-related brain atrophy, heart disease (and atherosclerosis related diseases), autoimmune disease, and adult onset diabetes. CR appears to lessen the risk for, and attenuates or even reverses the symptoms of Alzheimer's and possibly Parkinson's diseases; two major age-related neurodegenerative diseases that cause enormous human suffering. ... Interestingly, CR appears to promote the progression of Amyotrophic Lateral Sclerosis (Lou Gehrig's disease), indicating it does not protect from all human diseases. Aging causes extensive, often organ-specific changes in gene expression patterns. Analysis [has] shown that aging, calorically restricted mice show gene expression patterns resembling those of young animals, compared to ad libitum-fed mice of the same age. CR also lowers cellular oxidative damage by reducing mitochondrial oxygen free radical production, lessens age-related telomere shortening, lowers inflammation, increases DNA damage repair efficiency and lowers damage to DNA and RNA (thus promoting genomic stability), lowers insulin levels while promoting insulin sensitivity, reduces the number of senescent (non-dividing) cells that accumulate with aging, attenuates age-related cellular protein cross-linking, and increases the removal of damaged cellular proteins - a process called 'autophagy' which declines with age and plays a role in resistance to infection, cancer, heart disease, and neurodegeneration. "

Link: http://hplusmagazine.com/2012/04/04/caloric-restriction-and-longevity/

An open access review paper: "Several studies suggest that an increase in adult neurogenesis has beneficial effects on emotional behavior and cognitive performance including learning and memory. The observation that aging has a negative effect on the proliferation of neural stem cells has prompted several laboratories to investigate new systems to artificially increase neurogenesis in senescent animals as a means to compensate for age-related cognitive decline. ... recent evidences indicate that the relative abundance of stem cells in certain organs does not necessarily correlate with their impact on organ function. Specifically, the mammalian brain is perhaps the organ with the lowest regenerative potential but the one in which the signs of aging are more manifested. Using the words of the renaissance writer Michel de Montaigne, 'age imprints more wrinkles on the mind than it does on the face' indicating that age-related cognitive decline has the highest impact on the quality of life. To which extent this decline is dependent on neural stem and progenitor cells (together referred to as NSCs) is hard to tell but growing evidences indicate that, despite their negligible numbers, the few resident NSCs that are located in specific brain regions, most notably the subgranular zone of the hippocampus, seem to play a major role in cognitive functions such as learning, memory, and emotional behavior by generating, through intermediate progenitors, neurons that are constantly added to the brain circuitry throughout life. ... the available data strongly suggests that aging almost exclusively acts at the level of NSC proliferation. Yet, the many contradicting results and uncertainties on identifying the exact causes of this 'decreased proliferation' [need] to be fully acknowledged in order to give a rigorous and meaningful direction to this relatively new field. ... The fact that NSCs can efficiently respond to physiological and pathological stimuli to increase neurogenesis indicates that stimulation of endogenous NSCs offers a promising alternative to transplantation approaches that until now were intensely investigated."

Link: http://impactaging.com/papers/v4/n3/full/100446.html

Kingsley G. Morse Jr. is one of the regulars at the Gerontology Research Group mailing list. He maintains a spreadsheet of all the life span studies in various organisms that he has been able to find, and is generally willing to sell that data at white paper rates, should you happen to be interested. He recently posted a histogram assembled from the study results, which I'm sure you'll agree is interesting:

The history of working to extend life in laboratory animals - and of studying effects on longevity and mortality in humans - is largely a big null result. Other than calorie restriction, the effects of which were first formally cataloged by scientists in the 1930s, all of the excitement shows up in the past twenty years or so. The successes are a tiny fraction of the studies that showed nothing, or showed a result well within the margin of error, or produced results that could not be replicated. In mammals, mostly mice, the bulk of studies that do extend life significantly fall in to the 15% to 30% life extension bracket - on a par with moderate to severe calorie restriction. Only a few methods have been demonstrated to reach beyond that point.

To a large degree this is because near everything tried to date has been a form of metabolic manipulation - change the operation of metabolism to slow the effective rate at which damage accrues to the organism. I would be surprised to see any great improvement in the length of life lived by laboratory animals until the research community changes strategy to focus on actually repairing and reversing the cellular and molecular damage that causes aging. The difference between slowing aging and repairing aging will be as night and day when it comes to the practical results that can be achieved.

A look at some of the research aimed at reversing the damage caused by heart attacks: "Our ultimate hope is that, during the acute period following myocardial infarction (MI), patients will be able to receive direct injections of factors that transform the existing fibroblast cells in the 'scar' into new myocytes. The resulting increase in muscle mass should help MI survivors to live more normal lives. ... When heart muscle cells become injured and die following an MI, patients have the major problem that these cells have little or no capacity for regeneration. ... Part of the process of remodelling that occurs following the injury is that fibroblast cells migrate to the site and create the scar. ... The process at first can be considered beneficial since without fibroblasts adding structural support damaged hearts would rupture. But later difficulties arise when the fibrotic scar doesn't contract like the muscle it has replaced. Reduced global contractility means the heart has to work much harder, and the extra stress can ultimately lead to heart failure and even death. ... One of the Holy Grails of cardiovascular research has been to replace these lost myocytes and return functionality to the heart. Some of the first approaches to be investigated were the introduction of stem or progenitor cells to the sites of injury. ... But many hurdles have been encountered including getting cells to integrate with neighbouring cells in the heart, and there have been concerns that residual 'rogue' cells could persist with the potential to keep dividing and give rise to tumours. Harnessing the vast reservoir of fibroblasts already present in the heart, we felt, could overcome many of these issues. They've the big advantage they're already present in the organ and closely integrated with neighbouring cells. ... the team were able to identify three [genes] Gata4, Mef2c, and Tbx5 that could convert fibroblasts taken from the hearts of adult mice into new myocytes. ... In the second part of the study, the team injected fibroblasts that already had the three genes inserted directly into the scar tissue of mice. They were able to show the fibroblasts differentiated into cardiomyocyte-like cells. ... The fibroblasts converted into cells with nice patterns of striations, typical of myocytes, and developed units that could generate force. ... In the latest study [they] have been able to take the process one step further by injecting a viral vector encoding the genes for Gata4, Mef2c, and Tbx5 directly into the scar tissue of mice who had just experienced an MI. ... With these studies we've obtained even better results showing that the fibroblasts become more like cardiomyocytes and functionally couple with their neighbours. They could beat in synchrony and improve the function of the heart."

Link: http://www.eurekalert.org/pub_releases/2012-04/esoc-tst032312.php

Via ScienceDaily: scientists "have shown in animal models that the loss of memory that comes with aging is not necessarily a permanent thing. ... [Researchers] took a close look at memory and memory traces in the brains of both young and old fruit flies. What they found is that like other organisms - from mice to humans - there is a defect that occurs in memory with aging. In the case of the fruit fly, the ability to form memories lasting a few hours (intermediate-term memory) is lost due to age-related impairment of the function of certain neurons. Intriguingly, the scientists found that stimulating those same neurons can reverse these age-related memory defects. ... This study shows that once the appropriate neurons are identified in people, in principle at least, one could potentially develop drugs to hit those neurons and rescue those memories affected by the aging process. In addition, the biochemistry underlying memory formation in fruit flies is remarkably conserved with that in humans so that everything we learn about memory formation in flies is likely applicable to human memory and the disorders of human memory. ... Olfactory memory, which was used by the scientists, is the most widely studied form of memory in fruit flies - basically pairing an odor with a mild electric shock. These tactics produce short-term memories that persist for around a half-hour, intermediate-term memory that lasts a few hours, and long-term memory that persists for days. The team found that in aged animals, the signs of encoded memory were absent after a few hours. In that way, the scientists also learned exactly which neurons in the fly are altered by aging to produce intermediate-term memory impairment. ... the scientists took the work a step further and stimulated these neurons to see if the memory could be rescued. To do this, the scientists placed either cold-activated or heat-activated ion channels in the neurons known to become defective with aging and then used cold or heat to stimulate them. In both cases, the intermediate-term memory was successfully rescued."

Link: http://www.sciencedaily.com/releases/2012/04/120402185349.htm

Are you studying for a life science or biotechnology degree, teaching students, or otherwise a part of the academic life science community? Do you have an interest in helping to advance longevity science and the development of cures for the diseases of aging? The SENS Foundation Academic Initiative is looking for volunteers to help with their growth in funding and interest:

Over the last few months, the SENS Foundation Academic Initiative has witnessed a rapid increase in its membership numbers, and in the interest it receives from students across the United States and the world. In order to properly utilize and expand upon this interest, the Initiative will need new volunteers, new ideas, and new projects.

For this reason, the Academic Initiative is seeking additional volunteers to help it fulfill its purpose: specifically, to help the Initiative craft itself into an organization capable of launching a legitimate grassroots youth movement in support of SENS Foundation.

To join us in this mission, you can either fill out our brief online volunteer application or email Daniel Kimbel, the Academic Coordinator, at daniel dot kimbel at sens dot org. If you are interested in being involved, please don't hesitate to contact us. We can use volunteers from nearly any background.

The Initiative is focused on the groundwork necessary to build tomorrow's rejuvenation biotechnology research community: people who will enter the workforce to repair mitochondria, build the ultimate cure for cancer, find ways to safely break down the aggregated proteins and crosslinks that cause age-related degeneration - and more. The defeat of aging through biotechnology is a program that will last for decades and radically transform the medical and life science communities along the way. Working with the SENS Foundation and the Academic Initiative is a way to get in on the ground floor of this grand venture, and build connections that will serve you well in future years. The Foundation stands at the center of a web of medical and biotechnology research, with labs and projects around the world, involving many of the most noteworthy researchers in their fields - this is what the beginning of a great revolution looks like, and the years ahead will see great change and great excitement.

It is a good time to be a life scientist.

Of particular note in the SENS Foundation Academic Initiative is the Outreach Group, whose members are eager to find new contacts at academic institutions worldwide:

This group is in charge of reaching out to academic institutions in hopes of gaining support for SENS and students looking for internships/further study in our particular field of research. If anyone has contacts at colleges, research facilities, etc I would greatly appreciate you sharing them, as I will be building a list of organizations to contact over the next few weeks.

SENS is much more than just a plan and a research portfolio; it is a scientific community. One of the ways to help the long term development of working rejuvenation biotechnology - medicine that can reverse the degenerations of aging by repairing cellular and molecular damage - is to help that community grow. Connections are what drive success and progress in this world, and that is something we can all help with.

Via EurekAlert!: "injecting cardiovascular disease (CVD) patients with vaccines and monoclonal antibodies to combat atherosclerosis could soon change the treatment landscape of heart disease. Both approaches [can] be considered truly ground breaking since for the first time they target the underlying cause of CVD. ... with phase 2a trials on recombinant antibodies currently ongoing, [such] treatments could soon become a clinical reality. ... If all goes well, the first in class of these treatments could be licensed within four to five years ... Established therapies against atherosclerosis almost exclusively focus on risk factor modification - that is reduction of dyslipidaemia, hypertension and hyperglycaemia. ... It was in the early 1990s that identification of antibodies against oxidised low density lipoproteins (LDL) in artery plaques, first gave rise to the concept that CVD might be an autoimmune disease where the immune system attacks oxidised LDL. ... Since it is impractical to develop vaccines based on oxidised LDL (due to difficulty of standardising the particle) [researchers] looked to identify structures within the oxidised LDL that triggered the desired protective response. ... The team were able to identify three [peptides], which when formulated with a carrier and adjuvant, reduced development of atherosclerosis in mice by 60 to 70%. ... Further along the development pathway, and already in clinical trials, is an altogether different immune approach involving injection of antibodies directly targeting oxidised LDL. ... The rationale is that since oxidised LDL plays a major role in the development of atherosclerotic plaques and harmful inflammatory processes, directly targeting oxidised LDL should prevent plaque formation and reduce inflammation ... Preclinical studies show that administration of the BI-204 monoclonal antibody [reduced] the formation of atherosclerotic plaques and plaques already present by 50%. In the phase I study, which took place in 80 healthy volunteers with elevated levels of LDL, BI-204 was found to be safe and well tolerated. Now for the current phase 2a double blind [study], BI-204 is being delivered intravenously to 144 patients with stable coronary artery disease in addition to standard care."

Link: http://www.eurekalert.org/pub_releases/2012-03/esoc-itt032312.php

Artificial cells will be useful tools in the medicine of tomorrow: "Daniel Hammer, professor of chemical engineering and biological engineering at the University of Pennsylvania, is building white blood cells in the lab from plastics that can act as artificial cell walls. Think of a gel capsule of your preferred headache medicine but on a much smaller scale and with a programmable molecular brain. These synthetic cells, known as leuko-polymersomes, could one day deliver the latest cancer-killing drugs directly to a tumor or send out a chemical beacon that signals natural white blood cells to come and join the fight against a disease. ... Ultimately I think that we could program these cells to do things that we never thought white blood cells could do ... Instead of boosting immune response, for example, Hammer envisions synthetic cells that could act as inhibitors to the body's defenses, providing relief for people suffering from autoimmune disorders. Hammer has been studying how to turn plastics into cellular structures for more than a decade, but it's just in the past few years that the field has kicked into high gear. His team is learning to mimic the targeting capabilities that let natural white blood cells take the fight to viruses and bacteria - what Hammer describes as a kind of 'molecular zip coding' - and the adhesive properties that let them stand their ground when they arrive. In 2010, Hammer and colleagues from Duke University designed synthetic molecules shaped like the receptors white blood cells use to find and adhere to inflamed tissue. In-vitro tests showed that synthetic cells could seek out inflamed tissue and stick to it once they arrived."

Link: http://www.popularmechanics.com/science/health/breakthroughs/how-lab-created-cells-could-target-tumors-and-deliver-drugs-7698240