Fight Aging!

By way of following on from yesterday's thoughts on progress in longevity science, I'll point out that the August 2012 issue of Rejuvenation Research is available online. The leading editorial by Aubrey de Grey of the SENS Foundation covers much the same set of topics and is presently open access - so head on over and read it while that lasts.

What's Really Delaying the Defeat of Aging?

In the mid-1990s, when I decided to switch from computer science to gerontology, I recognized that the creation of a credible assault on aging would require solving three basic problems: (1) Creating a credible plan; (2) getting the people best placed to implement it to be interested in doing so; and (3) giving them the financial resources to get on with the job.

I broke the back of the first problem in mid-2000, when I realized that regenerative medicine - repairing the accumulating damage of aging - will probably be far simpler and easier to implement than the alternative followed by most biogerontologists, namely slowing the creation of that damage. By that time, I had also done most of the heavy lifting of item 2 (as I continued to do thereafter), by connecting with leading researchers worldwide, mostly face to face at conferences, and improving their understanding of how their expertise could be productively applied to aging. By way of illustration, quite a few of the most prestigious such people are named on the front cover of this journal as associate editors, and they accepted such a position for that reason. But what about item 3?

Unfortunately, I cannot tell so positive a story with respect to financial resources. Nearly a decade ago, I began to make public predictions of how soon we would achieve success in our crusade. I did so, as I still do, in the manner that (for better or worse) preoccupies the general public, namely in terms of longevity, but I have always been careful to incorporate two key caveats: (1) The level of uncertainty of the time frames, even if only scientific uncertainty is considered, and (2) the reliance of such estimates on adequate funding.

The first of these caveats is often elided, but it is simple: I estimate that we have a 50% chance of achieving the milestone of "robust human rejuvenation" (essentially, the rejuvenation of 60 year olds comprehensively enough that they won't be biologically 60 again until they're chronologically 90) within 25 years, but I also estimate that we have at least a 10% chance of not getting there in 100 years. But...that is all subject to the second caveat, namely funding.

Tragically, the level of funding that has been forthcoming during the past decade is only a few percent (at most) of what is necessary. The rate of progress in research to defeat aging has been quite amazing in view of that, but nonetheless, I estimate that it has been only about one-third of what could have been achieved with 10-20 times more money.

Which is much as I said yesterday: there are now plenty of researchers and research groups who would work on building real rejuvenation biotechnology as described in the SENS vision if they were given a budget to do so. That budget is, however, sadly lacking at this time. Millions of dollars are going to SENS and SENS-like research programs these days (which is a big improvement over their non-existence ten years ago) - but a hundred times that flow of resources would be needed to achieve earnest progress at the best possible rate.

One of the logical conclusions emerging from this point of view is that longevity science remains in that stage of growth wherein advocacy and education are the primary drivers of progress. There is sufficient buy-in from the scientific community to make institutional investment in research the bottleneck to progress, and obtaining that funding is a matter of persuasion.

In one sense this is encouraging: it is a characteristic state of affairs during a rapid shift in priorities for any field of human endeavor. Organizations with large sums to place into research tend to be the most conservative portions of their community, and thus among the last to heed the changing winds of knowledge and priority. This present stage, in which researchers are now interested and supportive but lacking in sources of funding that will allow them to actually work on the problem at hand, is a natural, albeit frustrating, part of the process. It is a considerable step up from the previous era in which few researchers had any interest in working on the biotechnologies of engineered human longevity, and even talking about it in public was discouraged.

This interesting research result adds a little more to the debate over whether nuclear DNA damage is relevant to aging beyond its effects on cancer risk - though I think it's still a bit early to point to differences in DNA repair as the definitive cause of SIRT6-related longevity in mice: researchers "found that the decline in a cell's ability to repair DNA during aging coincided with a global reduction in the levels of proteins involved in the repair process. [They] tried to reverse the age-related decline in DNA repair efficiency by restoring the proteins to their original levels and found only one protein, SIRT6, did the trick. ... [Other research results have shown] that overexpressing the SIRT6 protein extended the lifespans of mice. Our research looked at DNA repair and found a reason for the increased longevity, and that is SIRT6's role in promoting more efficient DNA repair. ... The next step [is] to study the factors that regulate SIRT6, in an effort to learn more about the early stages of the DNA repair process. ... multiple groups are trying to develop drugs that activate SIRT6, and [researchers hope] that this research will one day lead to therapies that help extend a person's lifespan and treat cancer. ... SIRT6 plays a critical role in repairing the most dangerous type of DNA damage: double-strand breaks. DNA is a two-stranded molecule, and breaks can occur to one strand of the molecule or to both. In the case of single-strand breaks, the unbroken strand guides the repair process and the DNA molecule is typically restored to its original state. However, double-strand breaks, in which both strands are severed, are particularly hazardous because they are more difficult to repair and can lead to a rearrangement of the cell's genetic material."

Link: http://phys.org/news/2012-08-protein-dna-aging-cells.html

Keeping up on the health basics makes a difference even in the last years of life: "It is well known that lifestyle factors, like being overweight, smoking and heavy drinking, predict death among elderly people. But is it uncertain whether these associations are applicable to people aged 75 years or more. So a team of researchers based in Sweden measured the differences in survival among adults aged 75 and older based on modifiable factors such as lifestyle behaviours, leisure activities, and social networks. The study involved just over 1,800 individuals who were followed for 18 years (1987-2005). Data on age, sex, occupation, education, lifestyle behaviours, social network and leisure activities were recorded. During the follow-up period 92% of participants died. Half of the participants lived longer than 90 years. Survivors were more likely to be women, be highly educated, have healthy lifestyle behaviours, have a better social network, and participate in more leisure activities than non-survivors. The results show that smokers died one year earlier than non-smokers. Former smokers had a similar pattern of survival to never smokers, suggesting that quitting smoking in middle age reduces the effect on mortality. Of the leisure activities, physical activity was most strongly associated with survival. The average age at death of participants who regularly swam, walked or did gymnastics was two years greater than those who did not. Overall, the average survival of people with a low risk profile (healthy lifestyle behaviours, participation in at least one leisure activity, and a rich or moderate social network) was 5.4 years longer than those with a high risk profile (unhealthy lifestyle behaviours, no participation in leisure activities, and a limited or poor social network). Even among those aged 85 years or older and people with chronic conditions, the average age at death was four years higher for those with a low risk profile compared with those with a high risk profile. In summary, the associations between leisure activity, not smoking, and increased survival still existed in those aged 75 years or more, with women's lives prolonged by five years and men's by six years, say the authors. These associations, although attenuated, were still present among people aged 85 or more and in those with chronic conditions."

Link: http://www.eurekalert.org/pub_releases/2012-08/bmj-hli082912.php

Here is a short email that I received yesterday:

I have been reading about [longevity research] for a week now and I was just wondering if you were making progress on this? I read some people think aging can be cured in 2029 could that actually happen?

So today, I'll scribe a brief perspective on recent progress in longevity science. I should preface this by noting that it is probably best to think of the life science and medical research community as an array of largely independent groups and factions, some large, some small. While there is a lot of cross-pollination in their work, they move at different rates towards different goals in medicine and biotechnology, and those goals are of varying degrees of usefulness when it comes to allowing humans to live longer, healthy lives. So I'll note what I see as the areas worthy of particular notice, and omit many other areas, some of which are still important or interesting in their own right:

Early Work on Rejuvenation Biotechnology

The SENS Foundation manages a small-in-budget but large-in-scope research project, and networks with a range of allied scientific groups. The vision is to build true rejuvenation biotechnology, an implementation of the detailed SENS vision for how to repair and reverse the causes of aging. The Foundation is as much about persuading more of the scientific community to undertake aspects of this work as they are about running their own research and development center.

Progress here over the past decade is measured by the fact that the SENS Foundation didn't exist as anything more than the beginnings of an idea back then, in a research community that was far more hostile towards engineered longevity than at present. The Foundation is now an actual entity, with many allies in the aging research community and a million-dollar yearly research budget provided by philanthropic donors. The scientific community itself is now open to work on engineering human longevity, and that is largely due to the efforts of the SENS Foundation principals, supporters, and allies.

You can't change the world with a million dollar budget, alas, but this is just the start of what will hopefully blossom to become the dominant form of aging research - work targeted on the reversal of aging, rather than merely understanding it or slowing it down.

Regenerative Medicine and Tissue Engineering

Stem cell medicine of all forms is growing very rapidly, a worldwide industry that is producing tangible results at a very fast pace: engineering patient-matched tissues and organs, controlling cells to spur regeneration, understanding why stem cells decline with age, and much more. This is a massive research and development community, enormously well funded, enjoying widespread public support, and still growing.

It is not unreasonable to expect that people in middle age today will be able to have lab-grown organs made to order when it comes time to need them, twenty years from now. More importantly, we can also fairly confidently expect to see major advances in reversing stem cell decline with age over that same time frame. Most of the market for stem cell based medicine involves elderly patients, and understanding how to revive stem cell populations in the old will be a necessary part of implementing new therapies. The financial incentives are strong here, and are already being acted on.

Harnessing the Immune System

At the highest level, we can think of regenerative medicine as the inevitable outgrowth of new tools and new understanding that allow stem cells to be manipulated. Control the cells that build tissue, and you can control healing, regeneration, and the ability to maintain tissues in working condition over time. But this very same technology and knowledge also enables immunology and immune therapies: understanding and manipulating the immune system, which is at root just another collection of specialized cells.

The immune system serves many vital purposes in the body, and decays in characteristic ways with advancing age. Many of the frailties of aging are caused by or exacerbated by the progressive failure of the immune system to do its job - not just protecting against pathogens, but policing the cells of the body to destroy those that cause harm.

Just as regenerative medicine will ascend to building new organs over the next few decades, so too will advances in immunology lead to control over the immune system, including restoration from age-related decline. These are closely related fields, and progress in both is enabled by the same underlying biotechnologies. In recent years, we have already seen the first demonstrations of the ability to reprogram, reset, and reverse some of the age-related declines in immune function. At the same time, many new therapies are under development based on manipulation of the immune system: to destroy cancers, repair autoimmune diseases, and so forth.

Calorie Restriction Research and Mimetics

A great deal of resources are pouring into understanding the metabolism of longevity, and one part of that is the quest to understand and replicate the effects of calorie restriction on health and life span. What probably amounts to a few billion dollars over the past ten years have gone into advancing this field, which in that time has grown from a tiny minority interest in a few labs to a large and growing concern that, despite little to show for the investment yet other than knowledge, doesn't look to be slowing down any time soon.

Progress here can probably best be measured in our increased understanding of exactly how metabolism can shift into states that boost health and life span in most species. Increasing numbers of potential drug compounds have been identified that somewhat recapitulate the beneficial effects of eating less, but it seems unlikely that anything other than a carefully designed small molecule drug with very specific biochemical targets will prove to be a true calorie restriction mimetic. As of yet it seems that too little is known to build such a thing, but there is a fairly good idea as which mechanisms it would affect in order to achieve its ends.

The Genetics of Longevity

A great deal more work is taking place on the genetics and epigenetics of longevity than was the case a decade ago. This is a growth field, both for human studies that try to pick apart genetic contributions that lead to long-lived families, and for comparison studies between long-lived and short-lived species, where researchers search out distinctive differences that might explain how large variations in life span come about.

In humans, we can now be more confident that there are many genetic contributions to longevity, varying widely by population, and few if any stand out as large and obvious targets for drug development. Meanwhile the attention paid to long-lived species such as naked mole-rats is producing data that steers the attention of other research communities to the most important determinants of longevity - our mitochondria and their resistance to damage, for example.

The Bottom Line

The bottom line is that the research community and state of the field today is very different from that of even a mere ten years ago. This is a time of rapid change and progress: far more is known and far more impressive feats of medicine can be performed in the lab and the clinic. There is every reason to believe that ten years from now we'll be able to say the same thing. Costs in biotechnology and life science research are falling rapidly, and with that trend more research can be accomplished in each new year.

That said, however, the only way that we'll see significant inroads into the defeat of aging by 2029 is for the SENS Foundation and its attendant research community to undergo the same sort of growth over the next decade as has been exhibited in recent years by regenerative medicine, calorie restriction research, or study of the genetics of longevity. A growth to billions in funding and thousands of researchers, in other words. It will require at least that and a decade of time in order to have a 50/50 shot at reversing aging in old mice in the lab - which is to say something that can make them live at least twice as long as they otherwise would have done.

Of all the items covered in this post, only SENS provides a path towards achieving this end. Even regenerative medicine and complete control over stem cells can't offer the possibility of reversing aging in and of itself - it is only the way to reverse one component of aging, the decline of tissue maintenance and frailty that results from stem cells shutting down. You will still get nailed by your own mitochondria and the build up of metabolic byproducts even if your stem cells are perfectly restored.

So to answer the original question posed in the email, no, there is no plausible road to the defeat of aging by 2029. But there is a plausible road to the first laboratory demonstrations of real, meaningful, but partial age reversal by then, ways to actually repair the root biological causes of aging rather than just slow it down. Whether that happens or not depends absolutely on funding - there are more than enough scientists and research groups out there who would work on the SENS vision for rejuvenation biotechnology if given a budget, but as of yet not enough funding sources to make it a reality.

How you manage your health in earlier parts of your life will have an effect further down the line: "To examine the association between midlife fitness and chronic disease outcomes in later life, participant data from the Cooper Center Longitudinal Study were linked with Medicare claims. We studied 18,670 healthy participants (21.1% women; median age, 49 years) who survived to receive Medicare coverage from January 1, 1999, to December 31, 2009. Fitness estimated by Balke treadmill time was analyzed [according] to age- and sex-specific quintiles. Eight common chronic conditions were defined [and] associations between midlife fitness and the number of conditions were assessed. ... After 120,780 person-years of Medicare exposure with a median follow-up of 26 years, the highest quintile of fitness [was] associated with a lower incidence of chronic conditions [in men and women]. After multivariate adjustment, higher fitness [was] associated with a lower risk of developing chronic conditions in [men and women]. ... In this cohort of healthy middle-aged adults, fitness was significantly associated with a lower risk of developing chronic disease outcomes during 26 years of follow-up. These findings suggest that higher midlife fitness may be associated with the compression of morbidity in older age."

Link: http://dx.doi.org/10.1001/archinternmed.2012.3400

A discussion on published results from this primate study suggest that both it and a comparison study are different in ways that make it harder to pull rigorous conclusions from the data - beyond the fact that diet clearly has influence, and the effects of calorie restriction on life span (average and maximum) are expected to be smaller in longer-lived species versus shorter-lived speces: "Scientists have found that calorie restriction - a diet composed of approximately 30 percent fewer calories but with the same nutrients of a standard diet - does not extend years of life or reduce age-related deaths in a 23-year study of rhesus monkeys. However, calorie restriction did extend certain aspects of health. ... The survival results in the study reported [by] NIA researchers differ from those published in 2009 by NIA-supported investigators at the University of Wisconsin-Madison. The Wisconsin study followed two groups of rhesus monkeys for 20 years and found that monkeys on a calorie-restricted diet lived longer than those on a standard diet. Beyond longevity, the parallel NIA and Wisconsin studies have reported similar beneficial health effects of calorie-restriction. Both studies found that certain age-related diseases - including diabetes, arthritis, diverticulosis and cardiovascular problems - occurred at an earlier age in monkeys on the standard diet compared to those on calorie restriction. However, this observation was not statistically significant in the NIA study. NIA researchers did find that monkeys started on calorie restriction at an early age had a statistically significant reduction in cancer incidence. NIA researchers also found that while calorie restriction had a beneficial effect on several measures of metabolic health and function in monkeys who were started on the special diet regimen during old age (at 16 to 23 years), it did not have the same positive outcome for monkeys started on calorie restriction at a young age (less than 14 years). In the Wisconsin study, all the monkeys were 7 to 14 years when started on calorie restriction. ... Differences in the monkeys' meal and other nutritional factors were cited as possible explanations for NIA's and Wisconsin's different outcomes. Both studies used a similar percentage of calorie restriction with their intervention groups; however, the Wisconsin monkeys in both the calorie restricted and control groups were eating more and weighed more than the matched NIA monkeys. ... NIA researchers cited genetics as another possible reason for their differing results. NIA monkeys had a greater genetic diversity, originating from China and India. Wisconsin's monkeys came only from an Indian colony."

Link: http://www.sciencedaily.com/releases/2012/08/120830085114.htm

For a society in the midst of accelerating, rapid, and evident technological progress, public discussion and attitudes show a surprising lack of optimism for the future. Optimism of course exists, but nowhere near as widely as it should. It seems self-evident at this point that a golden era lies ahead in which we defeat disease and aging, colonize the solar system, and expand the limits of what it means to be human. We and our descendants will discard pain and suffering along the way, just as we have already discarded so much of the pain and suffering that our ancestors bore.

The visible future is by any sensible measure nothing less than science fiction. Any given snapshot of that future is made up of countless trillions of ageless humans, sophisticated machine intelligences, and yet to be categorized hybrids of the two, spread throughout the solar system in palatial standards of living, and beginning to drift beyond to the nearby stars - a vast thistledown of intelligence and culture, a million times greater and more diverse than today's world, just beginning its explosion into the winds.

The upward ramp of the necessary underlying technology is within our grasp. But you wouldn't think this from listening to the public. Much of the world seems convinced that nothing but collapse and catastrophe lies ahead: their view of the future is the ever-mistaken Malthusian collection of beliefs revolving around static resources that are exhausted. They fail to see the dynamism of resource generation and progress that proved past Mathusians just as wrong as the present crop.

Looking back, I grew up in a culture whose mainstream was convinced that the destruction of nuclear war was inevitable. That was the lesson we ingested from fiction, news, what was taught in schools - it was the zeitgeist of the 70s and 80s, that on the one hand progress was right there all around us, while on the other we looked ahead to nothing but catastrophe. Talking to Russians of my generation in more recent years, those who grew up on the other side of the iron curtain, I get the impression that this part of the cultural indoctrination ran in much the same way for them.

One might argue that the feared exchange of warheads never happened because humanity had finally constructed a methodology of waging war that visited actual and immediate consequences upon the ruling class. Incentives matter. But I digress - the point is that in that period of life prior to establishing one's own ideas on how the world works, my generation largely thought the future was not at all golden in the near term.

Now it seems that this pessimism, lacking an outlet with the collapse of the Soviet Union, has sloshed over into the environmentalist bucket. Is pessimism for the future a cultural thing, or something that we humans just tend to do regardless of era? You might look back at the various apocalyptic panics (usually religious) in earlier times, for example, which seem to bear similar characteristics to both the past widespread belief in the certainty of nuclear war and the present widespread belief in the certainty of environmental collapse.

On the one hand, we seem to have managed technological progress at a fast rate over the past four centuries despite these manifestations of our collective human psychology. On the other hand, one can't help but feel that it would all run that much faster if more people believed in a better outcome.

A review paper: "Nutrition has important long-term consequences for health that are not only limited to the individual but can be passed on to the next generation. It can contribute to the development and progression of chronic diseases thus effecting life span. Caloric restriction (CR) can extend the average and maximum life span and delay the onset of age-associated changes in many organisms. CR elicits coordinated and adaptive stress responses at the cellular and whole-organism level by modulating epigenetic mechanisms (e.g., DNA methylation, posttranslational histone modifications), signaling pathways that regulate cell growth and aging (e.g., TOR, AMPK, p53, and FOXO), and cell-to-cell signaling molecules (e.g., adiponectin). The overall effect of these adaptive stress responses is an increased resistance to subsequent stress, thus delaying age-related changes and promoting longevity. In human, CR could delay many diseases associated with aging including cancer, diabetes, atherosclerosis, cardiovascular disease, and neurodegenerative diseases."

Link: http://www.ncbi.nlm.nih.gov/pubmed/22928085

Some of the damage that occurs in brain injury is secondary to the initial trauma and takes place at the level of cellular components. Researchers here demonstrate a possible way to stop that from happening: "Treatment with an agent that blocks the oxidation of an important component of the mitochondrial membrane prevented the secondary damage of severe traumatic brain injury (TBI) and preserved function that would otherwise have been impaired. ... For the study, the research team conducted a global assessment of all the phospholipids in rat brain cells. This revealed that damage from TBI was nonrandom and mostly involved cardiolipin, a phospholipid that is found in the membranes that form mitochondria, the cell's powerhouse. They noted that in the healthy animal, only 10 of the 190 cardiolipin species were modified by oxygen, but after a brain injury, the number of oxidized species rose many-fold. The researchers then developed an agent, called XJB-5-131, which can cross the blood-brain barrier and prevent the oxidation of cardiolipin. Using an established research model of severe TBI, the agent or a placebo was injected into the bloodstream of rats five minutes and again 24 hours after head injury. In the weeks that followed, treated animals performed akin to normal on tests of balance, agility and motor coordination, learning, and object recognition, while placebo-treated animals showed significant impairment. The results indicate that blocking cardiolipin oxidation by XJB-5-131 protected the brain from cell death. ... a targeted oxidation-blocker might also be beneficial in the treatment of other neurological disorders, such as Parkinson's disease, amyotrophic lateral sclerosis, or ALS, and stroke."

Link: http://www.eurekalert.org/pub_releases/2012-08/uops-pto082412.php

Calorie restriction (CR), eating fewer calories while still obtaining all the necessary micronutrients, extends life in a wide range of species. In humans we know that it is tremendously beneficial to health. As a phenomenon it has been studied for the better part of a century, but only very rigorously over the past two decades, as it became possible to think about building drugs that achieved the same changes in metabolic processes but without the dieting. Calorie restriction is a great poster child for the sheer, exuberant complexity of metabolism: it isn't an exaggeration to say that a couple of billion dollars have been poured into understanding how it works over the past ten years or so, and we're not there yet. Even a small, tiny slice of the way in which our metabolism works in practice, like calorie restriction and its beneficial effects on health and longevity, requires this level of resources to start to get a handle on what's going on under the hood.

This sort of research process will become easier as the tools and techniques of biotechnology continue to improve rapidly in the years ahead, but the expense in time and money remains one of the reasons why I don't advocate for work on slowing aging through metabolic manipulation. That is a hard, slow, expensive path, and the end result will be of little use to people already old. We should be spending that effort on ways to repair the damage that causes aging as outlined by the SENS Foundation and others.

In any case, I noticed an interesting open access paper on calorie restriction that does a good job of pulling together a high level view of what is currently known, while introducing the ideas of the authors. This diagram is a good starting point:

It isn't unreasonable to say that over the long term calorie restriction changes pretty much everything in your metabolism, either directly (such as through nutrient sensing mechanisms) or indirectly (such as through losing metabolically active visceral fat). So pulling out the important threads from "well, everything changed" has been a long haul. Still, researchers have made good inroads through the traditional route of using genetic engineering to remove pieces of the machinery of life and then seeing what breaks. For example, autophagy seems to be required for calorie restriction to produce benefits.

But take a look at the paper:

Caloric restriction, that is limiting food intake, is recognized in mammals as the best characterized and most reproducible strategy for extending lifespan, retarding physiological aging and delaying the onset of age-associated diseases. The aim of this mini review is to argue that p53 is the connection in the abilities of both the Sirt-1 pathway and the TOR pathway to impact on longevity of cells and organisms. This novel, lifespan regulating function of p53 may be evolutionarily more ancient than its relatively recent role in apoptosis and tumour suppression, and is likely to provide many new insights into lifespan modulation.

...

But which pathway is indispensable for prolonged lifespan by CR, inhibiting TOR or activating sirtuins? Evidence has emerged that sirtuins and mTOR are involved in the same longevity pathway. Importantly, resveratrol, an activator of sirtuins, antagonizes the mTOR/S6K pathway. Therefore, the two notions that CR prolongs lifespan either by activating sirtuins or by deactivating TOR are, in fact, complementary: CR deactivates the mTOR pathway in part by activating Sirt-1.

p53 is of course a well known cancer suppressant, a part of the mechanisms that enforce the trade-off between cancer risk and life span. If your increasingly damaged stem cells remain more active, your tissues are better maintained in later life but you have an increased risk of cancer. If the stem cells become less active, then you deteriorate more rapidly, but with a lower risk of cancer. Levels of p53 form a part of the system that determines which side of that line you are on, rising and falling in response to damage to cells and their molecular machinery. Interestingly, suitable manipulations of p53 can break this balance and let you have your cake and eat it too: less cancer and more life. You might see these posts from the archive on that subject:

• A New Look At p53, Cancer and Aging
• 50% Maximum Life Extension in Mice Via p53 and Telomerase

A great deal of data is being generated on patterns of DNA methylation, aging, and variations in human longevity: "(1) we evaluated the DNA methylation from peripheral leukocytes of 21 female centenarians, their 21 female offspring, 21 offspring of both non-long-lived parents, and 21 young women ... (2) we compared the DNA methylation profiles of these populations ... We observed an age-related decrease in global DNA methylation and a delay of this process in centenarians' offspring. Interestingly, literature data suggest a link between the loss of DNA methylation observed during aging and the development of age-associated diseases. Genome-wide methylation analysis evidenced DNA methylation profiles specific for aging and longevity: (1) aging-associated DNA hypermethylation occurs predominantly in genes involved in the development of anatomical structures, organs, and multicellular organisms and in the regulation of transcription; (2) genes involved in nucleotide biosynthesis, metabolism, and control of signal transmission are differently methylated between centenarians' offspring and offspring of both non-long-lived parents, hypothesizing a role for these genes in human longevity. Our results suggest that a better preservation of DNA methylation status, a slower cell growing/metabolism, and a better control in signal transmission through epigenetic mechanisms may be involved in the process of human longevity. These data fit well with the observations related to the beneficial effects of mild hypothyroidism and insulin-like growth factor I system impairment on the modulation of human lifespan."

Link: http://www.ncbi.nlm.nih.gov/pubmed/22923132

Cytomegalovirus (CMV) is a persistent and very common herpesvirus that is thought to be a major contributor to the age-related decline of the immune system, due to an ever increasing portion of its limited number of cells becoming specialized to CMV and thus unavailable for other duties. Various past studies have linked CMV with forms of age-related frailty, but here the researchers find an association with type 2 diabetes - which is interesting and perhaps somewhat unexpected, given that type 2 diabetes is essentially a lifestyle disease: "Cytomegalovirus (CMV) infection has been reported to contribute to the pathogenesis of type 1 diabetes and post-transplantation diabetes. However, CMV infection has not been evaluated as a possible risk factor for type 2 diabetes. Our aim was to investigate potential associations between CMV seropositivity, CMV IgG antibody level and glucose regulation in the oldest old. ... CMV seropositive subjects were more likely to have type 2 diabetes (17.2% vs 7.9%), had a higher level of HbA1c and higher non-fasting glucose in the oldest olds. These associations remained significant after adjustment for possible confounders. CMV IgG antibody level was not significantly associated with glucose regulation ... In the oldest old, CMV seropositivity is significantly associated with various indicators of glucose regulation. This finding suggests that CMV infection might be a risk factor for the development of type 2 diabetes in the elderly."

Link: http://dx.doi.org/10.1186/1742-4933-9-18

Having a plan to save Medicare is somewhat like wearing a tie or cufflinks, in that it is somewhat de reigueur in some parts of society - but ultimately a cultural signal of belonging, of little value otherwise. The economic future of the US is somewhat grim; the decline of an empire is inevitable as its increasingly unaccountable elite class debauch the currency, centralize power, and regulate all aspects of a citizen's life. They tax and waste ever more of the flow of resources whilst destroying the freedom and competition needed for the creation of those resources - in much the same way as a cancer is parasitic to its host but ultimately destroys both host and itself. This is an inexorable progression of society, built upon the foundation of human nature and the individual actions and interactions of millions of people. It has happened over and again and is just about as likely as the tide to be turned aside.

So having a plan to save Medicare is rather like having a plan to save a part of your cancer. That portion in the lower left, perhaps. Medicare is but one part of the network of regulation, perverse incentives, and regulatory capture that causes medicine in the US to be ever more expensive, wasteful, and poor in quality. It's large enough to be considered in the context of the more general economic decline across the board, which occurs for roughly the same set of reasons, and is just as hard to turn back. Medicine is in a more advanced state of socialist decrepitude than most other US industries, but the same process operates throughout society.

From there let me segue into a discussion of responses to shortage. Regulation inevitably creates shortage and rationing: we see this in the provision of medicine in countries like Canada and the UK, where regulators set up waiting systems or simply forbid treatment, especially to the old. Much of the public discussion that results from this state of affairs looks at what to do about the shortages - though of course without a great deal of reflection on how they came to exist in the first place, sad to say. There are two broad lines of thinking here: firstly, use less of whatever is rationed; secondly try to create more of whatever is in short supply.

One of the defining and frankly rather sorry aspects of our age is that public debates veer towards cutting back on use far more often than towards creating abundance. See the bulk of the environmentalist or other Malthusian movements for example - they have little to say about building more of whatever it is they think is in short supply.

When it comes to Medicare, and given that very few people are calling to get rid of the whole system and let freedom and free markets rule the day, the two sides of the coin look much like (a) a call for increased rationing of services to ensure that people use less in the way of medicine, and (b) a call for ways to create greater health such that people use less in the way of medicine. There are of course many different approaches to either of these paths, but both ultimately sidestep the real issue, the real cause of the problem - and this again is absolutely characteristic of debate over societal organization and politics in our age.

That all said, here is one researcher's call for using progress in longevity-enhancing medical technology to save Medicare - an example of the "create greater health" approach to patching over the problem whilst ignoring its root causes.

How to save Medicare: the anti-aging remedy:

One solution is to cut Medicare and other health care benefits, to narrow treatment options, to slow the growth in benefits somewhat for wealthier recipients. Another solution is to increase taxes (in whatever form) and/or to increase the federal budget deficit. These solutions are political. Here I will discuss a biomedical solution, which can be easily incorporated into their political program by both Democrats and Republicans.

...

There is a misconception that an anti-aging medicine would increase the number of chronically ill people because they are old. On the contrary, it would decrease the ratio of unhealthy to healthy population because an anti-aging medicine will delay the onset of aging, diseases and their complications at older age. Fast-aging animals (mice) develop diseases of aging fast, whereas slowly aging organisms such as humans acquire these diseases at 40 times older age than mice. Centenarians, people who live more than 100 years, age slowly and generally experience good health until very old ages, when diseases that kill them finally develop. ... Slowing down aging both increases lifespan and postpones diseases. One may even say that anti-aging interventions increase lifespan by postponing diseases.

...

Unfortunately, the only way to stop the rising costs of Medicare completely [without the use of anti-aging medicine] is to prevent the use of more effective (and expensive) medical options and to stop further biomedical research. This draconian option would accelerate the mortality of the sickest elderly, further decreasing Medicare costs. Of course this is unacceptable. So costs must continue to rise. But this wouldn't necessarily lead to a fiscal crisis, given that anti-aging medicine could increase health span and therefore the ratio of healthy to unhealthy individuals in the elderly population. In conjunction with the increase in health span, the age of retirement could be increased. This would increase federal revenues and provide a means to cover increasing costs of Medicare.

Here is an example to show that the urge to conform is somewhat stronger than the urge to live, and never mind the urge to think critically. People will tend to say that they want to be in the majority position now, no matter what that might be, and depending on how you phrase the question, the vast majority will tell you that they want to age to death and have a life that is no longer than that of their parents. Yet if longer lives were already common, those very same people would answer that they wanted to live those longer lives. It is frustrating, to say the least, the degree to which people live in the moment and blind themselves to what might be created: "How many years might be added to a life? A few longevity enthusiasts suggest a possible increase of decades. Most others believe in more modest gains. And when will they come? Are we a decade away? Twenty years? Fifty years? Even without a new high-tech 'fix' for aging, the United Nations estimates that life expectancy over the next century will approach 100 years for women in the developed world and over 90 years for women in the developing world. (Men lag behind by three or four years.) Whatever actually happens, this seems like a good time to ask a very basic question: How long do you want to live? Over the past three years I have posed this query to nearly 30,000 people at the start of talks and lectures on future trends in bioscience, taking an informal poll as a show of hands. To make it easier to tabulate responses I provided four possible answers: 80 years, currently the average life span in the West; 120 years, close to the maximum anyone has lived; 150 years, which would require a biotech breakthrough; and forever, which rejects the idea that life span has to have any limit at all. I made it clear that participants should not assume that science will come up with dramatic new anti-aging technologies, though people were free to imagine that breakthroughs might occur - or not. The results: some 60 percent opted for a life span of 80 years. Another 30 percent chose 120 years, and almost 10 percent chose 150 years. Less than 1 percent embraced the idea that people might avoid death altogether. These percentages have held up as I've spoken to people from many walks of life in libraries and bookstores; teenagers in high schools; physicians in medical centers; and investors and entrepreneurs at business conferences. I've popped the question at meetings of futurists and techno-optimists and gotten perhaps a doubling of people who want to live to 150 - less than I would have thought for these groups. Rarely, however, does anyone want to live forever, although abolishing disease and death from biological causes is a fervent hope for a small scattering of would-be immortals."

Link: http://www.nytimes.com/2012/08/26/sunday-review/how-long-do-you-want-to-live.html

This is interesting, the early stirrings of something that may change the tenor of future tissue engineering if carried through to its logical conclusions. Why build a plain heart if you can build a sensor-laden heart with its own embedded network for monitoring and medical intervention? From the release: "A multi-institutional research team has developed a method for embedding networks of biocompatible nanoscale wires within engineered tissues. These networks - which mark the first time that electronics and tissue have been truly merged in 3D - allow direct tissue sensing and potentially stimulation, a potential boon for development of engineered tissues that incorporate capabilities for monitoring and stimulation, and of devices for screening new drugs. ... One of the major challenges in developing bioengineered tissues is creating systems to sense what is going on (e.g., chemically, electrically) within a tissue after it has been grown and/or implanted. Similarly, researchers have struggled to develop methods to directly stimulate engineered tissues and measure cellular reactions. ... In the body, the autonomic nervous system keeps track of pH, chemistry, oxygen and other factors, and triggers responses as needed. We need to be able to mimic the kind of intrinsic feedback loops the body has evolved in order to maintain fine control at the cellular and tissue level. ... With the autonomic nervous system as inspiration, [scientists] built mesh-like networks of nanoscale silicon wires - about 80 nm in diameter - shaped like flat planes or in a 'cotton-candy'-like reticular conformation. The networks were porous enough to allow the team to seed them with cells and encourage those cells to grow in 3D cultures. ... Previous efforts to create bioengineered sensing networks have focused on 2D layouts, where culture cells grow on top of electronic components, or on conformal layouts where probes are placed on tissue surfaces. It is desirable to have an accurate picture of cellular behavior within the 3D structure of a tissue, and it is also important to have nanoscale probes to avoid disruption of either cellular or tissue architecture."

Link: http://www.eurekalert.org/pub_releases/2012-08/bch-rdm082412.php

The public attitude towards cryonics has shifted greatly over the past ten years, at least as measured by the changing tenor of articles in the popular press. They are more favorable, more respectful, and more accurate on technical details. So greater exposure and publicity over the past decade has brought benefits, and increasing familiarity with the topic has allowed more people to overcome whatever knee-jerk reactions they normally have to all novel ideas. This is a positive trend, perhaps driven as much by the general proliferation of media enabled by the internet as by efforts made by the cryonics community, and will hopefully continue apace.

The Cryonic Man: How Alcor Life Extension preserves your dead body

What is it to die? For some, death is our body's expiration date, for others it is an absolute point where the soul leaves the body. For a group of scientists in Scottsdale, Arizona, however, it is merely an arbitrary natural accident, an engineering problem we have yet to find a solution for.

The Alcor Life Extension Foundation is the world's leading provider of cryonics, the practice of using ultra-cold temperatures to preserve humans until such a time when medicine is advanced enough to restore good health. The widely-held belief that it involves freezing is actually something of a red herring. As soon as possible after legal death is pronounced, cryoprotectant solution - a sort of antifreeze - is administered to a patient through their circulatory system, entering almost every cell in the body. Known as vitrification, this process avoids ice crystal formation and allows the body to be cooled with virtually no freezing damage, before being placed in liquid nitrogen in a Dewar container and moved to storage indefinitely.

For a long time cryonics was dismissed by many as science-fiction, an unnatural or even immoral procedure, but while the company make no bones about cryonics being an entirely speculative process, futurist and Alcor chief executive Max More says that the field is gaining legitimacy in the eyes of others. "People have certainly grown less hostile," he told Metro. "In terms of how science looks at cryonics we've definitely seen an improvement over time." Mr More added that Alcor's teams which intervene at members' deathbeds are also being treated more favourably by doctors. "Our relationship with hospitals and hospices has also improved; they used to be very adversarial and reluctant to even let us in, now hospital staff are usually fascinated and want to help in any way they can. They even let us position our equipment in the room next to the patient before clinical death, their whole attitude has really turned around."

Cryonics is an important industry, the only option for all too many people who will die before the advent of rejuvenation biotechnology. It has not found the level of growth that it deserves, sadly, but that doesn't change the fact that it is still the sole chance at a longer life in the future for those who are very old today.

The cancer stem cell hypothesis continues to show promise as a way to strike at the root of many different forms of cancer: "Cancer stem cells are defined by three abilities: differentiation, self-renewal and their ability to seed a tumor. These stem cells resist chemotherapy and many researchers posit their role in relapse. A [new study] shows that melanoma cells with these abilities are marked by the enzyme ALDH, and imagines new therapies to target high-ALDH cells, potentially weeding the body of these most dangerous cancer creators. ... We've seen ALDH as a stem cell marker in other cancer types, but not in melanoma, and until now its function has been largely unknown. ... [Researchers] transplanted ALDH+ and ALDH- melanoma cells into animal models, showing the ALDH+ cells were much more powerfully tumorigenic. In the same ALDH+ cells, the group then silenced the gene that creates this protein, finding that with ALDH knocked down, melanoma cells died in cultures and lost their ability to form tumors in animal models. In cell cultures, silencing this ALDH gene also sensitized melanoma cells to existing chemotherapies. When the group explored human tumor samples, they found distinct subpopulations of these ALDH+ cells, which made up about 0.1-0.2 percent of patients' primary tumors. In samples of metastatic melanoma - the most aggressive form of the disease - the percentage of ALDH+ cells was greater, even over 10 percent in some tumors, further implying the powerful danger of these cells."

Link: http://www.coloradocancerblogs.org/news/study-identifies-human-melanoma-stem-cells

Many different sources of stem cells remain under investigation, such as those derived from amniotic fluid: "We recently reported isolation of viable rat amniotic fluid-derived stem (AFS) cells. Here, we tested the therapeutic benefits of AFS cells in a rodent model of ischemic stroke. Adult male Sprague-Dawley rats received a 60-minute middle cerebral artery occlusion (MCAo). Thirty-five days later, animals exhibiting significant motor deficits received intravenous transplants of rat AFS cells or vehicle. At days 60-63 post-MCAo, significant recovery of motor and cognitive function was seen in stroke animals transplanted with AFS cells compared to vehicle-infused stroke animals. Infarct volume [was] significantly reduced, coupled with significant increments in the cell proliferation marker, Ki67, and the neuronal marker, MAP2, in the dentate gyrus (DG) and the subventricular zone (SVZ) of AFS cell-transplanted stroke animals compared to vehicle-infused stroke animals. ... This study reports the therapeutic potential of AFS cell transplantation in stroke animals, possibly via enhancement of endogenous repair mechanisms."

Link: http://www.ncbi.nlm.nih.gov/pubmed/22912905

I note that the Russian community behind the well-backed 2045 initiative are trying their hands at launching a political party to further the cause. There is a website for the Evolution 2045 party concept; at this point it would seem to be chiefly worthwhile as a way to gain some additional insight into the thinking of those steering the 2045 initiative:

The Initiative 2045 announces the creation of its own political party - "Evolution 2045" - in order to advocate for a new strategy for human development. This is a Russia-based party, but its goals are international and global. Our ultimate goal is to inspire other countries to follow suit, and compete not in the arms race, but in the race for building a bright future for mankind.

There is a fair amount of money behind this project, so they can certainly afford the luxury of trying a great many different approaches in the course of gathering greater support for their cause. In this sense a nascent political party falls into exactly the same bucket as the series of international conferences being organized: outreach, education, advocacy.

This all seems to be an idea very much in the air at the Russian end of the longevity advocacy community. See this recent and unrelated item, for example:

we made the first step towards the creation of the Longevity Party. The initiative group of 10 people gathered together in Moscow to establish the first political party aimed at extending human lifespan using technological advances. ... . This is the very first step in the long and hard process of legally registering a political party. ... The next big thing we need to do is to finalize the Program of the Party. Then we have to have at least 2 people in 42 regions of Russia as representatives of the Party and have the founding meeting after which the Party can be registered and eventually appear in the voting ballots. Our goal is to influence the authorities to support life extension technologies and increase funding for research aimed at improving people's health and extending longevity.

Single issue political parties are a long-standing and widely used methodology for advancing particular causes in Europe and further East, far more so than across the pond in the US, though they do exist there as well. In most European countries you'll find a range of these organizations, some more successful than others. The Green parties are perhaps the exemplar of the type, formed around a movement and grown to staid success in terms of delivering their message, with the Pirate parties as another, younger and still dynamic example.

Either way, radical optimism about what can be achieved in the near future - if we just worked at it - is in comparatively short supply in our culture. Visionaries who talk about the path to humanity ascendant are a small minority in comparison to the masses and the talking heads who are blinkered by the present and look little further than the bounds of what is. So more vision and more optimism are very welcome, even if harnessed to a program that isn't my first choice for how to proceed towards engineering greatly extended lives.

Research into the detailed mechanisms of calorie restriction continues apace: "Dietary restriction (DR), limiting nutrient intake from diet without causing malnutrition, delays the aging process and extends lifespan in multiple organisms. The conserved life-extending effect of DR suggests the involvement of fundamental mechanisms, although these remain a subject of debate. To help decipher the life-extending mechanisms of DR, we first compiled a list of genes that if genetically altered disrupt or prevent the life-extending effects of DR. We called these DR-essential genes and identified more than 100 in model organisms such as yeast, worms, flies, and mice. In order for other researchers to benefit from this first curated list of genes essential for DR, we established an online database called GenDR. To dissect the interactions of DR-essential genes and discover the underlying lifespan-extending mechanisms, we then used a variety of network and systems biology approaches to analyze the gene network of DR. We show that DR-essential genes are more conserved at the molecular level and have more molecular interactions than expected by chance. Furthermore, we employed a guilt-by-association method to predict novel DR-essential genes. In budding yeast, we predicted nine genes related to vacuolar functions; we show experimentally that mutations deleting eight of those genes prevent the life-extending effects of DR. Three of these mutants [had] extended lifespan under ad libitum, indicating that the lack of further longevity under DR is not caused by a general compromise of fitness. These results demonstrate how network analyses of DR using GenDR can be used to make phenotypically relevant predictions. ... comparing the influence of gene expression changes during DR on the interactomes of multiple organisms led us to suggest that DR commonly suppresses translation, while stimulating an ancient reproduction-related process."

Link: http://dx.doi.org/10.1371/journal.pgen.1002834

Here is another of many studies to link being overweight with cognitive decline: "People who are obese and suffer from high blood pressure and other problems linked to heart disease and diabetes may also see a faster decline in their mental abilities, according to a new study ... Yet even obese people without these physical conditions experienced a faster decline in functions such as memory, the researchers noted. This finding belies the concept of being obese and healthy ... Participants came from the long-running Whitehall II study, which began in 1985 and follows British civil servants from middle age onward. For the new findings, researchers followed more than 6,400 people aged 39 to 63 for 10 years. At the start of the study, they recorded patients' risk factors, including weight. During the follow-up decade, participants also took tests on memory, reasoning and overall mental function at three intervals. People with metabolic syndrome who were also obese saw a more rapid decline - 22.5 percent faster - in their mental function than those who weren't obese and didn't suffer from the syndrome. Moreover, those who did not have metabolic syndrome but were obese also saw mental function decline more quickly than participants who were not obese."

Link: http://health.usnews.com/health-news/news/articles/2012/08/20/obesity-in-middle-age-tied-to-more-rapid-mental-decline-study

Today I thought I'd point out an interesting article on a Japanese research group that works on tissue engineering of brain and eye structures. There is already considerable specialization in this young field: making headway in deciphering the chemical and gene expression instruction sets for cells and tissue growth is a massive undertaking, and it is different for every type of tissue in the body. There is enough here to keep a growing community of researchers busy for decades yet.

Tissue engineering: The brainmaker

Yoshiki Sasai, a stem-cell biologist at the RIKEN Center for Developmental Biology in Kobe, Japan, [has] impressed many researchers with his green-fingered talent for coaxing neural stem cells to grow into elaborate structures. As well as the optic cup, he has cultivated the delicate tissue layers of the cerebral cortex and a rudimentary, hormone-making pituitary gland. He is now well on the way to growing a cerebellum - the brain structure that coordinates movement and balance.

Sasai's work is more than tissue engineering: it tackles questions that have puzzled developmental biologists for decades. How do the proliferating stem cells of an embryo organize themselves seamlessly into the complex structures of the body and brain? And is tissue formation driven by a genetic program intrinsic to cells, or shaped by external cues from neighbouring tissues? By combining intuition with patient trial and error, Sasai has found that it takes a delicate balance of both: he concocts controlled environments that feed cells physical and chemical signals, but also gives them free rein to 'do their thing' and organize themselves into tissues.

What does one do with the ability to tissue engineer a brain? This will be possible not too many years from now. It's not as obviously useful as the ability to engineer a heart, as the brain can't be replaced outright in the same way - although that said it seems possible, based on present knowledge, for a least a few small portions of the brain to be successfully transplanted without affecting the mind. Not every part of the brain is greatly involved in the data and processing mechanisms that make up the self. But this seems as though it will be far harder than transplanting any other organ elsewhere in the body, and hard enough that parallel lines of research into repairing tissue in situ through stem cells and signaling manipulation may win out from the outset.

So the likely primary benefit resulting from the sort of work carried out by Sasai's group will be knowledge: information that can be applied to the development of ways to rebuild damaged brain tissue in place rather than building outside the body and then undergoing a transplant operation.

Some more data to add to the muddy waters of sirtuin research: "Since the discovery that overexpression of yeast Sir2 deacetylase extends lifespan by as much as 30% over a decade ago, much effort has been invested in researching whether this effect is conserved in higher organisms as well. Indeed, in worms and flies, two separate groups found that SIR2 extended lifespan as well, by 50% and 18%, respectively. ... In parallel to the work in worms and flies, researchers were trying to make headway in the role of sirtuins in higher organisms. There are seven mammalian homologs to the yeast Sir2, SIRT1-SIRT7. SIRT1 is the most well-researched and has been shown to regulate metabolism and age-related diseases. However, SIRT1 overexpression did not increase lifespan, although this was said to be due to the relatively weak expression of the transgene. Therefore, a role for sirtuins in regulating lifespan of mammals looked bleak. Despite the controversy surrounding sirtuins and longevity, there has never been any doubt that mammalian sirtuins are important regulators of health and disease. Previous results from our lab have shown SIRT6 to be involved in the calorie restriction response, and demonstrate that SIRT6 overexpression in mice protects against diet-induced obesity and its metabolic consequences. These results, along with data that SIRT6 knockout mice display a premature aging-like phenotype, prompted us to turn towards SIRT6 as a potential regulator of mammalian aging. Over the course of three years, we measured the lifespan of mice overexpressing exogenous SIRT6 (MOSES). This study was performed in two separate lines from distinct founders, to ensure that the random integration of the transgene into the genome did not influence the results. We found that the gene insertion in both lines did not disrupt any neighboring genes, and results were similar in both lines. In this way we overcame the issue of site-specific integration, which was previously shown to be a problem in sirtuin studies. Additionally, we chose to work with a mixed background, to ensure no strain-specific effects. Strikingly, both male MOSES lines had significant mean and median lifespan extension, of 14.5% and 9.9%. Even more interesting, there was no lifespan extension in either female lines examined, attesting to a gender-specific role for SIRT6."

Link: http://impactaging.com/papers/v4/n8/full/100478.html

In the latest case report from Alcor, there is a cautionary note on the need to solidify the arrangements and financing of cryopreservation before the last minute: "Alcor member A-2628 (he wishes his identity to be kept private) was pronounced legally deceased on July 23, 2012. A whole body member, A-2628 became Alcor's 112th patient. On Friday, July 20th, Alcor was notified through the TeleMed alert system that a 90 year old individual wishing to be cryopreserved was in serious condition in a Las Vegas hospital. This individual had filled out an application for membership in 2009 (and was provisionally assigned the number A-2628) but never followed through with the necessary paperwork and funding. Since he became unable to make cryonics arrangements, this case had to be treated as a third-party arrangement. Because of the greater risk involved, Alcor requires additional conditions to be met before accepting such a case. These conditions are rarely met. These include some past interest in cryonics on the part of the person for whom cryopreservation is sought; lack of opposition by close relatives; finances in place without undue hardship; no long ischemic time; and informed consent of persons making the arrangement. This case was one of the rare ones to proceed, in large part due to the determined efforts of A-2628's granddaughter supported by the family accountant."

Link: http://www.alcor.org/blog/?p=2633

The concept of "successful aging" is one put forward by a fairly wide-ranging group of people in medicine and research. When you break it down, "aging successfully" means that a bunch of really horrible things happen to you and your body, and then you die, but at least you weren't suffering as much as those guys over there.

This seems wrongheaded on a number of levels. It is the sort of thing that a researcher talks about when they are trying to avoid any mention of lengthening human life through medicine - which was at one time very much required:

If you want to stay in the conventional funding game, you can't even talk about therapies for degenerative aging; you must disavow any potential anti-aging application of your work, and stick to working towards therapies for specific conditions. This all ties back into last week's post on strategies for developing large-scale funding for directed anti-aging research - funding required for rapid progress towards far longer healthy life spans and the first stages of actuarial escape velocity.

This is no longer completely the case, but old habits die hard and there remains a sizable contingent in the research community who refuse to acknowledge that extending life is an ongoing goal. Hence talk of "successful aging" and "compression of morbidity" in connection with efforts to eliminate age-related disease or slow the pace at which people decline in old age. Anything other than raising the prospect of extending maximum life span in addition to healthy life span.

This is all somewhat complicated by the fact that no good definition for successful aging exists - and, really, how could it? In trying, you'll end up with something as ridiculous and self-defeating as the first paragraph in this post. You are in effect, and within the bounds of the philosophy of medicine, setting out to define an acceptable level of suffering, pain, and degeneration, rather than proposing to do treat it - which I think becomes ever more evident the more that you think about the whole thing.

Here is an open access paper on successful aging, whatever it might be in the minds of the various researchers and others pushing it as a concept. I think that final paragraph in the discussion well sums up the problems with successful aging as a goal:

It may be difficult to achieve successful aging in extremely late life. There is still no agreement on the definition of successful aging, and future work needs to expand the criteria for successful aging. In addition, more work needs to be done to examine predictors of successful aging as parts of developmental processes. Future work will contribute to the study of successful aging and help older adults achieve successful aging for as long as possible with a systematic approach to consider the past and present life and with a holistic view to understand age-related changes and challenges.

Implicit in this is the acceptance of aging and disability - the underlying assumption that aging must happen, and along with it great suffering. Aging cannot be successful. It is not a success to suffer, degenerate, and die. It isn't success to point out other people who are suffering more than you are. This whole way of thinking about about aging is a wrong, bad path that leads away from what needs to be done, which is to consider aging as a medical issue that should be addressed, just like every other medical issue that causes pain and hardship.

There is no "successful terminal cancer" movement. Why should aging sport such a thing?

Via the New Scientist: "Could we stem the tide of ageing by delaying the deterioration of stem cells? A new compound that appears to do just that could help us find ways to protect our organs from age-related wear and tear, experiments in mice suggest. As we age, so do our mesenchymal stem cells (MSCs): their numbers in our bone marrow decline, and those that are left lose the ability to differentiate into the distinct cell types - such as bone, cartilage, fat and possibly muscle cells - that help in the healing process. ... We think this ageing of stem cells may be linked to the onset of some age-related disorders, such as osteoporosis ... Earlier research in mice had suggested that the prion protein expressed by MSCs might play a role in holding back stem cell ageing. Mice lacking the prion protein were less able to regenerate blood cells. [Researchers] have now found that the prion protein performs a similar function in humans - older MSCs from human bone marrow expressed less of the protein than younger ones. In a bid to find a compound that might slow MSC ageing, the team tested numerous molecules known to target prion proteins on dishes of human stem cells. One molecule emerged as a potential candidate - stem cells treated with it produced 300 times the number of cells over 250 days than untreated stem cells. The treated cells kept on dividing for longer. The team then injected treated cells into the thigh bones of mice, and three days later found that they had produced three times as many new cells as they would normally produce. After five weeks, there were 10 times as many cells. The new cells appeared to be of higher quality, too, and readily differentiated into bone and fat cells, as well as those that support the tissue and blood vessels. [Researchers] think the molecule works by helping the prions protect the stem cells from the DNA damage associated with normal ageing."

Link: http://www.newscientist.com/article/mg21528784.600-protecting-prion-protein-keeps-stem-cells-young.html

For those following the progress of Organovo, a business-focused review: "In the classical approach to tissue engineering, cells are seeded and grown in a biocompatible matrix designed to direct cell differentiation and function. Scaffoldings play an important role in providing the cell architecture for structure and migration, as well as enabling the diffusion of vital nutrients and expressed product. Unfortunately, there are challenges that exist with the classical approach. Scaffolds, made from both natural and synthetic polymers, must be engineered to degrade at a rate in which the cells within them deposit and build their own extracellular matrix. Scaffold choice, immunogenicity, degradation rate, toxicity of degradation products, host inflammatory responses, fibrous tissue formation due to scaffold degradation, and mechanical mismatch with the surrounding tissue are key issues that may affect the long term behavior of the engineered construct, and directly interfere with its primary biological function. Additionally, scaffolds may elicit adverse host responses and interfere with direct cell-cell interaction. To get around the challenges of classical tissue engineering, Organovo has developed the first 3D bioprinter, called NovoGen MMX. The NovoGen MMX Bioprinter is a novel, fully automated, hardware and software platform developed to fabricate three-dimensional (3D) primary human or other living mammalian cells into tissue, with tremendous cellular viability and biology that is superior to even an animal model. Organovo's NovoGen MMX mechanical extruder enables the fabrication of three-dimensional tissue constructs in a wide variety of geometries (tubular structures, networked sheets, etc...). The speed and precision of this instrument enables the production of small-scale tissue models for drug discovery as well as various drug absorption and toxicology assays. NovoGen MMX works similar to an inkjet printer, in where cells are printed in tiny spheres; essentially 'bio-ink'. The concept of bioprinting relies on the demonstrated principle that groups of individual cells will self-assemble to generate aggregates, through the actions of cell surface proteins that bind to each other and form junctions. Furthermore, if two or more compatible self-assembled aggregates are placed in close proximity, under the proper conditions they will fuse to generate larger, more complex structures."

Link: http://seekingalpha.com/article/817361-an-in-depth-look-at-organovo

Animal studies of aging are costly, especially when researchers are working with genetically altered breeds: in order to see what happens, you have to wait. In mice, you wait for years, and that requires considerable ongoing expenditures to maintain laboratory animals and the staff who tend to them. This is one of the reasons why nowhere near every open question is well investigated at this time: a gap in the knowledge of aging biology has to be fairly compelling to justify the cost of a mouse study.

Over at the SENS Foundation, you'll find an interesting article on the application of better organization to this issue, with the aim of reducing to costs of some kinds of study of aging in laboratory animal populations.

The problem with testing rejuvenation biotechnologies in laboratory animals is that it takes them so long to get old. It takes more than two years for the exponential age-related increase in morbidity and mortality to become obvious in well-cared-for, wild-type laboratory mice and rats of a healthy strain. For that very reason, it takes at least this much time for the long-term health effects of the cellular and molecular lesions that accumulate with age in their tissues to reveal themselves, allowing researchers to probe the relationship -- and, more importantly, to test therapies that remove such damage from aging tissues, in order to restore youthful functionality to aging bodies. Feeding, housing, cleaning, and providing basic veterinary and other care to a colony of small mammals for this long is expensive, and introduces a burdensome delay between experimental conception and execution -- and just as you begin to want to study the animals, the colony begins suffering from attrition.

...

Now, a collaboration of British research organizations has come up with a completely new model to give scientists greater access to the aging animals that are the linchpin of progress in basic biogerontology and rejuvenation research. [They] recently devised a model to get much more data out of the aged mice that are already in rodent vivaria across the UK and beyond. [This] new Shared Ageing Research Models (ShARM) resource is now up and running. ... ShARM uses a collaborative, decentralized, and "lean" approach to increasing scientists' access to aging animals for biogerontology research. The approach is quite different from the system used by the NIA. Instead of providing more mice to the scientists that need them for research, ShARM gives more scientists access to the limited supply of aged animals and tissues that are already in the British and international research system, allowing them to unlock lifesaving information out of biological materials that would otherwise be lost to science.

Imagine a biogerontologist who has raised a colony of rats into senescence in order to study (for example) the relationship between age-related decline in cognitive function and associated changes in hippocampal gene expression. She runs the aged animals and young controls through a Morris water maze, and then sacrifices them to obtain brain tissue for a microarray study. Under status quo ante, two or three years' worth of investment in those mice -- and an unquantifiable amount of additional data on the impact of aging on the remainder of the aged organism -- would simply go out in the biological waste material stream. But by participating in ShARM's biorepository, the researcher can open up access for multiple additional laboratories to mine what the degenerative aging process has seared into the same animals' otherwise-forfeited tissues and serum.

You might look on this as an example to show that openness in scientific research still has a fair way to go. Many benefits to efficiency and speed of research might yet be unlocked by improvements in opening up the infrastructure and organization of science.

Autophagy, a collection of processes by which a cell breaks down damaged components to recycle their materials, is important in many mechanisms known to extend life in various laboratory animals. Better maintained cells are better for a longer life: more autophagy is a good thing, but it declines with age, because of a gradual buildup of materials that cannot be recycled and thus clog up the cellular components that perform autophagy - and for other, less well understood reasons. Here is an open access review on some of the controlling mechanisms: "One part of the aging process involves a decline in cellular housekeeping functions disturbing the maintenance of organism homeostasis. The accumulation of damaged and defective components increases cellular stress, for example, oxidative stress, which activates cellular defence mechanisms including NF-κB signaling pathway and innate immunity system, such as inflammasomes. Aging is associated with a low-grade proinflammatory phenotype which further interferes with housekeeping and cellular homeostasis. Recent studies have indicated that autophagy is a crucial cleansing system preventing inflammation but its capacity clearly declines with aging. The NF-κB signaling system and the autophagic degradation pathway have been closely conserved during evolution and emerging studies indicate that these systems have many context-dependent interactions with each other. We will review the recent literature on the control mechanisms of autophagy by NF-κB signaling and particularly we will focus on its context-dependent regulation during the aging process."

Link: http://www.hindawi.com/journals/ijcb/2012/849541/

An open access paper: "Cognitive impairment associated with subtle changes in neuron and neuronal network function rather than widespread neuron death is a feature of the normal aging process in humans and animals. Despite its broad evolutionary conservation, the etiology of this aging process is not well understood. However, recent evidence suggests the existence of a link between oxidative stress in the form of progressive membrane lipid peroxidation, declining neuronal electrical excitability and functional decline of the normal aging brain. The current study applies a combination of behavioural and electrophysiological techniques and pharmacological interventions to explore this hypothesis in a gastropod model (Lymnaea stagnalis feeding system) that allows pinpointing the molecular and neurobiological foundations of age-associated long-term memory (LTM) failure at the level of individual identified neurons and synapses. ... Classical appetitive reward-conditioning induced robust LTM in mature animals in the first quartile of their lifespan but failed to do so in animals in the last quartile of their lifespan. LTM failure correlated with reduced electrical excitability of two identified serotonergic modulatory interneurons (CGCs) critical in chemosensory integration by the neural network controlling feeding behaviour. Moreover, while behavioural conditioning induced delayed-onset persistent depolarization of the CGCs known to underlie appetitive LTM formation in this model in the younger animals, it failed to do so in LTM-deficient senescent animals. ... The results identify the CGCs as cellular loci of age-associated appetitive learning and memory impairment in Lymnaea and buttress the hypothesis that lipid peroxidation-dependent depression of intrinsic excitability is a hallmark of normal neuronal aging."

Link: http://www.biomedcentral.com/1471-2202/13/103/abstract

Type 2 diabetes is a self-inflicted medical condition for the vast majority of sufferers. You get it by consistently eating too much and accumulating a large amount of visceral fat tissue, thereby suffering all of the unpleasant metabolic consequences that it brings. The more you do this, the greater your risk. The path to diabetes is a gradual increase in metabolic disarray that first passes through what is known as metabolic syndrome before becoming full blown diabetes. Some people are susceptible than others as a result of genetic differences, but the road is basically the same for everyone: eating yourself into sickness takes years of effort, but in a wealthy society nearly everyone has the resources to do it.

Here is the interesting thing: at almost any point along the way, right up until either morbid obesity or later stage diabetes, this can all be reversed. A person can step off the path of increasing disability and head back to a healthier lifestyle, turning back the progression of diabetes. This can even be accomplished in a fairly drastic way by enlisting calorie restriction:

An extreme eight-week diet of 600 calories a day can reverse Type 2 diabetes in people newly diagnosed with the disease .... the low-calorie diet reduced fat levels in the pancreas and liver, which helped insulin production return to normal. Seven out of 11 people studied were free of diabetes three months later.

Not that I'm suggesting that it's smart to eat gluttonously for half your life and then rely on having your fat pulled from the fire this way - there are other consequences to being overweight for an extended period of time, as shown by risk levels of suffering age-related diseases in later life. But here is another more recent study to illustrate the point that cutting back and changing lifestyle is very powerful when it comes to diabetes, as it restores some of the brain's activity with respect to food that becomes disarrayed in diabetics.

Short-Term Caloric Restriction Normalizes Hypothalamic Neuronal Responsiveness to Glucose Ingestion in Patients With Type 2 Diabetes:

The hypothalamus is critically involved in the regulation of feeding. Previous studies have shown that glucose ingestion inhibits hypothalamic neuronal activity. However, this was not observed in patients with type 2 diabetes. Restoring the energy balance by reduction of the caloric intake and weight loss are important therapeutic strategies in patients with type 2 diabetes. We hypothesized that caloric restriction would have beneficial effects on the hypothalamic neuronal response to glucose ingestion.

Functional magnetic resonance imaging was performed in 10 male type 2 diabetic patients before and after a 4-day very low calorie diet (VLCD) [to measure] neuronal activity in the hypothalamus in response to an oral glucose load.

...

Post-VLCD scans showed a prolonged signal decrease after glucose ingestion. The results of the current study demonstrate that short-term caloric restriction readily normalizes hypothalamic responsiveness to glucose ingestion in patients with type 2 diabetes.

Other than calorie restriction, regular exercise is the most potent presently available method available to maintain health and extend life expectancy - which is actually more of a criticism of our lack of advanced biotechnology than praise for the merits of exercise. Exercise is beneficial even for the elderly, however, and one part of the downward spiral that comes with age is that loss of strength and increasing frailty constrain the ability to exercise sufficiently vigorously to obtain its benefits. This is true even for the longest-lived humans: "Ageing is a continuum of biological processes characterized by progressive adaptations which can be influenced by both genetic and physiological factors. In terms of human maturation, physically and cognitively functional centenarians certainly represent an impressive example of successful healthy ageing. However, even in these unique individuals, with the passage of time, declining lung function and sarcopenia lead to a progressive fall in maximal strength, maximal oxygen uptake, and therefore reduced exercise capacity. The subsequent mobility limitation can initiate a viscous downward spiral of reduced physical function and health. Emerging literature has shed some light on this multi-factorial decline in function associated with aging and the positive role that exercise and physical capacity can play in the elderly. Recognizing the multiple factors that influence ageing, the aim of this review is to highlight the recently elucidated limitations to physical function of the extremely old and therefore evaluate the role of exercise capacity in the health and longevity of centenarians."

Link: http://www.ncbi.nlm.nih.gov/pubmed/22883374

Many research groups are working on building blood vessels. Here is one: scientists "have developed [an] artificial functioning blood vessel outside of the body, made from reprogrammed stem cells from human skin. The team also saw the cells develop into a blood vessel inside the body for the first time. The new technique could have real potential to treat patients with heart disease [by] either injecting the reprogrammed cells into the leg or heart to restore blood flow or grafting an artificially developed vessel into the body to replace blocked or damaged vessels. ... this new study demonstrates that a new type of partial stem cell developed from fibroblasts (skin cells) can be reprogrammed into vascular cells before going into the body, which have no risk turning into tumours. The [team] introduced four genes to human fibroblasts in the laboratory to reprogramme them into partial stem cells so they could become vascular cells. When these newly created cells were injected into an ischemic leg (a leg with restricted blood flow) in an animal model, the function of the leg was improved. The process of developing vascular cells from skin cells took two weeks, which makes a personalised approach of turning a patient's own skin cells into vascular cells feasible for treatment of vessel-blocking related diseases. The researchers say the next step is to test this approach in cells from patients with vascular disease."

Link: http://www.kcl.ac.uk/newsevents/news/newsrecords/2012/08-Aug/pioneering-heart-disease-treatment.aspx

At root, medicine is driven by the urge remain alive. It is a process of engineering the means to prevent death, and so setting out to deliberately create greater longevity by tackling the root causes of aging - rather than addressing named diseases, one by one - is no more than the logical next step in this process. We know more than enough to get started down this path, and there are some few organizations working on it even today, though far from enough and with far from enough funding.

Consider a world with the means to prevent aging - say, though a package of therapies that a person undergoes every twenty years or so. Infusions of fresh stem cell populations, engineered enzymes to degrade metabolic waste products that build up in and around cells to impair their function, some form of mitochondrial DNA repair, culling excess memory T cells, and so on. These therapies prevent and reverse the build up of damage, allowing a body to continue in good health indefinitely. There is no good reason for them to be any more expensive than your average run of clinical treatments today: they would require little time from a physician, and would operate in much the same way for everyone, allowing economies of scale in production and distribution.

In such a society, all of the pressures associated with the short span of life we presently enjoy evaporate. We are so steeped in that omnipresent pressure of time that it's somewhat hard to envisage what a society without it would look like. Every strategic decision that we make in the course of our lives is based on time - that we have ever less of it remaining, the clock is ticking, and have only a few shots at getting anything significant accomplished. It requires a decade to become truly talented in any particular profession or skill, for example, and at least a few years to figure out whether not we can follow through to that level. That is a vast investment of time when we only have a few decades in which we are at our prime. The same goes for careers and relationships of any significance. We are pressured and choices have great weight precisely because we must forever give up an ocean of possibilities in order to swim in any particular pool.

There is a related school of thought among those opposed to engineering longevity: they say that the pressures of time created by the fact that we age to death due to our inadequate medical technology are a good thing. To me this has the look of rushing to justify what is, regardless of what might be, but they argue that the industry of individuals and humanity as a whole requires the deadline of dying; that without it, no-one would accomplish anything. They look upon the unending holocaust of death and destruction caused by aging - 100,000 lives every day, all they knew, all they could accomplish in the future, all they might have done, erased - and say it is necessary.

This is a hideous nonsense, serving to illustrate that little but a veneer separates us from the barbarians who actively slaughtered millions in past decades. It is true that rapid progress is very necessary in today's world - but we need it because we are dying, and the only way to save ourselves is through technological progress. The faster the better, every increment of speed representing countless lives that might be saved on some future date. If more people were more aware and more interested in doing something about this, we might move faster yet towards the biotechnologies of rejuvenation. Unfortunately, for all that each and every human life is shaped completely by the foreknowledge of future disability and death, all too few are willing to help change this state of affairs.

But so what if the medical technologies that can prevent death by aging make our societies slower-paced, more considered, less energetic? I'm not of the mind that this is a terrible thing - free-wheeling use of a resource is characteristic of wealth, and when we are wealthy in time, we will have the luxury to use it in ways that presently make little sense, or are called wasteful. Caring about waste is a sign of poverty, a sign that we don't have enough of whatever we worry about wasting, which in turn suggests we should do all we can to accumulate more of it. Besides, I don't for one moment believe that the slowing of economic engines and technological progress will in fact happen as feared by those who advocate for the continuation of mass death and suffering. There are all sorts of economic pressures upon human action that have next to nothing to do with aging and our current all-too-short span of life: consider the shifting desires for security, food, property, knowledge, and novelty, for example. The timescales on which those urges operate will not much change in an ageless society, as people will still have the same human nature as exists today. There will continue to be dynamic and ever-changing industries devoted to keeping people fed, clothed, and entertained.

These responses to irrational fears are, at the bottom line, unnecessary to some degree. 100,000 people died today of a cause that we can do something about. Tens of millions die every year, and hundreds of millions more suffer terribly on their way to that end. There is no argument that can possibly outweigh the need to address what is by far the greatest cause of death, suffering, and loss in the world - yet, for some strange combination of reasons, many people keep trying to find one.

Another branch of targeted therapies is the design of nanofactories that can be steered to specific locations in the body and there produce proteins and other drugs in response to local conditions or external commands. Early work in this field is underway: "Science is one step closer to producing drugs in the right place at the right time in the body, avoiding the collateral damage of untargeted treatments. Researchers [have] designed nanoparticles that can be stimulated via UV light to produce proteins on demand in vivo. The new method, which involves packaging the molecular machinery for making proteins into a membraned capsule, allows the researchers to spatially and temporally regulate protein production ... The scientists created the nano-sized 'protein factories' by using lipids to encapsulate polymerase and other machinery necessary for protein production from E. coli, along with a DNA plasmid containing a gene of interest. To block transcription until the right moment, they added a DNA 'photo-labile cage' to the plasmid - a small chemical that inhibits transcription but is cleaved by exposure to UV light. To test the principle in vivo, the researchers used luciferase as the reporter protein and injected mice with the nanovesicles. After zapping them with UV light at the site of injection, they were able to measure a local burst of luminescence. ... We have a long way to go still before we have a drug factory that will land in a target tissue to produce a drug of interest ... The study has proved the principle of the first step - getting the protein expressed on signal - but future research will need to ensure that the nanoparticles and the proteins they produce aren't toxic in the wrong place, and that they get to the right location. Targeting the nanoparticles to the appropriate tissues might be achieved by 'decorating' the surface of the vesicles with specific proteins."

Link: http://the-scientist.com/2012/08/13/next-generation-in-vivo-drug-factories/

A novel form of targeted therapy under development in the cancer research community: "By sequencing cancer-cell genomes, scientists have discovered vast numbers of genes that are mutated, deleted or copied in cancer cells. This treasure trove is a boon for researchers seeking new drug targets, but it is nearly impossible to test them all in a timely fashion. To help speed up the process, [researchers] have developed RNA-delivering nanoparticles that allow for rapid screening of new drug targets in mice. In their first mouse study [they] showed that nanoparticles that target a protein known as ID4 can shrink ovarian tumors.What we did was try to set forth a pipeline where you start with all of the targets that are pouring out of genomics, and you sequentially filter them through a mouse model to figure out which ones are important. By doing that, you can prioritize the ones you want to target clinically using RNA interference ... researchers decided to focus on the ID4 protein because it is overexpressed in about a third of high-grade ovarian tumors (the most aggressive kind), but not in other cancer types. The gene, which codes for a transcription factor, appears to be involved in embryonic development: It gets shut down early in life, then somehow reactivates in ovarian tumors. To target ID4, [researchers] designed a new type of RNA-delivering nanoparticle. Their particles can both target and penetrate tumors, something that had never before been achieved with RNA interference. ... Within the nanoparticles, strands of RNA are mixed with a protein that further helps them along their journey: When the particles enter a cell, they are encapsulated in membranes known as endosomes. The protein-RNA mixture can cross the endosomal membrane, allowing the particles to get into the cell's main compartment and start breaking down mRNA. In a study of mice with ovarian tumors, the researchers found that treatment with the RNAi nanoparticles eliminated most of the tumors."

Link: http://www.eurekalert.org/pub_releases/2012-08/miot-nns081512.php

The cautious majority believes that human life span will continue to increase, but only incrementally, much as it has done for the past few decades - both life expectancy at birth and life expectancy after 60, due to the continued introduction of new medical technologies. (Which proceeds far more slowly than it could, thanks to the heavy hand of the state). One faction of epidemiologists even argues for the possibility of a dip in overall life expectancy as present trends in obesity take their toll - to their eyes the consequences of being overweight look set to outweigh modest gains due to advances in medicine.

To my mind, arguing for incrementalism in any trend relating to medicine at the present time is choosing to go against the tide. The biotechnologies that underpin advances in medicine are going through a period of massive, revolutionary change. While it is true that organizations such as the FDA do pretty much everything short of shooting scientists to slow down and increase the cost of turning research into therapies, the rapid pace of progress in the life sciences will win through.

Allow me to put forward a historical analogy: standing in 2012 and arguing a case for gentle future changes in life expectancy over the next few decades, based on the past few decades, is something like standing in 1885 or so and arguing that speed and convenience of passenger travel will steadily and gently increase in the decades ahead. The gentleman prognosticator of the mid-1880s could look back at steady progress in the operating speed of railways and similar improvement in steamships throughout the 19th century. He would be aware of the prototyping of various forms of engine that promised to allow carriages to reliably proceed at the pace of trains, and the first frail airships that could manage a fair pace in flight - though by no means the equal of speed by rail.

Like our present era, however, the end of the 19th century was a time of very rapid progress and invention in comparison to the past. In such ages trends are broken and exceeded. Thus within twenty years of the first crudely powered and fragile airships, heavier than air flight launched in earnest: a revolutionary change in travel brought on by the blossoming of a completely new branch of applied technology. By the late 1920s, the aircraft of the first airlines consistently flew four to five times as fast as the operating speed of trains in 1880, and new lines of travel could be set up for a fraction of the cost of a railway. Little in the way of incrementalism there: instead a great and sweeping improvement accomplished across a few decades and through the introduction of a completely new approach to the problem.

This is one of many historical examples of discontinuities in gentle trends brought about by fundamentally new technologies. Returning to the medicine of the present day, there are any number of lines of work we could point to as analogous to the embryonic component technologies of an aircraft in 1885. They are still in the lab, or only being trialed, or still under development - but they exist in great numbers. There are the SENS technologies; a range of advanced applications of immunotherapy; targeting methodologies to safely destroy specific cell types; organ engineering; and others. Just because we can't see the exact shape of the emerging technologies that will be constructed atop these foundations doesn't make them any less likely to be created: great changes are coming down the line in medicine. The future is not one of steady and incremental progress.

From ScienceDaily: "researchers have built pancreatic tissue with insulin-secreting cells, surrounded by a three-dimensional network of blood vessels. The engineered tissue could pave the way for improved tissue transplants to treat diabetes. The tissue [has] some significant advantages over traditional transplant material that has been harvested from healthy pancreatic tissue. The insulin-producing cells survive longer in the engineered tissue, and produce more insulin and other essential hormones ... When they transplanted the tissue into diabetic mice, the cells began functioning well enough to lower blood sugar levels in the mice. ... The well-developed blood vessel network built into the engineered tissue is key to its success, the researchers concluded. The blood vessels encourage cell-to-cell communication, by secreting growth hormones and other molecules, that significantly improve the odds that transplanted tissue will survive and function normally. ... One reason transplants fail [is] that the islets are usually transplanted without any accompanying blood vessels. ... Until the islets begin to connect with a person's own vascular system, they are vulnerable to starvation. The 3-D system developed by [the] researchers tackled this challenge by bringing together several different cell types to form a new transplantable tissue. Using a porous plastic material as the scaffold for the new tissue, the scientists seeded the scaffold with mouse islets, tiny blood vessel cells taken from human umbilical veins, and human foreskin cells that encouraged the blood vessels to develop a tube-like structure. ... The advantages provided by this type of environment are really profound ... the number of islets used to lower blood sugar levels in the mice was nearly half the number used in a typical islet transplant. Islets grown in these rich, multicellular environments lived three times as long on average as islets grown by themselves."

Link: http://www.sciencedaily.com/releases/2012/08/120814110751.htm

Via EurekAlert!: "Most people probably know that heart disease remains the nation's No. 1 killer. But what many may be surprised to learn is that cholesterol has a major accomplice in causing dangerous arterial plaque buildup that can trigger a heart attack. The culprit? Inflammatory cells produced by the immune system. A number of research studies have demonstrated inflammation's role in fueling plaque buildup, also known as atherosclerosis, which is the underlying cause of most heart attacks and strokes, but knowledge of which immune cells are key to this process has been limited - until now. Researchers [have] identified the specific type of immune cells (CD4 T cells) that orchestrate the inflammatory attack on the artery wall. Further, the researchers discovered that these immune cells behave as if they have previously seen the antigen that causes them to launch the attack. ... The thing that excites me most about this finding is that these immune cells appear to have 'memory' of the molecule brought forth by the antigen-presenting cells. Immune memory is the underlying basis of successful vaccines. This means that conceptually it becomes possible to consider the development of a vaccine for heart disease. [Researchers believe] the antigen involved is actually a normal protein that the body mistakes as being foreign and therefore launches an immune attack resulting in inflammation in the arteries. ... Essentially, we're saying that there appears to be a strong autoimmune component in heart disease. Consequently, we could explore creating a 'tolerogenic' vaccine, such as those now being explored in diabetes, which could induce tolerance by the body of this self-protein to stop the inflammatory attack."

Link: http://www.eurekalert.org/pub_releases/2012-08/ljif-avf081412.php

Let us contemplate for a moment the level of effort that people put in to just one method of papering over just one of the changes caused by aging - just to keep up appearances, and making no difference at all to the underlying processes that cause degeneration. The method I had in mind is the use of dye to camouflage the progressive graying of hair. The fading of color of hair is an early sign that stem cell populations are responding to rising levels of damage, becoming less active in maintaining tissue. For whatever reason the pigment cells that give hair its color are more sensitive than others to the accumulating cellular and molecular damage of aging. Painting your hair in brightly colored chemicals does absolutely nothing other than cover up the evidence of this process, of course. You're still degenerating underneath that dye.

Individually, touching up graying hair isn't a great undertaking, and nor does it cost much. But when many, many people do it, that adds up. Ten years ago, hair dye was an industry with $7 billion in yearly sales worldwide - give or take. While that certainly includes the Manic Panic youth brigade, a large fraction of that commerce involves coloring gray hair. So it's not a stretch to suggest that the world's elder folk have a great enough interest in hair dye to fund the NIA several times over, or for something more constructive, provide the budget to implement the SENS vision of rejuvenation biotechnology a couple of times every year.

This sort of comparison serves to illustrate just how small research and development expenditures in medicine are in comparison to almost any form of day to day commerce. They tell us nothing about how to change that state of affairs, however. It's already something of a mystery as to why people are so relentlessly irrational when it comes to directing resources towards actual improvements in health and longevity versus papering over the cracks with hair dye or funding culturally accepted fraud in the form of "anti-aging" products.

Is it the case that people decide between funding research and hiding the gray, and choose to hide the gray? Or is it that funding meaningful research doesn't really even enter that choice matrix? To reframe these questions, is the solution to adequately funding the best and most promising longevity science more a matter of persuasion or more a matter of education?

Present prosthetic retina technology consists of an implanted electrode grid; progress is increasing the resolution by adding more electrodes to the grid. Here researchers take a different route, investigating ways to encode information such that neural cells will better process the resulting image: "More than 20 million people worldwide become blind owing to the degeneration of their retina, the thin tissue at the back of the eye that turns light into a neural signal. Only one prosthesis has been approved for treatment of the condition - it consists of an array of surgically implanted electrodes that directly stimulate the optic nerve and allow patients to discern edges and letters. Patients cannot, however, recognize faces or perform many everyday tasks. Sheila Nirenberg, a physiologist at the Weill Medical College at Cornell University in New York thinks that the problem is at least partially down to coding. Even though the retina is as thin as tissue paper, it contains several layers of nerves that seem to encode light into neural signals. 'The thing is, nobody knew the code,' she says. Without it, Nirenberg believes that visual prostheses will never be able to create images that the brain can easily recognize. Now, she and her student, Chethan Pandarinath, have come up with a code and developed a device that uses it to restore some sight in blind mice. The duo began by injecting nerve cells in the retinas of their mice with a genetically engineered virus. The virus had been designed to insert a gene that causes the cells to produce a light-sensitive protein normally found in algae. When a beam of light was then shown into the eye, the protein triggered the nerve cells to send a signal to the brain, performing a similar function to healthy rod and cone cells. Rather than feeding visual signals directly into the eye, they processed them using a code that the pair had developed by watching how a healthy retina responds to stimuli. After receiving the encoded input, the mice were able to track moving stripes, something that they hadn't been able to do before. The pair then looked at the neural signals that the mice were producing and used a different, 'untranslate', code to figure out what the brain would have been seeing. The encoded image was clearer and more recognizable than the non-encoded one. ... Nirenberg hopes to test the system in human trials soon. The encoding is simple enough to be done by a microchip, which, together with a small video camera could fit onto a pair of glasses. The camera would record a signal and the encoder would then flash it directly onto the genetically treated nerve cells in the eye."

Link: http://www.nature.com/news/prosthetic-retina-helps-to-restore-sight-in-mice-1.11164

An important regulatory gene for muscle atrophy is identified: "We now understand a key molecular mechanism of skeletal muscle atrophy. This finding could help us find a therapy for treating muscle atrophy in patients. ... The team has identified a single protein, called Gadd45a, and determined that it orchestrates 40 percent of the gene activity that ultimately causes skeletal muscle to atrophy. ... The researchers learned that Gadd45a affected muscles in two main ways: it instructed muscle cells to produce fewer proteins (needed to maintain muscle), and it caused proteins already existing in muscle fibers to break down. The result on both counts: muscle atrophy. The team then turned to find out how Gadd45a did its work. The nucleus of a muscle cell that is stressed changes from a cigar shape to a swollen bulb, with enlarged nucleoli (protein containers inside the nucleus). When Adams and his team injected Gadd45a into a muscle cell, the nucleus changed shape the same way as if it were stressed. ... To put this all together, it means Gadd45a is going into the muscle nucleus, and it totally changes it, so much so that the changes are visible. It's turning genes on, and it's turning genes off. It's changed the cell. ... Gadd45a changes roughly 600 genes associated with muscle atrophy, by increasing mRNAs charged either with breaking down muscle proteins or reducing muscle protein growth. ... Gadd45a is like a central switch for muscle atrophy. If you can block it, you can conceivably stunt muscle atrophy to a large extent."

Link: http://now.uiowa.edu/2012/08/researchers-identify-key-culprit-causing-muscle-atrophy

Longecity has funded modest scientific projects relating to longevity and aging for a few years now, raising funds through many modest donations from the community - efforts that predate the present crop of crowdfunding sites for scientific research, largely modeled after Kickstarter. Past Longecity projects include a study on laser ablation of lipofuscin, and a test of transplanting microglia into the brains of aging mice. These projects are generally funding for less than $20,000 - one of the noteworthy results of the ongoing biotechnology revolution is that significant small projects can be accomplished at this sort of funding level.

I note that the Longecity volunteers are seeking proposals for new projects to fund in the next cycle this year:

LongeCity continues its proud tradition to support small-scale, high-impact life extension research in 2012. (For a review from 2011 see here).

Projects should:

• aim to make a scientific contribution to the extension of the human lifespan
• be applied research or basic research with some potential for applied development
• present short updates for LongeCity Members with interim data, photos from the facility etc at agreed intervals
• be led or overseen by a person with a postgraduate qualification in the relevant field or by a person with demonstrable equivalent experience
• have a flexible project structure that can be adjusted according to the amount of money raised
• be small in scale - one or two key workers
• be short in duration - approx 6 months maximum
• not be confidential. LongeCity will expect open and public presentation and discussion of research results. However, confidentiality will be accepted where a manuscript or patent is in preparation.

LongeCity will be able to support a project with a minimum of $2000 and up to $8000, subject to matching by other donors. LongeCity will launch a call for matching donations and every donation generated in that call will go towards the project budget (Thus projects can have a total budget of $4000 - $16,000).

Interested parties should send:

• a project outline of no more than 800 words written in lay language (can be supported by up to 10 literature references)
• a curriculum vitae of the project leader

to research@longecity.org.

Initial Deadline: August 31st 2012!

The 2011 review of funded projects is well worth reading. Not everything runs smoothly, and to the credit of the Longecity team they are open on the shortfalls as well as the successes. Crowdfunding science and organization of projects at these levels of funding can be a challenge, as no-one has the exact recipe for success - but as demonstrated by the present greater interest in science and community funding, it clearly has a role in the future. Advocacy organizations with an interest in specific branches of science, such as the development of ways to slow and reverse aging, should definitely be getting involved in this area. Only by forging ahead can the best practices and methodologies be developed.

Some people knee-jerk against the prospect of a greatly extended healthy life by thinking of boredom - they can't imagine what they'd do with additional time. To my mind this fits well with the demographic who are ambivalent about being alive at all. To live a longer or shorter life will always be a choice, however. You won't have to undergo the rejuvenation therapies when they are available, just as you don't have to exercise, eat less, or otherwise maintain your health today: a shorter life is right there for the taking, if you feel so inclined. Here is a piece from io9 on the subject: "Some futurists predict that we'll be able to halt the aging process by the end of this century - if not sooner. The prospect of creating an ageless society is certainly not without its critics, with concerns ranging from the environmental right through to the spiritual. One of the most common objections to radical life extension, however, is the idea that it would be profoundly boring to live forever, and that by consequence, we should not even attempt it. So are the critics right? Let's take a closer look at the issue and consider both sides. To help us make sense of the problem, we spoke to two experts who have given this subject considerable thought: Bioethicist Nigel Cameron, the President of the Center for Policy on Emerging Technologies, and philosopher Mark A. Walker, Assistant Professor and Richard L. Hedden Chair of Advanced Philosophical Studies at New Mexico State University. It was through our conversations with them that we realized how difficult this question is to answer - mostly because no one has ever lived long enough to know. But given what's at stake, it's an issue that's certainly worth considering. Now, before we get into the discussion, there are a couple of things to note. First, this is not idle speculation. An increasing number of gerontologists, biologists, and futurists are predicting significant medical breakthroughs in the coming decades that could result in so-called 'negligible senescence' - the indefinite prolongation of healthy human life. And second, this discussion is limited to the question of boredom. Clearly, there are many other serious implications to radical life extension, but those are outside the scope of this article. Okay, let's do this thing."

Link: http://io9.com/5933409/would-it-be-boring-if-we-could-live-forever

There is a pervasive mythology surrounding aging: that it includes many harmless changes, things that are "normal" and therefore not worthy of the attention of medicine. This is all nonsense. All changes that happen with aging are damage-driven declines, but because the overall effect is so disastrous it can be hard to pin down and separate out the lesser components. As biotechnology improves, we will see ever more pieces of aging segmented off and named as specific diseases - but in reality it's all harmful, and the full breadth of aging should be fought against: researchers "say a common condition called leukoaraiosis, made up of tiny areas in the brain that have been deprived of oxygen and appear as bright white dots on MRI scans, is not a harmless part of the aging process, but rather a disease that alters brain function in the elderly. ... In the past, leukoaraiosis has been considered a benign part of the aging process, like gray hair and wrinkles. ... [Researchers] performed functional MRI (fMRI) scans on cognitively normal elderly participants recruited from the Mayo Clinic Study of Aging between 2006 and 2010. In 18 participants, the amount of leukoaraiosis was a moderate 25 milliliters, and in 18 age-matched control participants, the amount of disease was less than five milliliters. The patients were imaged in an MRI scanner as they performed a semantic decision task by identifying word pairs and a visual perception task that involved differentiating straight from diagonal lines. ... Although both groups performed the tasks with similar success, the fMRI scans revealed different brain activation patterns between the two groups. Compared to members of the control group, patients with moderate levels of leukoaraiosis had atypical activation patterns, including decreased activation in areas of the brain involved in language processing during the semantic decision task and increased activation in the visual-spatial areas of the brain during the visual perception task. ... Different systems of the brain respond differently to disease. White matter damage affects connections within the brain's language network, which leads to an overall reduction in network activity."

Link: http://www.eurekalert.org/pub_releases/2012-08/rson-cs080712.php

The immune system is vital for many reasons. It is not just a barrier against pathogens of all sorts, such as bacteria, fungi, and viruses, but also a watchdog that hunts down and destroys harmful cells, such as those that have entered senescence or are in danger of becoming cancerous. In later life the immune system declines and fails in characteristic ways, partly a consequence of its evolved structure and resource limits, and partly the same general accumulation of damage that affects all cells in the body. The failure of the immune system is important because it contributes to other threads in aging: allowing senescent cells to build up, failing to catch cancers when they can be easily destroyed, and generating ever higher levels of inflammation. This increasing incapacity alongside increasing inflammation is known as immunosenescence or inflammaging.

Here is an open access paper on the subject:

Hallmarks of human "immunosenescence": adaptation or dysregulation?

Is immunosenescence an intrinsic ageing process leading to dysregulation of immunity or an adaptive response of the individual to pathogen exposure? Age-associated differences in bone marrow immune cell output and thymic involution suggest the former. Accepted hallmarks of immunosenescence (decreased numbers and percentages of peripheral naïve T cells, especially CD8+ cells, and accumulations of memory T cells, especially late-stage differentiated CD8+ cells) suggest the latter, viewed as the result of depletion of the reservoir of naïve cells over time by contact with pathogens and their conversion to memory cells, the basis of adaptive immunity.

Thymic involution beginning early in life limits the generation of naive cells such that the adult is believed to rely to a great extent on the naïve cell pool produced mostly before puberty. Thus, these hallmarks of immunosenescence would be markedly affected by the history of the individual's exposure to pathogens, [and] in humans, particularly to infection with CMV.

...

One very striking difference [between industrialized Western populations and those of poorer regions is that in] the "wild-type" situation, all humans are infected with CMV from the age of ca. 2 months on, when they no longer receive only anti-CMV antibody in the mother's milk, but also the infectious virus that has reactivated in the meantime. CMV-negativity is an artifact of civilization, hygiene and decreased breast feeding. Hence, in our pilot study of young and old men in rural Pakistan, all the young were already CMV-positive. As "old" is viewed as [greater than] 50 years in this society, we sought to establish whether age-associated differences in immune phenotypes that we and others had established in older European and US populations were similar in Pakistanis, and whether they manifested earlier in the latter.

We concluded that there were two major differences between the Pakistani population and the historical controls of [subjects from Western, industrialized regions]. One was that we did indeed see age-associated differences in CD8+ T cells earlier in the Pakistanis, and the other was that we saw for the first time in a healthy population that not only the CD8+ subset but also the CD4 + T cells were affected. This we had otherwise only seen in pathological European populations, eg. those with Alzheimer's. We interpret this to mean that the level of "antigenic stress" in the Pakistani population, old at 50, could indeed be leading to "premature immunosenescence".

Some thoughts on what can be done to reverse some of the declines in the aging immune system - alongside a few concrete results in laboratory animals - can be found a little way back in the Fight Aging! archives.

• Prospects for Immune System Rejuvenation Through Selective Destruction
• Immune System Rejuvenation Achieved Through Targeted Cell Destruction
• Exercise and the Destruction of Age-Damaged Immune Cells

There are a great many theories of aging, and here is another for the pile from a researcher who leans towards aging as genetic programming rather than aging as accumulated damage: "The biological mechanisms at the heart of the aging process are a long-standing mystery. An influential theory has it that aging is the result of an accumulation of molecular damage, caused in particular by reactive oxygen species (ROS) produced by mitochondria. This theory also predicts that processes that protect against oxidative damage (involving detoxification, repair and turnover) protect against aging and increase lifespan. ... However, recent tests of the oxidative damage theory, many using the short-lived nematode worm Caenorhabditis elegans, have often failed to support the theory. This motivates consideration of alternative models. One new theory [proposes] that aging is caused by hyperfunction, i.e. over-activity during adulthood of processes (particularly biosynthetic) that contribute to development and reproduction. Such hyperfunction can lead to hypertrophy-associated pathologies, which cause the age increase in mortality. ... Here we assess whether the hyperfunction theory is at all consistent with what is know about C. elegans aging, and conclude that it is. In particular, during adulthood C. elegans show a number of changes that may reflect pathology and/or hyperfunction. Such changes seem to contribute to mortality, at least in some cases (e.g. yolk accumulation). ... Our assessment suggests that the hyperfunction theory is a plausible alternative to the molecular damage theory to explain aging in C. elegans."

Link: http://extremelongevity.net/2012/08/09/is-aging-due-to-hyperfunction/

Progress towards a non-invasive test for Alzheimer's disease: "Reliability and failure to replicate initial results have been the biggest challenge in this field. We demonstrate here that it is possible to show consistent findings. ... [Researchers] measured the levels of 190 proteins in the blood of 600 study participants [including] healthy volunteers and those who had been diagnosed with Alzheimer's disease or mild cognitive impairment (MCI). MCI, often considered a harbinger for Alzheimer's disease, causes a slight but measurable decline in cognitive abilities. A subset of the 190 protein levels (17) were significantly different in people with MCI or Alzheimer's. When those markers were checked against data from 566 people participating in the multicenter Alzheimer's Disease Neuroimaging Initiative, only four markers remained: apolipoprotein E, B-type natriuretic peptide, C-reactive protein and pancreatic polypeptide. Changes in levels of these four proteins in blood also correlated with measurements from the same patients of the levels of proteins [beta-amyloid] in cerebrospinal fluid that previously have been connected with Alzheimer's. The analysis grouped together people with MCI, who are at high risk of developing Alzheimer's, and full Alzheimer's. ... Though a blood test to identify underlying Alzheimer's disease is not quite ready for prime time given today's technology, we now have identified ways to make sure that a test will be reliable."

Link: http://www.eurekalert.org/pub_releases/2012-08/eu-btf080912.php

A number of diverse lines of research and development will lead to new technologies that replace or repair organs. The present list looks much as follows:

• Electromechanical and blended biological-electromechanical systems: artificial hearts, prosthetic limbs and eyes, dialysis machines that contain cultured kidney tissue, and so forth.
• Repair of organs in situ using transplanted stem cells or stem cell signaling to spur regrowth that otherwise would not happen.
• Engineering of complete organs from a patient's own cells, such as through bioprinting.
• Decellularization to replace the cells in human donor tissue and organs in order to form patient-matched transplants.
• Xenotransplantation: the use of decellularized organs and tissues from animals, which provide the structure and chemical cues to allow repopulation with the patient's human cells.

A recent article at the Scientist looks at a couple of these lines of work - organ engineering versus xenotransplantation, both of which draw heavily upon the comparatively new techniques of decellularization in order to achieve new and better results, both in the laboratory and for patients in trials:

Today, the organ shortage is an even bigger problem than it was in the 1980s. ... he supply has stagnated despite well-funded attempts to encourage donations, and demand is growing, especially as the organs of a longer-lived population wear out.

Faced with this common problem, Vacanti and Cooper have championed very different solutions. Cooper thinks that the best hope of providing more organs lies in xenotransplantation - the act of replacing a human organ with an animal one. From his time in Cape Town to his current position at the University of Pittsburgh, he has been trying to solve the many problems that occur when pig organs enter human bodies, from immune rejection to blood clots. Vacanti, now at Massachusetts General Hospital, has instead been developing technology to create genetically tailored organs out of a patient's own cells, abolishing compatibility issues. "I said to myself: why can't we just make an organ?" he recalls.

In the race to solve the organ shortage, xenotransplantation is like the slow and steady tortoise, still taking small steps after a long run-up, while organ engineering is more like a sprinting hare, racing towards a still-distant finish line. Most of those betting on the race are backing the hare. Industry support has dried up for xenotransplantation after years of slow progress, leaving public funders to pick up the expensive tab. Stem cells, meanwhile, continue to draw attention and investment. But both fields have made important advances in recent years, and the likely winner of their race - or whether it will result in a draw - is far from clear.

...

Xenotransplants will always have to deal with an immune clash of some degree, so growing an organ that is perfectly matched to a patient would be preferable. The question is whether tissue-engineering technologies will reach that point before genetic engineering enables the first transgenic pig hearts or kidneys to be successfully installed in patients. Sachs says, "I consider xenotransplantation still the nearest-term, best hope for solving the organ shortage, but in the long run, I think tissue engineering will replace it."

There is also the matter of scale. Platt thinks that organ engineering is too costly to meet the needs of everyone waiting for a transplant. "You'd have to turn over the entire GDP of a country to accomplish that," he says. On the other hand, "I could get a pig for a couple of hundred dollars." But Macchiarini argues that organ engineering is in its infancy, and every advance improves efficiency and lowers cost. "What we did in 2008 in 6 months, we can now do in a few weeks," he says. "We do care about getting this to every patient." Vacanti adds that mass-producing artificial scaffolds will make organ engineering even more cost-effective. "When you scale them up, the bulk materials and manufacturing tech are extremely cheap," he says. "I think it's going to be cheaper than growing lots of pigs."

We shall see. The only sure thing in my book is that vigorous competition is good for both speeding progress and producing higher quality solutions. That is just as true in medicine as for every other field of human endeavor.

Efforts continue to correlate longevity with the activity levels of specific genes: "MicroRNAs (miRNAs) are small, non-coding RNAs that regulate gene expression and play a critical role in development, homeostasis, and disease. Despite their demonstrated roles in age-associated pathologies, little is known about the role of miRNAs in human aging and longevity. ... We employed massively parallel sequencing technology to identify miRNAs expressed in B-cells from Ashkenazi Jewish centenarians, i.e., those living to a hundred and a human model of exceptional longevity, and younger controls without a family history of longevity. ... we discovered a total of 276 known miRNAs and 8 unknown miRNAs ranging several orders of magnitude in expression levels, a typical characteristics of saturated miRNA-sequencing. A total of 22 miRNAs were found to be significantly upregulated, with only 2 miRNAs downregulated, in centenarians as compared to controls. Gene Ontology analysis of the predicted and validated targets of the 24 differentially expressed miRNAs indicated enrichment of functional pathways involved in cell metabolism, cell cycle, cell signaling, and cell differentiation. A cross sectional expression analysis of the differentially expressed miRNAs in B-cells from Ashkenazi Jewish individuals between the 50th and 100th years of age indicated that expression levels of miR-363* declined significantly with age. Centenarians, however, maintained the youthful expression level. This result suggests that miR-363* may be a candidate longevity-associated miRNA.

Link: http://dx.doi.org/10.1186/1471-2164-13-353

NAD+ is featured in the energy generation cycle that takes place in mitochondria within cells, as well as many other roles. Its levels appear to influence and be influenced by all sorts of mechanisms related to longevity and aging. "Nicotinamide adenine dinucleotide (NAD+) is an essential electron transporter in mitochondrial respiration and oxidative phosphorylation. In genomic DNA, NAD+ also represents the sole substrate for the nuclear repair enzyme, poly(ADP-ribose) polymerase (PARP) and the sirtuin family of NAD-dependent histone deacetylases. Age associated increases in oxidative nuclear damage have been associated with PARP-mediated NAD+ depletion and loss of SIRT1 activity in rodents. In this study, we further investigated whether these same associations were present in aging human tissue. Human pelvic skin samples were obtained from consenting patients aged between 15-77 and newborn babies (0-1 year old) ... DNA damage correlated strongly with age in both males and females whereas lipid oxidation (MDA) levels increased with age in males but not females. PARP activity significantly increased with age in males and inversely correlated with tissue NAD+ levels. These associations were less evident in females. A strong negative correlation was observed between NAD+ levels and age in both males and females. SIRT1 activity also negatively correlated with age in males but not in females. Strong positive correlations were also observed between lipid peroxidation and DNA damage, and PARP activity and NAD+ levels in post pubescent males. This study provides quantitative evidence in support of the hypothesis that hyperactivation of PARP due to an accumulation of oxidative damage to DNA during aging may be responsible for increased NAD+ catabolism in human tissue. The resulting NAD+ depletion may play a major role in the aging process, by limiting energy production, DNA repair and genomic signalling."

Link: http://dx.doi.org/10.1371/journal.pone.0042357

In comparison to the ubiquitous fruit fly various species of bee do not often feature in studies on longevity and metabolism. Here researchers tested resveratrol on bees and found an extension of life:

To test whether honey bee lifespan, learning performance, and food perception could be altered by resveratrol, we supplemented the diets of honey bees and measured lifespan, olfactory learning, and gustatory responsiveness to sucrose. Furthermore, to test the effects of resveratrol under metabolic challenge, we used hyperoxic environments to generate oxidative stress. Under normal oxygen conditions, two resveratrol treatments - 30 and 130 μM - lengthened average lifespan in wild-type honey bees by 38% and 33%, respectively. Both resveratrol treatments also lengthened maximum and median lifespan. In contrast, hyperoxic stress abolished the resveratrol life-extension response.

The gloss is off resveratrol, you might recall, with studies showing increasingly little of interest in terms of concrete results. The same goes for once-hyped sirtuins: again, little to show for a great deal of time and money expended, and no great expectation that this state of affairs will change.

Given all of that it is at first interesting to see research results in which resveratrol clearly extends life. The details, however, once again show the need to watch all such studies for signs of reduced calorie intake. Calorie restriction has a strong effect on longevity in almost all species studied to date, and here resveratrol probably achieved its extension of life through suppressing appetite in the bees:

resveratrol treatment did significantly change the gustatory responsiveness score. Unsupplemented honey bees exhibited greater responsiveness to sugar during this test, while animals supplemented with resveratrol were less responsive to sugar. ... We hypothesized that an altered gustatory response score could indicate that resveratrol was eliciting a satiety effect on honey bees. This prompted us to measure individual food consumption in resveratrol-supplemented and unsupplemented subjects.

The bees consuming resveratrol ate approximately 25% less by the look of it - well into moderate calorie restriction territory.

A piece on the continuing tradition of Russian cosmism, influential on the transhumanist movement and the modern community that advocates for radical life extension through biotechnology: "According to Dr. Igor Vishev (b. 1933), a distinguished Russian scientist and philosopher, it is likely that there are people alive today who will never die. Just stop for a moment and think about that. Alive today. Never die. ... Vishev's line of thought is a 21st-century variation of Russian cosmism, a philosophical tendency that started with the eccentric 19th-century librarian and thinker Nikolai Fedorov (1829-1903) and continued through the 20th century ... Vishev is convinced that medical technology is advancing so rapidly that sometime later in this century, Homo sapiens will become Homo immortalis. He believes that our current lifespan of up to 90 or, in extreme instances, slightly over 100 years, is not cast in stone or fixed in nature but an evolutionary stage out of which we are now emerging. Genetic engineering, replacement of natural organs with artificial instruments, nanotechnology, and other developing technologies could now extend our lives well beyond today's assumed limits. He proposes that a 200-year-old person is a present possibility, and a person who could live at least as long as a 2,000-year-old redwood tree is certainly imaginable. Such longevity will be self-propelling. New discoveries during the 200-year (or 2,000-year) lifespan would make what Vishev calls 'practical immortality' a fairly safe bet. By 'practical' he means 'realizable' but not absolute. People could still die, accidentally or otherwise, but eventually techniques of 'practical resurrection,' toward which today's cloning is a primitive first step, would be able to restore life to those who somehow lose it. Vishev's philosophy, which he calls 'practical immortology,' is an attempt to shift our entire culture and worldview from one based on the certainty of human mortality to one based on the prospect of human immortality. This shift requires radical new directions not only in science and technology but in economics, politics, morality, ecology, art - everything. Not easy, of course, but he thinks it's possible."

Link: http://www.huffingtonpost.com/george-m-young/do-you-want-to-be-immortal_b_17

Here is a short piece on the immortal dictator argument that shows up from time to time as one of the reasons given to continue to let billions die of aging: "But what if, the critics continue, you had a dictator who could live more or less for thousands of years? Wouldn't it be a good thing if he was guaranteed to die at some point and the people he oppressed had a chance to start anew? Wouldn't the sacrifice be worth it? No, it wouldn't, and here's why. Basically, we're being asked to give a potential means of extending our life spans so we can be sure that just a small handful of people and their cronies would be dead at some point in time. We can't always kill them or depose them, so we'll be outsourcing the assassination to nature. Anyone see the problem here? Of the over seven billion people who aren't dictators, who do we think is expendable enough to die alongside our targets for the sake of the anti-dictator cause? If I may reach for a little hyperbole, how different is the logic that all the billions who will die in the process are fair game because their death helps the cause from that of all terrorist groups who believe that civilians of the countries they hate can be on the hit list because killing them hurts an enemy and may force him to retreat? This is a rather crass way of saying that the ends justify the means and I doubt that they really do in this case. We could take this logic further and cast all modern medicine as being a dictator enabling technology. Maybe last week Assad would've tripped, fallen, hurt himself, then got his wound infected and was soon dead from septic shock, helping to end the civil war in Syria. Does this mean we must now give up our disinfectants and advanced medical treatments to make sure bad people die easier?"

Link: http://worldofweirdthings.com/2012/08/01/a-terrible-reason-to-oppose-life-extension/

At the present time two groups of people well placed to influence progress in rejuvenation biotechnology are, for the most part, acting against their own self-interest. It is generally the case that such situations do not last: self-interest wins out in the long term.

On the one hand we have the world's high net worth individuals, most of whom do very little in the way of funding research into aging or the conditions of aging. It is their inaction that is opposed to their own self-interest: they are all aging to death at the same pace as the rest of us, after all. When it comes to access to medical technology the world is remarkably flat: the poor struggle in this as in everything else, but the wealthy have no more ability to buy a way out of aging (or heart disease, or cancer, or any of the other conditions that attend aging) right this instant than does anyone else. What they do have is a far greater ability to create a near future in which rejuvenation biotechnologies exist and are just as widely available as any present day clinical procedure.

It is in the self-interest of everyone who can significantly speed up the development of ways to reverse aging to set forth and do exactly that - but very few are making the effort. At some point it will become evident to the public and the world at large that aging to death whilst surrounding by wealth is insanity in an age in which those resources could be used for the development of age-reversing medicine: ways to repair mitochondrial DNA, break down accumulated metabolic byproducts that clog up cells, clear out senescent cells, restore declining stem cell activity, and so forth. But as yet this is not obvious enough to those people who matter.

The second group acting against their own self-interest in the matter of rejuvenation biotechnology are those researchers who could be working on relevant scientific projects but are not. Much of the aging research community doesn't in fact do any more than study aging, and the minority who do work on development of therapies are largely investigating the slow and unproductive path of slowing aging via metabolic manipulation. A far better road exists: the pursuit of ways to repair the damage that causes aging, as outlined by the SENS Foundation but by no means limited to their chosen methods of implementation. Work on the repair of aging is far more likely to produce radical advances in medicine worthy of this age of accelerating progress: ways to restore the old to vigor and greatly extend health human life. Researchers who are not working on something that looks a lot like SENS are locking themselves out of the most interesting and most valuable room in the house.

But as I said above, self-interest tends to win out in the long run. As more attention is given to SENS, longevity science, and the repair of aging, it becomes ever more likely it is that self-interest will emerge as a driving force in funding and research.

Via ScienceDaily, news of a possible basis for a therapy to block the progression of dry macular degeneration: "Previous research [showed] that in human eyes with geographic atrophy [GA] there is a deficiency of the enzyme DICER1, leading to accumulation of toxic Alu RNA molecules in the retinal pigmented epithelium. Another paper [showed] that when these RNAs build up in the eye they trigger activation of an immune complex known as the NLRP3 inflammasome. In turn, this leads to the production of a molecule known as IL-18, which causes death of retinal pigmented epithelial cells and vision loss by activating a critical protein known as MyD88. Importantly, [researchers] found evidence that activity of the inflammasome, IL-18, and MyD88 were all increased in human eyes with GA. They then showed that blocking any of these components could prevent retinal degeneration in multiple disease models. The researchers are excited that blocking these pathways could herald a new potential therapy for GA, for which there is no approved treatment."

Link: http://www.sciencedaily.com/releases/2012/08/120806151248.htm

A conference to be held this coming December in Brussels: "Your presence can be key to convince the European Commission to count more on biology of ageing, preventive and regenerative medicine to extend healthy lives in the not so distant future. Heales (Healthy Life Extension Society) is a European non-governmental association promoting and advocating scientific research into longevity and biogerontology. We are a group of biologists, biochemists, medical doctors and diverse other professions throughout Europe. Having followed the evolution of the European Innovation Partnership on Active and Healthy Ageing we have reached the conclusion that biology of ageing needs to be highlighted more clearly as an important solution. Innovations based on biology of ageing can contribute to improve healthy life in a very significant way and we want to address this message to the European Union through this conference. In this conference, we will let scientists explain how their research contributes or can contribute to extend the healthy lifespan of European citizens; we will put scientists, entrepreneurs, medical doctors and other key actors together to build the business of long term health, towards a living Europe rather than a dying Europe. We hope that people who work for the European Union, politically active persons and others will be interested and will further help biology of aging reach concrete implementations."

Link: http://www.eha2012.org

The use of decellularized animal tissue as a basis for reconstructive therapies is spreading: the tissue can be stripped of cells leaving only the extracellular matrix to act a growth-inducing scaffold for a patient's own cells - and with no immune rejection issues, even though it came from a different species. With these tools it is possible to rebuild a wider range of tissues than in the past, and produce a better end result. Much of the public attention on tissue engineering focuses on the end goal of complex organs built from scratch, new hearts, kidneys, and livers, but this remains a decade or more in the future. Meanwhile a great deal of presently achievable work is already taking place, the reconstruction and replacement of less complex structures in the body such as the trachea.

A recent article goes into some detail as to how decellularized pig tissues are used to greatly improve one particular form of reconstructive therapy:

Mike Wright's new esophagus continues to work like "a newborn baby's" - his way of describing the organ he came within weeks of losing in 2010. The 56-year-old Columbus, Ohio, man - the world's second to undergo experimental esophagus-replacement surgery in Pittsburgh, his occurring in January 2010 - remains the biggest cheerleader for the still-experimental surgery soon to be tested in a human clinical trial. ... The trial will test whether regrowth of the esophagus lining, as occurred with Mr. Wright, produces better results than the current practice of removing the entire esophagus to treat esophageal cancer, then creating a makeshift esophagus with a portion of the stomach.

...

Dr. Jobe's success in treating six patients to date without failure represents the latest advance in pioneering tissue-engineering research ... The current line of research began with the development of two-dimensional tissue replacement, including tubes or tracts and skin, with efforts now under way to replace tendons. The research is progressing to creating whole human organs. Dr. Jobe said the replacement of esophageal linings in six patients represents "proof of principle for this approach, and we must now validate the results in a clinical trial in order to responsibly introduce this technique into clinical practice."

...

The scaffolding is "extracellular matrix," or ECM - a matrix or tissue framework developed from pig tissue from which all the pig's cells have been removed. The ECM naturally contains growth factors and proteins among other molecules that appear to signal the recipient's adult stem cells, and possibly other cells, to transform themselves into site-specific cells needed at that particular location of the body. ... For the right candidate for the surgery, Dr. Jobe cuts the cylindrical tube of lining at either end of the damaged area [of the esophagus], as if he were removing a damaged piece of pipe, before pulling it out of the throat in a way similar to taking off a tube sock. If nothing else were done, resultant scarring would prevent swallowing and clog the throat. The ECM process regenerates healthy tissue without scarring.

Next Dr. Jobe uses pig ECM that Dr. Badylak developed and now produced commercially to form a new esophageal lining. The ECM tube is soaked until it is flaccid and then slipped over a collapsed spring-like stent. Once in place, the stent is expanded until it presses the ECM against the esophageal wall where the lining had been removed. In a process known as wallpapering, the stent holds the ECM in place until it adheres to the wall. In a matter of days the ECM fully attaches to the esophagus wall to serve as a framework for stem cells or other cells to migrate there and heed signals from the ECM or from neighboring esophagus cells to transform into esophageal lining. Soon after the surgery with the stent in place, the patient can consume liquids. Full replacement of the lining occurs within several weeks. In time, the pig ECM is replaced naturally with human tissue. Mr. Wright said he can eat and drink anything he wants without any difficulty in swallowing.

As the article points out, this is a big improvement over the previous form of surgical reconstruction of the esophagus, which tends to have a high rate of complications and quality of life issues. This sort of incremental improvement will continue throughout the years between now and the development of means to build entire organs like hearts and lungs from nothing more than a patient's own cells. This isn't just a matter of waiting for a distant goal, but a matter of constant, ongoing progress in the quality and effectiveness of medicine.

Advice on financial planning for those who are not paying attention to progress in medicine: "My take on the mortality tables [used in financial planning]: they are excessively pessimistic. The mortality tables assume a fairly static biomedical treatment environment in which only small incremental improvements to medical care are possible. No discontinuities are part of the forecast. This seems a very big mistake. On the horizon we can see the approach of effective gene therapies, cell therapies, and other treatments that attack the underlying mechanisms of aging. The scientists doing research on these treatments will succeed. Once they do we will have biotechnology that enables us to repair aged tissue. For a long time mortality has declined fairly slowly. That's because we've had no tools for attacking the underlying mechanisms of aging. Our bodies gradually wear out just like bodies 50 or 100 years ago. We've got medical treatments that reduce the consequences of failing tissue (e.g. blood pressure medicine) and treatments that slow the rate of development of some types of problems (e.g. cholesterol lowering drugs). But we can't do much about the rate at which we accumulate mutations or the rate at which we accumulate toxic intracellular junk. We aren't going to stay helpless against aging tissues. The legions of scientists experimenting with pluripotent stem cells, tissue engineering, gene therapies, and other promising therapies will succeed and they will succeed in the first half of the 21st century. Once we can fix and replace failing parts the mortality tables go out the window as we gain the ability to do what we can now do to old cars: replace parts and keep on going. At some point in the 21st century we will reach actuarial escape velocity where the rate at which we can repair the body exceeds the rate at which pieces of the body wear out and fail. Our rejuvenated bodies will then go on for many more decades and eventually centuries. In a nutshell: If you are in your 30s or below I think your odds of dying of old age are remote. Whether folks in their 40s, 50s, and beyond will live to benefit from rejuvenation therapies probably depends on how long they will live naturally. Someone who is 50 years old and has 40 years to go even without biomedical advances will certainly live long enough to enjoy the benefits of biotechnologies that will enable them to live well beyond 90 years."

Link: http://www.futurepundit.com/archives/008687.html

The BBC on intermittent fasting, from the Horizon series: "Scientists are uncovering evidence that short periods of fasting, if properly controlled, could achieve a number of health benefits. ... Calorie restriction, eating well but not much, is one of the few things that has been shown to extend life expectancy, at least in animals. We've known since the 1930s that mice put on a low-calorie, nutrient-rich diet live far longer. There is mounting evidence that the same is true in monkeys. ... One area of current research into diet is Alternate Day fasting (ADF), involving eating what you want one day, then a very restricted diet (fewer than 600 calories) the next, and most surprisingly, it does not seem to matter that much what you eat on non-fast days. [Researchers] carried out an eight-week trial comparing two groups of overweight patients on ADF. ... If you were sticking to your fast days, then in terms of cardiovascular disease risk, it didn't seem to matter if you were eating a high-fat or low-fat diet on your feed (non-fast) days."

Link: http://www.bbc.co.uk/news/health-19112549

For whatever reason, a number of public voices seem to be talking about immortality all of a sudden, largely meaning physical immortality in the sense of immunity to aging but vulnerability to fatal accidents. Topics ebb and flow like tides, I suppose, the signs of many hidden connections that underlie our culture - that grand conversation of innumerable threads held in the myriad communication channels available to us.

• Russian Mogul Soliciting Billionaires to Achieve Immortality
• Kurzweil Talks About Achievable Immortality On PBS NewsHour
• Do All Transhumanists Want Immortality? No? Why Not?
• We Talk To The Philosopher Being Given $5 Million To Study Immortality

It's a big project so it's hard to summarize to its core being but I'd say we're investigating two different kinds of immortality. One would be the possibility of living forever without ever dying. The main questions there are whether it's technologically plausible or feasible for us, either by biological enhancement such as those described by Ray Kurzweil, or by some combination of biological enhancement and uploading our minds onto computers in the future. I think another more interesting and important question is would we choose to be immortal in that sense, or does death and finitude give life meaning?

And so forth, repeated in the echo chamber. Immortality can be a useful term - such as on the occasions on which you want to plant a flag a long way out in the discussion and make waves. It is, I think, becoming less useful with time, however. So many people use it without meaning or with so many varied and half-thought meanings that it is, like "anti-aging", becoming more harmful than helpful. Too much baggage, too many charlatans of various types hitching their carts to the bandwagon.

Putting in serious time and thought on physical immortality - $5 million here and $5 million there adds up pretty quickly - seems to me to be premature. There is a great deal of work that lies between here and first generation rejuvenation biotechnology, something that will allow us to live additional decades in good health, never mind what comes after that. The rise and rapid obsolescence of many massive industries in medicine will happen over the next fifty years in order to extend the outer limits of human health and life span far beyond the present century-and-a-bit. Each of those churning engines of progress will see millions of individuals working in hundreds of competing companies, a world of intricate detail.

The result of all of that? Possibly humans that can live for two centuries or more before hitting as-yet unknown limits to presently envisaged biological repair technologies. This is a drop in the ocean of time. But that will give a hundred years of grace in which to work feverishly on the next generations of technology: replacements for biological systems, improving on the ways to repair and rebuild our cells, merging with our machines as those machines become ever smaller and more capable. The world of a century and a half from now will be as distant and strange and capable to us as our tools and society would seem to a 18th century peasant.

My point is that many transformative, world-sweeping changes brought by advancing technology will occur in the decades between now and even a mere hard-fought doubling of the human life span. We'll be starting in earnest to settle the Moon and Mars by then. Our machines will be able to think for themselves. Desktop and motile nanofactories will be capable of fabricating everything from houses to gene therapies from raw materials. A sea of historical and cultural manuscripts will be written on those changes, and still fail to easily capture the scope of the way in which the world changes.

And then it starts over again, ever building new and greater edifices as we push on to overcome the next set of limits to the human condition. All of this grand and complex near future of increasing longevity and massive change seems far more worthy of thought than immortality, given the length of the road between here and there, and how much has to be done to even start talking seriously about lives of tens of thousands of years.

We have a great deal more control over the age-related decline of the brain than was once thought - "use it or lose it", and the ability to affect change through challenging the mind. Yet it remains the case that new biotechnology and medicine will be required to get to where we want to be, a world without the risk of dementia, fuzzy memory, and slow cognition. Still, the plasticity of the aging brain is encouraging: "There is growing evidence that, beyond what was previously believed, the adult human brain is remarkably malleable and capable of new feats - even in the last decades of life. In fact, new experiences can trigger major physical changes in the brain within just a few days, and certain conditions can accelerate this physical, chemical and functional remodeling of the brain. ... We used to think that the brain was completely formed by development and its basic structure didn't change much in adults, but as research went on we discovered that wasn't true, at least in the cerebral cortex. We now know that an underlying portion of the brain called the thalamus, which feeds the cortex information from our senses, is also remarkably plastic. ... There is no evidence that there is any part of the adult brain that is not plastic. But studies indicate that some aspects of musical training, such as the ability to perceive temporal patterns, require the brain to be trained during early developmental periods when its primed for certain types of stimuli. For other aspects of musical development, such as the ability to perceive and repeat a sequence of tones, it's irrelevant whether you've had that experience and training early in life. ... The brain is plastic for life. The fundamental thing that determines how much [persons with brain disorders] will improve is the level of their initial impairment, but not their age."

Link: http://www.newswise.com/articles/researchers-find-the-brain-more-malleable-than-believed

There is no shortage of theories as to why women live longer than men - an apparently simple question, but one balanced on such a mountain of complex data and partial knowledge that it cannot be definitively answered at the present time. Here is another theory for the stack: "Mitochondria are inherited only from mothers, never from fathers, so there is no way to weed out mutations that damage a male's prospects. ... [Researchers] analysed the mitochondria of 13 different groups of male and female fruit flies. Mitochondria, which exist in almost all animal cells, convert food into the energy that powers the body. ... the results point to numerous mutations within mitochondrial DNA that affect how long males live, and the speed at which they age. ... Intriguingly, these same mutations have no effects on patterns of ageing in females. All animals possess mitochondria, and the tendency for females to outlive males is common to many different species. Our results therefore suggest that the mitochondrial mutations we have uncovered will generally cause faster male ageing across the animal kingdom. ... They suggest this is because there is no evolutionary reason for the faults that affect males to be picked up - because mitochondria are passed down by females. ... If a mitochondrial mutation occurs that harms fathers, but has no effect on mothers, this mutation will slip through the gaze of natural selection, unnoticed. Over thousands of generations, many such mutations have accumulated that harm only males, while leaving females unscathed."

Link: http://www.bbc.co.uk/news/health-19093442

A recent open access commentary by researcher Michael Rose and colleagues looks at the following question: what, exactly, is aging? Much like art, we might know it if we see it, but there's plenty of room for debate over the details.

What is Aging?

In 1991, the book Evolutionary Biology of Aging offered the following definition of aging: a persistent decline in the age-specific fitness components of an organism due to internal physiological deterioration (Rose, 1991). This definition has since been used by others a number of times. However, it was only a modest generalization of a definition proffered by Alex Comfort over three editions (1956-1979) of his key book The Biology of Senescence (Comfort, 1979): "a progressive increase throughout life, or after a given stadium, in the likelihood that a given individual will die, during the next succeeding unit of time, from randomly distributed causes."

...

Yet a mere definition does not necessarily tell a scientist what causally underlies the phenomenon that is so defined. The latter issue is much broader, implicitly raising fundamental scientific questions regarding mechanisms.

From here the piece heads off into a discussion of late life plateaus in aging, for example in flies where it is observed that the chance of death per unit time stops rising at advanced ages - in other words the flies stop aging by one definition of the term, left with a high but steady mortality rate. There are some arguments for this phenomenon to exist in humans, but the data is sparse and other results argue the opposite conclusion. Still, the researchers here argue that the demonstrated existence of this phenomenon in lower animals requires further thought to be directed towards how to define aging:

it appears that the cessation of aging occurs at the individual level, and is not just an artifact of population structure. Yet this is clearly paradoxical, if we think of the machinery of aging in terms of such physiological processes as steadily cumulative damage. If it is supposed that some process of cumulative damage or disharmony is supposed to underlie aging, why should that process abruptly stop at the very point, late in adult life, when it has greatly reduced the ability of the surviving individuals to sustain life and reproduction?

...

These results call for some fundamental re-thinking of what aging is: [that] aging is not inevitably a cumulative and unremitting process of deterioration. Instead, aging might be best conceived as a facet of [evolutionary] adaptation ... under sufficiently benign environmental conditions, individuals from species as disparate as humans and fruit flies can survive a protracted aging period and reach a subsequent late-life respite in which fitness-component deterioration stops, a phase permitted by the complete attenuation of the forces of natural selection relative to the effects of genetic drift.

The details of the way in which these researchers put forward their hypothesis to reconcile the late-life plateau in aging with existing ideas on the evolution of aging is not conceptually straightforward or easy to understand - but is interesting. As they put it:

This vision of what underlies aging may be off-putting for some, given its theoretical complexities and difficulties for experimental design. No doubt many physicists felt the same way about the destruction of the elegant late nineteenth Century version of Newtonian mechanics by the advent of relativistic and quantum mechanics, in the period from 1905 to 1945. But paradigm transitions in science are generally like that, requiring that we abandon comfortable theories in favor of those that are significantly less wrong.

It remains to be seen whether this view of aging merits comparison with the signature physics of the 20th century, but it is certainly true that a lot of new theorizing on evolution and aging is taking place these days - no doubt driven by an increasing interest in the biology of aging and the prospects of new medicine to intervene in the aging process.

Some viruses show promise in terms of preferentially attacking cancer cells - but they can be engineered to be far more effective in the role of therapeutic agent: "Parvoviruses specifically kill cancer cells and are already in the clinical trial stage for treating malignant brain tumors. However, they can also infect normal cells - without doing any harm to them - so a large portion of viruses is lost during therapy. [Researchers] have now modified parvoviruses in such a way that they initially lose their ability to infect cells. In a second step, they equipped the viruses with a molecular key for infecting cancer cells. ... the researchers chose H1 parvoviruses, which normally infect rodents but are also infectious for human cells. H1 viruses kill tumor cells on the basis of their natural properties, i.e., their genetic material does not need to be modified for them to do so. ... The viruses exclusively destroy cancer cells. But with the same efficiency that they infect cancer cells, they also infect healthy cells. There they do not cause any damage and cannot replicate, but we lose a large portion of therapeutic viruses every time ... To solve this problem, the researchers [first] modified the genetic material of the virus in such a way that it loses its ability to infect cells. In a second step, this non-infectious virus was equipped with a molecular key for cancer cells. ... This is first evidence that it is basically possible to modify properties of H1 according to a plan. We will surely need several more attempts in order to target the viruses more specifically to cancer cells in the second step. We also already have ideas how to further enhance the infectious capacity and the potential to destroy cancer cells."

Link: http://www.kurzweilai.net/tailor-made-viruses-for-enhanced-cancer-therapy

Any commonality in present in varied types of cancer is important, as it provides a potential path to a comparatively low-cost, robust suite of therapies that work for many cancers - and a robust cancer cure is an important component of any future rejuvenation biotechnology toolkit. Here researchers add some weight to the cancer stem cell hypothesis: "Cancer researchers can sequence tumour cells' genomes, scan them for strange gene activity, profile their contents for telltale proteins and study their growth in laboratory dishes. What they have not been able to do is track errant cells doing what is more relevant to patients: forming tumours. Now three groups studying tumours in mice have done exactly that. Their results support the ideas that a small subset of cells drives tumour growth and that curing cancer may require those cells to be eliminated. It is too soon to know whether these results - obtained for tumours of the brain, the gut and the skin - will apply to other cancers, [but if they do], there is going to be a paradigm shift in the way that chemotherapy efficacy is evaluated and how therapeutics are developed. ... Underlying this scenario is the compelling but controversial hypothesis that many tumours are fuelled by 'cancer stem cells' that produce the other types of cancer cell, just as ordinary stem cells produce normal tissues. ... The papers provide clear experimental evidence that cancer stem cells exist ... They have made a major contribution to validating the concept of cancer stem cells. ... Researchers are already busy hunting for ways to kill these cells; now they have more tools to tell whether such a strategy will work."

Link: http://www.nature.com/news/cancer-stem-cells-tracked-1.11087

Calorie restriction is very potent in mice and other laboratory species: even a seemingly modest decrease in calorie intake can have beneficial effects on health and longevity that are comparable to the effects of whatever medicine, compound, or biological mechanism is actually being tested. If your prospective treatment happens to reduce mouse appetite, easy to achieve accidentally, then it's likely that the resulting study data will appear beneficial - but not for the right reasons. This is why those of us interested in longevity science must carefully examine promising studies to see whether the authors controlled for the effects of varying calorie intake. Care on this front has been slow to arrive, sad to say, and a lot of past data has to be thrown out or taken with a grain of salt because of the ubiquitous effects of calorie restriction.

One wide-ranging and positive result of the modern interest in calorie restriction research is a greater rigor in the diet of laboratory animals. The more of that the better, as results will improve across the board.

This scale tilts the other way as well, however. Regular readers will know that a high and sustained intake of calories eventually overwhelms natural storage mechanisms - deposition of fat tissue - and leads to metabolic dysfunction and more serious conditions such as diabetes and dementia. It is possible to argue that "high and sustained" well describes the calorie intake of laboratory mice in many studies, meaning that there is as much pervasive distortion in this fashion as for calorie restriction elsewhere:

All-they-can-eat diet for lab mice and rats may foster inaccurate test results

The widespread practice of allowing laboratory rats and mice to eat as much as they want may be affecting the outcome of experiments in which scientists use these "test-tubes-on-four-feet" to test new drugs and other substances for toxicity and other effects. ... the millions of lab rodents used in laboratory studies each year have a nutritional status that is different from other test animals. While other test animals are fed meals, rodents have round-the-clock access to food. And eat they do, gaining more weight and more body fat than meal-fed rodents. The authors cite other research indicating that lab rodents with free access to food tend to develop abnormally high blood fat levels, high cholesterol, nerve and heart damage, cancer and other disorders.

Meal-Feeding Rodents and Toxicology Research

Most laboratory rodents used for toxicology studies are fed ad libitum, with unlimited access to food. As a result, ad libitum-fed rodents tend to overeat. Research demonstrates that ad libitum-fed rodents are physiologically and metabolically different from rodents fed controlled amounts of food at scheduled times (meal-fed). Ad libitum-fed rodents can develop hypertriglyceridemia, hypercholesterolemia, diet-induced obesity, nephropathy, cardiomyopathy, and pituitary, pancreatic, adrenal, and thyroid tumors, conditions likely to affect the results of toxicology research studies.

It should go without saying that overfed humans also tend to develop the conditions on that list, amongst others, to a far greater degree than their calorie-controlled peers - which is something to think on.

An open access paper, and an example of the way in which researchers are closing in on common mechanisms that explain the operation of many diverse ways found to extend healthy life in laboratory animals: "Many mutations that increase animal lifespan also confer stress tolerance, suggesting that cytoprotective mechanisms underpin the regulation of longevity. It has not been established, however, whether the induction of individual cytoprotective pathways is essential for lifespan extension, or merely correlated. To establish whether the regulatory pathways for the induction of cytoprotective responses are key in the extension of lifespan, we performed an RNAi screen for gene inactivations that decouple the activation of cytoprotective pathways from xenobiotic stimuli that normally induce them. The screen identified 29 genes that constitute the regulatory cascades of the unfolded protein response, oxidative stress response, and detoxification. ... If cytoprotective responses contribute directly to lifespan extension, inactivation of these genes would be expected to compromise the extension of lifespan conferred by decreased insulin/IGF-1 signaling, disruption of mitochondrial function, or caloric restriction ... We find that inactivation of 25 of 29 cytoprotection-regulatory genes shortens the extension of longevity normally induced by decreased insulin/IGF-1 signaling, disruption of mitochondrial function, or caloric restriction, without disrupting normal longevity nearly as dramatically. These data demonstrate that induction of cytoprotective pathways is central to longevity extension."

Link: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3400582/

A research position is open at the SENS Foundation: "SENS Foundation is hiring for our research center located in Mountain View, CA. We are seeking a team lead for our LysoSENS group to work both on established projects and new independent lysosomal-based research geared towards the SENS mission ... Qualified candidates will have a Ph.D. in the chemical/biological sciences and at least 5 years of work experience that must include prior project management experience. Duties will include bench work, management of a small team of lab researchers, the preparation of grant proposals, internal and external progress reports, individual and collaborative publication. The project lead will develop, interpret and implement standards, procedures, and protocols for the LysoSENS research program and may collaborate on determining strategic directions in the research program. Bench experience should include standard laboratory techniques, including but not limited to standard cell biology/biochemistry/molecular biology techniques. Good fundamental laboratory skills to include safety, microbial and mammalian cell culture. Experiments may include cell culture, transfection, organelle (lysosomal) purification and imaging, microscopy, protein production and analysis in addition to supervisory duties. As a project lead, candidates must have the ability to design, develop and direct experiments that establish the viability of the SENS mission and chosen therapeutic goals."

Link: http://sens.org/node/2853