A range of methods to target specific types of cell in the body are presently under development: immune cells, nanoparticles, viruses, and bacteria can all be used to deliver payloads to specific cells, provided that a suitable sensor mechanism can be established for the target in question. One of the benefits of this approach is that almost all existing methods used to destroy cells can be adapted for this new world of precision therapies. Tiny amounts of proven chemotherapy compounds can be loaded into nanoparticles and remain effective in destroying the cancer cells they are delivered to, but the severe side effects of standard chemotherapy are almost entirely eliminated. Chemotherapy in its present incarnation is a very unpleasant exercise, and targeting is a great leap forward in the application of chemical attacks on cancer.

Radiation is also used as a cancer treatment. As for chemotherapy, the present state of the art in available treatments involves a range of techniques that aim to to hurt the cancer more than the rest of the patient. It's still a pretty unpleasant exercise - not something that anyone would choose to undergo unless it were the least worst available option. Like chemotherapy compounds, radioactive compounds can also be cut down to amounts as small as individual atoms and loaded up onto nanoparticles or other delivery systems. For example, last month researchers reported on the use of a type of bacteria that only infects cancer cells as a carrier for radioactive materials that destroy those infected cells.

Tiny amounts of highly radioactive compounds are like tiny amounts of poison - they don't cause much harm at all outside the target cells, and this is the key to building therapies that have minimal side-effects. Here is another recent example of targeted therapy development using radioactive materials, but with nanoparticles as the delivery agent this time:

Researchers Develop Radioactive Nanoparticles that Target Cancer Cells

Cancers of all types become most deadly when they metastasize and spread tumors throughout the body. Once cancer has reached this stage, it becomes very difficult for doctors to locate and treat the numerous tumors that can develop. Now, researchers at the University of Missouri have found a way to create radioactive nanoparticles that target lymphoma tumor cells wherever they may be in the body.

In an effort to find a way to locate and kill secondary tumors [researchers] have successfully created nanoparticles made of a radioactive form of the element lutetium. The MU scientists then covered the lutetium nanoparticles with gold shells and attached targeting agents. [Previous research] has already proven the effectiveness of similar targeting agents in mice and dogs suffering from tumors. In that research, the targeting agents were attached to single radioactive atoms that were introduced into the bodies of animals with cancer. The targeting agents were able to seek out the tumors existing within the animals, which were then revealed through radio-imaging of those animals.

In their current research, the MU scientists have shown the targeting agents can deliver the new radioactive lutetium nanoparticles to lymphoma tumor cells without attaching to and damaging healthy cells in the process. "This is an important step toward developing therapies for lymphoma and other advanced-stage cancers. The ability to deliver multiple radioactive atoms to individual cancer cells should greatly increase our ability to selectively kill these cells."

Twenty years from now cancer will be comparatively well controlled: the trend is towards highly effective therapies, thousands of researchers are involved in building them, and a lot of money is flowing into this work. Cancer doesn't worry me anywhere near as much as common causes of sudden death in the elderly such as heart failure and stroke. If, against the odds, you find yourself nailed by cancer in the 2030s - and I think that this is an unlikely outcome for anyone in a wealthier region of the world - then even the worst case scenarios still allow you plenty of time to wrap up matters and arrange your own cryopreservation. Heart failure and stroke arrive with no such warning, and the only way to reliably deal with all of the causes of functional degeneration in the heart and brain is to implement SENS rejuvenation biotechnologies. Despite tremendous progress in recent years the SENS program remains in a comparatively early stage of funding and support within the research community - it is tiny in comparison to the cancer research community, and funding is the greatest obstacle to faster progress.

Researchers investigate the ability of lower animals like the salamander to regenerate limbs and organs with the hopes that some of these mechanisms also exist in humans, just turned off at some point in our evolutionary history. Even if this is not the case, it may be that a greater understanding of the mechanisms of salamander regeneration will lead to ways to improve human regenerative capacity.

Salamanders' immune systems are key to their remarkable ability to regrow limbs, and could also underpin their ability to regenerate spinal cords, brain tissue and even parts of their hearts. [Researchers] found that when immune cells known as macrophages were systemically removed, salamanders lost their ability to regenerate a limb and instead formed scar tissue. "Now, we need to find out exactly how these macrophages are contributing to regeneration. Down the road, this could lead to therapies that tweak the human immune system down a more regenerative pathway."

Salamanders deal with injury in a remarkable way. The end result is the complete functional restoration of any tissue, on any part of the body including organs. The regenerated tissue is scar free and almost perfectly replicates the injury site before damage occurred. There are indications that there is the capacity for regeneration in a range of animal species, but it has, in most cases been turned off by evolution. "Some of these regenerative pathways may still be open to us. We may be able to turn up the volume on some of these processes. We need to know exactly what salamanders do and how they do it well, so we can reverse-engineer that into human therapies."

Link: http://www.eurekalert.org/pub_releases/2013-05/mu-dsh051613.php

Ten years from now targeted therapies that selectively deliver cell-killing mechanisms to cancer cells will be the dominant method of treating cancer. This sort of technology offers the prospect of removing cancer cells even after metastasis, and with few side effects:

Nanomedicine started creating its own footprint in the sands of cancer research back in the mid-1970s when a group of European researchers discovered what would eventually become known as the liposome. These nano-sized, spherical structures form spontaneously when naturally occurring or synthetic lipids are exposed to water. Although they were identified by accident, these same researchers soon realized the potential of liposomes to carry drugs to diseased cells and tissues.

Around the same time, Massachusetts Institute of Technology research engineer Robert Langer also developed nanoparticles as chains of hydrocarbons known as polymers. Decades later, researchers have shown that such targeted nanoparticle therapies can effectively deliver drug cargo to tumors, while sparing the rest of the body's cells from the drug's toxic effects. Indeed, both types of nanoparticles are in clinical development as cancer-drug delivery vehicles, and some liposome-based have even made it to the market. There are now a total of three nanoparticles on the market as cancer therapies, and at least a dozen more are currently making their way through clinical trials.

The liposome platform is limited, however, in that it cannot release the drug into the tumor in a regulated way. The mechanism of drug release from liposomes is not well-understood, and may involve complex processes such as disruption of the liposome membrane or fusion with cellular membranes. In contrast, the polymer-based nanoparticles [allow] researchers to design treatments that release the chosen drug at a predictable rate controlled by diffusion. "While the first generation of drugs using [lipid] nanotechnology were considered pioneering at the time and became successful blockbuster cancer drugs, they were essentially reformulations of older drugs. Now, the next generation [using polymers] is taking nanotechnology to a whole new level with the ability to fundamentally change the efficacy and safety of drugs. The properties of these advanced compounds are well suited to target rapidly proliferating cells such as cancer cells, and several are already in the clinic."

Link: http://www.the-scientist.com/?articles.view/articleNo/35629/title/Nano-vehicles-for-Cancer-Drugs/

It wouldn't be too far wrong to regard ourselves as ambulatory chemical processing plants: biology is very complicated and highly organized chemistry, a collection of reactions and products. The operation of our metabolism is as much based on processing oxygen as it is on processing food. Thus you don't don't have to wander all that far into the scientific literature on the biology of aging to find mention of reactive oxygen species (ROS), the mechanisms of oxidative stress, and the various oxidative theories of aging, such as the mitochondrial free radical theory of aging. All sorts of reactive molecules containing oxygen can be found in our biology at any given time, an inevitable byproduct of being an oxygen-processing species.

Cells and their components are intricate assemblies of protein machinery, but all it takes to disrupt a component is for it to react with a passing ROS molecule. It'll quickly be replaced by a cell's repair mechanisms, but in the meanwhile it is broken. Oxidative stress refers to the level of ongoing damage caused by ROS; ambient levels of ROS can rise due to environmental circumstances such as heat or radiation exposure, but we're more interested in what happens during aging. Older theories of aging based on oxidative damage suggest that aging is caused by an accumulation of this damage, and indeed levels of oxidative stress rise with aging, but the relationship isn't that simple.

Evolutionary selection is very ready to use any tool to hand. An individual's biology is a set of interconnected systems that share component molecules, and which are tied together into feedback loops and signal exchanges. Just like every other molecule in our biology reactive oxygen species were long ago co-opted into all sorts of vital mechanisms. This means that it is far from straightforward to talk about ROS and aging, as there are many different roles in metabolism for what at first sight seems to be nothing but a damaging, toxic class of molecule, and these roles are affected by rising levels of ROS in different ways. The specific location in cells and the body and the present circumstances all matter when it comes to what happens when ROS levels increase.

For example, it has been shown that some of the benefits of exercise are based on slightly increased levels of ROS as a signal. Increased use of muscle results in a higher output of ROS from the mitochondrial power plants working away in muscle cells, and cells react to this change with greater housekeeping efforts - an outcome known as hormesis. If tissues and bloodstream are bathed in antioxidants that soak up those ROS, then these benefits of exercise can be blocked. Thus general use of antioxidants in a normal metabolism may potentially do more harm than good.

Similarly, it seems fairly clear at this point, based on work in mice, that targeting antioxidants specifically to mitochondria is a beneficial strategy, and this presumably works by soaking up ROS at source before they can cause harm. How does this impact exercise and its effects on health? As yet unknown. Further, a range of life-extending genetic alterations in nematode worms work by globally increasing or globally reducing ROS output from mitochondria, with either outcome resulting in longer-lived worms. Increased ROS works through hormesis, by increasing repair activities, while reduced ROS output directly reduces damage, or at least that is the present consensus.

Mitochondria are important in aging - that much is worth taking away as a lesson here. I view much of the research into ROS and mitochondria as little more than a confirmation that it is vital to develop the range of envisaged biotechnologies that enable mitochondrial repair and replacement. The mitochondrial free radical theory of aging suggests that aging is in large part caused by the way in which mitochondria damage themselves with their own ROS output. It is that damage that is the important thing, not the ROS, but mitochondrial damage has such a great impact on aging and longevity that even modest changes in either (a) the pace at which they damage themselves or (b) the likelihood of damaged mitochondria being replaced by cellular maintenance mechanisms, both of which are influenced by rates of ROS production, have a measurable effect on longevity in shorter-lived species.

But back to complexity resulting from the uses that ROS are put to in our biology. Here are a couple of papers that illustrate a few more of the ways in which nothing is simple:

Rejuvenation of Adult Stem Cells: Is Age-Associated Dysfunction Epigenetic?

The dysfunctional changes of aging are generally believed to be irreversible due to the accumulation of molecular and cellular damage within an organism's somatic cells and tissues. However, the importance of potentially reversible cell signaling and epigenetic changes in causing dysfunction has not been thoroughly investigated. Striking evidence that increased oxidative stress associated with hematopoietic stem cells (HSCs) from aging mice causes dysfunction has been reported. Forced expression of SIRT3, which activates the reactive oxygen species (ROS) scavenger superoxide dismutase 2 (SOD2) [to] reduce oxidative stress, functionally rejuvenates mouse HSCs.

These data, combined with numerous other reports, suggest that ROS act as a signal transducer to play a critical regulatory role in HSCs and at least in some other stem cells. It is likely that ectopic expression of SIRT3 restores homeostasis in gene expression networks sensitive to oxidative stress. This result was surprising because age-associated damage from impaired DNA repair had been thought to be irreversible in old HSCs. These data are consistent with a hypothesis that potentially reversible processes, such as aberrant signaling and epigenetic drift, are relevant to cellular aging. If true, rejuvenation of at least some aged cells may be simpler than generally appreciated.

Endothelium, heal thyself

[The endothelium] cooperates with leukocytes to create openings to provide the infection-fighting cells ready access to their targets. By and large, these ensuing "micro-wounds" are short-lived; as soon as the cells have crossed the endothelium, these pores and gaps quickly heal, restoring the system's efficient barrier function. In cases when these gaps fail to close - and leakage occurs - the results can be devastating, leading to dramatic pathologies including sepsis and acute lung injury.

[Researchers] set up experimental models that mimicked acute, intense inflammation. Using dynamic time-lapse and high-resolution confocal microscopy, the investigators could see the process by which leukocytes were breaching the endothelial cell. In the course of a 10-minute span, they observed that a single endothelial cell tolerated the passage of at least seven leukocytes directly through its body, and that within this brief period, the gaps closed, leaving no sign of the pores.

This response [is] fundamentally dependent on proteins (i.e. NADPH oxidases) that can generate reactive oxygen species (ROS), specifically hydrogen peroxide. ROS are widely implicated in causing cellular, tissue and organ damage when present at excessive levels in the body. But, these findings show that low levels of these molecules - when produced in discrete locations within the cell - are highly protective. "It's tempting to speculate that excess ROS causes vascular breakdown by short-circuiting the recuperative response process and creating 'white noise' that dis-coordinates and disrupts micro-wound healing. It appears that we've got an essential homeostatic self-repair mechanism that is completely dependent on the generation of intracellular ROS, which is opposite to our typical thinking about ROS in cardiovascular health and disease."

A recent publication by the Institute of Economic Affairs (PDF format) looks at studies that suggest retirement leads to worse long-term health and shorter remaining life expectancy. You'll find the meaningful discussion on how researchers went about trying to identify cause and effect in the PDF rather than the press article quoted below: does the data actually show that retirement causes worsening health versus a tendency for people with worsening health to retire, for example?

A study out of the U.K. suggests that while it may provide an initial sense of relief and well-being, over the long-term, retirement is bad for your health, increasing the likelihood of developing depression and at least one physical illness. The study's author [analyzed] data from a survey of 11 European countries that sampled 7,000 to 9,000 people between the ages of 50 and 70 using two separate methodologies. He found that retirement had a "consistent negative impact" on physical health that worsens as the number of years spent in retirement increase.

[The author] also analyzed past studies on the subject of retirement and health and found that their results were mixed, with some finding a positive impact and others a negative or neutral one. The researcher attributes these varied results largely to a failure to distinguish short-term effects from long-term ones and to take the length of retirement into account. In the short term, retirees may experience a boost to health, he says, but this is outweighed by the negative impacts that manifest over the medium and long term.

[The author] acknowledges that there are many variables in any one individual's retirement that can often have contradictory effects on physical and mental health. Retirement can decrease work-related pressures and stress, for example, but it can also cut retirees off from the social networks they formed at work and lead to greater isolation, which can negatively affect health. By contrast, it can lead to more leisure time, which can result in new non-work-related social contacts or more participation in physical activities that positively affect health and well-being. "Untangling cause and effect in the relationship between retirement and health is very difficult. Whereas the short-term impacts of retirement on health is somewhat uncertain, the longer-term effects are consistently negative and large."

Link: http://www.cbc.ca/news/business/story/2013/05/16/business-retirement-health.html

Osteoarthritis is one of the more common age-related conditions, and at the present time little can be done to treat the causes other than to alter lifestyle in ways that usually slow down the progression of the condition. Signs of progress towards effective therapies are on the horizon, however:

[Scientists] have turned their view of osteoarthritis (OA) inside out. Literally. Instead of seeing the painful degenerative disease as a problem primarily of the cartilage that cushions joints, they now have evidence that the bone underneath the cartilage is also a key player and exacerbates the damage. In a proof-of-concept experiment, they found that blocking the action of a critical bone regulation protein in mice halts progression of the disease.

Using mice with ACL (anterior cruciate ligament) tears, which are known to lead to OA of the knee, the researchers found that, as soon as one week after the injury, pockets of subchondral bone had been "chewed" away by cells called osteoclasts. This process activated high levels in the bone of a protein called TGF-beta1, which, in turn, recruited stem cells to the site so that they could create new bone to fill the holes. But the bone building and the bone destruction processes were not coordinated in the mice, and the bone building prevailed, placing further strain on the cartilage cap. It is this extraneous bone formation that [researchers] believe to be at the heart of OA, as confirmed in a computer simulation of the human knee.

With this new hypothesis in hand, complete with a protein suspect, the team tried several methods to block the activity of TGF-beta1. When a TGF-beta1 inhibitor drug was given intravenously, the subchondral bone improved significantly, but the cartilage cap deteriorated further. However, when a different inhibitor of TGF-beta1, an antibody against it, was injected directly into the subchondral bone, the positive effects were seen in the bone without the negative effects on the cartilage. The same result was also seen when TGF-beta1 was genetically disrupted in the bone precursor cells alone.

Link: http://www.eurekalert.org/pub_releases/2013-05/jhm-nto051713.php

In the past few years two ongoing studies of long term calorie restriction (CR) in primates have started to publish their results on longevity. Both research programs have been underway for more than 20 years, one run by the National Institute on Aging and the other by the University of Wisconsin-Madison. Researchers have followed small groups of rhesus monkeys to see how the benefits to health and life expectancy resulting from a restricted calorie intake compare with those obtained in mice and other short-lived species. At this point the results are ambiguous, unfortunately: one study shows a modest gain in life expectancy that has been debated, while the other shows no gain in life expectancy, and that result has also been debated.

Calorie restriction does produce considerable benefits in short term measures of health in rhesus monkeys and humans, that much is definitive, but the present consensus in the research community is that it doesn't greatly extend life in longer-lived primates - perhaps a few years at most in humans. Differences and issues in the two primate studies mean that effects of this size on longevity may never be clear from the data generated. Other factors will wash it out, such as differences in the diet fed to the control groups, or the different age at which calorie restriction started. Certainly the results so far support the conjecture that calorie restriction is exceedingly good for health but doesn't have the same impressive effects on longevity as it does in short-lived animals. Why that is the case is a puzzle to be solved - but not one that has a great deal of relevance to the future of human longevity. One would hope that we'll be a long way down the road to rejuvenation therapies by the time another set of better constructed primate studies are nearing completion.

You'll find a long article over at the SENS Research Foundation that examines the NIA and Wisconsin primate studies, their differences, and their results in great detail - but I'm just going to skip ahead and quote some of the conclusions:

CR in Nonhuman Primates: A Muddle for Monkeys, Men, and Mimetics

In this post, I have sketched out in detail two major possible interpretations of the disparate mortality outcomes in the NIA and WNPRC nonhuman primate CR studies. The "Diminishing Returns" hypothesis posits that the health and longevity benefits of "CR" reported in the WNPRC study were merely the unsurprising results of one group of animals being fed a high-sucrose, low-nutrient chow on a literally ad libitum basis, and another group being kept to portions of that diet low enough to avoid the deranged metabolisms flowing from obesity and (possibly) fructose toxicity. In this interpretation, the more severe restrictions of energy intake imposed at the NIA - particularly when the chow to which access was restricted may have been healthier to begin with - led to no further health benefit, because there are none to be gained: the dramatic age-retarding effects of CR observed in laboratory rodents and other species do not translate into longevous species such as primates, and the sole benefit of controlling energy intake is avoidance of overweight and obesity.

The "Dose-Response" hypothesis begins from the same interpretation of the WNPRC study, but posits that far from being excessive (or, at best, superfluous) to that required for good health, the additional energy restriction imposed at NIA were too little, and imposed during too narrow a window, to elicit a clear signal in health and lifespan benefits; this is supported by the evidence that the NIA primates were not especially hungry, and only weakly and inconsistently exhibited improvements in risk factors and endocrine signatures of CR that are seen both in life-extending CR in rodents, and in humans under rigorous CR.

Unfortunately, it seems very unlikely that this question will be resolved. Even the narrow question of whether the age-retarding effects of CR in laboratory rodents translate into nonhuman primates could only be established with confidence after yet another trial in nonhuman primates. [Such] a study is extremely unlikely in light of the enormous expense of the first two trials, disappointment (and possibly embarrassment) with the results, [and] the ill winds for nonhuman primate research. [Even] if such a well-designed and well-executed study were initiated: what then? Supposing that support were maintained for the duration of the experiment [it] would be a further three decades before the earliest point at which survival data could be reported.

The timescales involved in resolving these questions cannot be reconciled with the immediate imperatives that drive us to pose them. With the scale of the humanitarian, economic, and social crisis that looms in the coming decades due to global demographic aging and associated ill-health, the near-term need for effective interventions against the aging process could not be greater. Whether CR can retard aging in nonhuman primates or not; whether it can retard aging in humans or not; whether even effective CR mimetics can somehow be shepherded through clinical trials - even the most optimistic projection for retarding aging through such approaches is inadequate to the needs and suffering of aging world.

The point made in the article is the same one that should be made for all means of slowing the pace of aging by altering metabolism, whether by the use of drugs to replicate some of the changes caused by calorie restriction or via other mechanisms. These are very difficult and challenging projects, certainly very expensive in time and funds, and which will produce poor and uncertain end results even if successful. Ways to modestly slow aging do nothing for people who are already old, and we will grow old waiting for success in the development of drugs that can safely tinker our metabolisms into a state of slower aging.

The better approach is that outlined by the SENS Research Foundation: targeted therapies to repair the known forms of cellular and molecular damage that cause aging. This path is cheaper, more certain, and the resulting therapies will be capable of rejuvenation - of reversing degenerative aging, not just slowing it down a little. They will be greatly beneficial for the old, and extend the length of life lived in health and vigor. This is why I say that calorie restriction studies are irrelevant to the future of our health and longevity: the only thing that really matters is whether or not the SENS vision or similar repair therapies are prioritized, funded, and developed.

There are any number of techniques under development that allow individual cells to be destroyed provided that you can distinguish them from their neighbors: the challenge is in finding characteristic differences in the cells you want destroyed, such as cancer cells or senescent cells. Most of the efforts aimed at producing targeted cell destruction therapies are taking place in the cancer research community, but senescent cells accumulate with age and contribute to degenerative aging - they must also be destroyed. Unfortunately good ways to target senescent cells are somewhat lacking. Candidate mechanisms are emerging, however, and here is another of them:

Due to its role in aging and antitumor defense, cellular senescence has recently attracted increasing interest. However, [the] detection of senescent cells remains difficult due to the lack of specific biomarkers. ndeed, most determinants of cellular senescence, such as the upregulation of p53, p16Ink4a, p21WAF/CIP1 or SASP-associated cytokines, are not exclusively observed in senescence, but can also occur in other types of stress responses. In addition, alterations like SAHF or DNA-SCARS formation are frequently observed, but not necessarily a mandatory feature or exclusive to senescent cells.

The current gold standard for the detection of senescence is the so-called senescence-associated β-galactosidase (SA-β-Gal) activity. Although SA-β-Gal has been first suggested as a distinct enzyme, its activity is derived from lysosomal β-Gal encoded by the GLB1 gene. β-Gal is an accepted marker of senescence, but its reliability and specificity have been questioned, as a positive β-Gal reaction has also been detected in human cancer cells that were chemically induced to differentiate, or upon contact inhibition. Moreover, several cell types, such as epithelial cells and murine fibroblasts generally show a weak β-Gal staining.

In the present study, we investigated several lysosomal hydrolases for their suitability as senescence markers and identified α-fucosidase, a lysosomal glycosidase involved in the breakdown of glycoproteins, oligosaccharides and glycolipids, as a novel biomarker for senescence. We demonstrate that α-fucosidase is upregulated [in] all canonical types of cellular senescence, including replicative, DNA damage- and oncogene-induced senescence. Our results suggest that detection of α-fucosidase might be a highly valuable biomarker for senescence in general and in particular in those cases where SA-β-Gal activity fails to properly discriminate between senescent- and non-senescent cells.

Link: http://www.landesbioscience.com/journals/cc/article/24944/?show_full_text=true

Progress towards a therapy for the rare accelerated aging condition progeria continues. It remains unclear as to whether the mechanisms responsible for progeria exist in normal aging to a level that is in any way significant. Progeria is caused by malformed prelamin A, and tiny amounts of broken prelamin A can be found in old tissues - but it would really require a therapy for progeria that addressed the issues with prelamin A to easily find out whether this has any meaningful contribution to normal aging.

The classical form of progeria, called Hutchinson-Gilford Progeria Syndrome (HGPS), is caused by a spontaneous mutation, which means that it is not inherited from the parents. Children with HGPS usually die in their teenage years from myocardial infarction and stroke.

The progeria mutation occurs in the protein prelamin A and causes it to accumulate in an inappropriate form in the membrane surrounding the nucleus. The target enzyme, called ICMT, attaches a small chemical group to one end of prelamin A. Blocking ICMT, therefore, prevents the attachment of the chemical group to prelamin A and significantly reduced the ability of the mutant protein to induce progeria. "We are collaborating with a group in Singapore that has developed candidate ICMT inhibitor drugs and we will now test them on mice with progeria. Because the drugs have not yet been tested in humans, it will be a few years before we know whether these drugs will be appropriate for the treatment of progeria."

"The resemblance between progeria patients and normally-aged individuals is striking and it is tempting to speculate that progeria is a window into our normal aging process. The children develop osteoporosis, myocardial infarction, stroke, and muscle weakness. They display poor growth and lose their hair, but interestingly, they do not develop dementia or cancer." [The researchers are] also studying the impact of inhibiting ICMT on the normal aging process in mice.

Link: http://www.eurekalert.org/pub_releases/2013-05/uog-ptf051413.php

We'll take a short excursion into ranking futurists for today, prompted by a recent article that offers a (transhumanism-slanted) opinion on the identity of the most important futurists of the past few decades.

The Most Significant Futurists of the Past 50 Years

Our visions of the future tend to be forged in the pages of science fiction. But for the past half-century, a number of prominent thinkers, activists, and scientists have made significant contributions to our understanding of what the future could look like. Here are 10 recent futurists you absolutely need to know about. Needless to say, there were dozens upon dozens of amazing futurists who could have been included in this article, so it wasn't easy to pare down this list. But given the width and breadth of futurist discourse, we decided to select thinkers whose contributions should be considered seminal and highly influential to their field of study.

Those selected include Robert Ettinger, one of the founders of modern cryonics, and Aubrey de Grey, who presently works to make his SENS roadmap to human rejuvenation a reality. Ray Kurzweil is notably absent from the list.

It isn't mentioned as a selection criteria in the article, but I think that ranking the importance of futurists by how effectively they help to create the future that they envisage isn't all that bad of an idea. Advocates and popularists play a needed role in moving from vision to reality, but progress also needs people to perform and orchestrate the actual work of research and development. Kurzweil, for example, is a popularist and an advocate with respect to his futurism: beyond the books and films and persuasion his day job as an inventor and entrepreneur is so far largely irrelevant to the future he envisages. I don't think anyone can argue that he isn't important in the arena of ideas regarding machine intelligence, accelerating change, and how this will all play out in the decades ahead. But how much more important would Kurzweil be if, for example, he had decided a decade or two back to create a company like Zyvex as a long term play to advance molecular manufacturing, or something equivalent in AI work?

In contrast Ettinger and de Grey both founded successful organizations devoted to realizing their particular visions: the Cryonics Institute and the SENS Research Foundation. Both were instrumental in creating the groundwork and the early community of supporters to enable a new industry and branch of research in applied medicine. That seems like the best approach to futurism to me: not just persuasion, but also working to create the change you want to see in the world.

There are all sorts of good reasons to avoid becoming fat. Excess fat tissue is linked to an increased risk of all the common diseases of aging, and correlates well with a shorter life expectancy and higher lifetime medical expenditures. Fat tissue creates higher levels of chronic inflammation and alters the signaling environment in the body, causing a wide range of changes. Here is another of them:

Having too much body fat makes arteries become stiff after middle age, a new study has revealed. In young people, blood vessels appear to be able to compensate for the effects of obesity. But after middle age, this adaptability is lost, and arteries become progressively stiffer as body fat rises - potentially increasing the risk of dying from cardiovascular disease. The researchers suggest that the harmful effects of body fat may be related to the total number of years that a person is overweight in adulthood. Further research is needed to find out when the effects of obesity lead to irreversible damage to the heart and arteries, they said.

Researchers [scanned] 200 volunteers to measure the speed of blood flow in the aorta, the biggest artery in the body. Blood travels more quickly in stiff vessels than in healthy elastic vessels, so this allowed them to work out how stiff the walls of the aorta were using an MRI scanner. In young adults, those with more body fat had less stiff arteries. However, after the age of 50 increasing body fat was associated with stiffer arteries in both men and women. Body fat percentage, which can be estimated by passing a small electric current through the body, was more closely linked with artery stiffness than body mass index, which is based just on weight and height.

"We don't know for sure how body fat makes arteries stiffer, but we do know that certain metabolic products in the blood may progressively damage the elastic fibres in our blood vessels. Understanding these processes might help us to prevent the harmful effects of obesity."

Link: http://www.sciencedaily.com/releases/2013/05/130515085333.htm

Therapeutic cloning or somatic cell nuclear transfer are names given to a method of producing embryonic stem cells from a patient's own cells. These embryonic stem cells could then be used to generate cells of any type as a basis for regenerative therapies. Making the process work has proven to be challenging, however, both from a technical point of view and thanks to misguided attempts to make it illegal. In recent years the focus shifted towards work on induced pluripotent stem cells instead, but a research group now claims success in the original goal:

Scientists [have] successfully reprogrammed human skin cells to become embryonic stem cells capable of transforming into any other cell type in the body. It is believed that stem cell therapies hold the promise of replacing cells damaged through injury or illness. The technique used [is] a variation of a commonly used method called somatic cell nuclear transfer, or SCNT. It involves transplanting the nucleus of one cell, containing an individual's DNA, into an egg cell that has had its genetic material removed. The unfertilized egg cell then develops and eventually produces stem cells.

Previous unsuccessful attempts by several labs showed that human egg cells appear to be more fragile than eggs from other species. Therefore, known reprogramming methods stalled before stem cells were produced. To solve this problem, the [researchers] studied various alternative approaches first developed in monkey cells and then applied to human cells. Through moving findings between monkey cells and human cells, the researchers were able to develop a successful method. The key to this success was finding a way to prompt egg cells to stay in a state called "metaphase" during the nuclear transfer process. Metaphase is a stage in the cell's natural division process (meiosis) when genetic material aligns in the middle of the cell before the cell divides. The research team found that chemically maintaining metaphase throughout the transfer process prevented the process from stalling and allowed the cells to develop and produce stem cells.

Link: http://www.eurekalert.org/pub_releases/2013-05/ohs-ort051313.php

If you visit Fight Aging! on a regular basis you'll know that I strongly favor the SENS Research Foundation and the approach taken by its founders, advisors, and staff to speed the development of human rejuvenation. I think we could do with another ten or twenty similar organizations, and certainly a hundredfold increase in the funding for rejuvenation research, but right now we have just the one. So send the Foundation a donation if you're feeling flush today, because there's no-one else out there at the moment who can do as much for your future longevity with that money.

Or rather I should say that there are dozens and possibly hundreds of people out there who can do as much for your future longevity with those funds - it's just that you don't know who they are. Would you know enough to chase down William Bains in the UK and ask him to work on AGE-breaker drugs for glucosepane, for example? Or pick the group at the Buck Institute best placed work on ways to selectively destroy senescent cells by interfering in their characteristic biology? Or have Janko Nikolich-Žugich in Arizona work on restoring the aged immune system by removing unwanted T cells? Of course not. But there is a whole world of researchers out there with useful specialist knowledge and who are these days quite willing to work on the foundation technologies needed for human rejuvenation - provided that the funding can be found.

Organizations like the SENS Research Foundation are the interface between you and the research community: the Foundation staff provide domain knowledge and relationships needed in order to direct funds effectively. Without their work it would be impossible for folk like you or I to help make this field of science move faster - we wouldn't know where to start or who to talk to, never mind where to send funds, and finding out would be so costly in comparison to what we could donate as to make the whole exercise pointless.

The SENS Research Foundation is the watering hole, not the herd. It is the gateway, not the city. It is the door to a network of researchers who are interested in human rejuvenation, but that network is a greater and broader thing than the Foundation. I bring up this point because many people look no further than the gateway: they see the SENS Research Foundation and think of an enclosed group, off to one side of the scientific community, doing its own thing in isolation, and therefore easy to dismiss. For all that this point of view is absolutely incorrect, it is not uncommon. You'll see it liberally applied to biotechnology companies, noted laboratories, and other organizations that are also gateways to broader scientific networks. People look at an organization, see its staff performing some research work in its own domain, but fail to see beyond that to take in the great tree of relationships and connections behind the name plate.

The greatest achievement of the folk behind the SENS Research Foundation (and the Methuselah Foundation before it) is their construction of a lasting and growing network of supporters of rejuvenation research within the life sciences. This was quite the task over the past decade and involved a lot of persuasion, changing the culture of the research community to become more receptive towards longevity science, building relationships, holding conferences, and tireless advocacy. It is that web of relationships, and not the existence of the Foundation per se, that enables growth in funding and progress towards the goal of ending aging. As for all areas of human endeavor, it is relationships and networking that make the world turn: the Foundation is a mailbox, a guidebook, and a banner for a larger community, an outgrowth of that community even, and it is the community that gets things done.

This is worth bearing in mind, because it's all to easy to focus on organizations rather than people and thus miss the whole point of the exercise.

Women tend to live longer than men, and there are any number of competing explanations as to why this is the case. They range from risk of mortality relating to lifestyle choices to evolutionary selection operating on the male role in reproduction to various differences in biochemistry that exist between the genders. That the female immune system ages more slowly shouldn't be terribly surprising - but it might be cause or consequence.

Women's immune systems age more slowly than men's, [and] the slower decline in a woman's immune system may contribute to women living longer than men. Researchers looked at the blood of healthy volunteers in Japan, ranging in age between 20 and 90 years old; in both sexes the total number of white blood cells per person decreased with age. The number of neutrophils decreased for both sexes and lymphocytes decreased in men and increased in women. Younger men generally have higher levels of lymphocytes than similarly aged women, so as aging happens, the number of lymphocytes becomes comparable.

Looking in more detail it became apparent that the rate in decline in T cells and B cells was slower for women than men. Both CD4+ T cells and NK cells increased with age, and the rate of increase was higher in women than men. Similarly an age-related decline in IL-6 and IL-10 was worse in men. There was also a age-dependent decrease in red blood cells for men but not women.

"The process of aging is different for men and women for many reasons. Women have more oestrogen than men which seems to protect them from cardiovascular disease until menopause. Sex hormones also affect the immune system, especially certain types of lymphocytes. Because people age at different rates a person's immunological parameters could be used to provide an indication of their true biological age."

Link: http://www.alphagalileo.org/ViewItem.aspx?ItemId=131061&CultureCode=en

Amyloids are solid masses that form in tissues as a result of misfolded proteins. The amount of amyloid increases with age, perhaps due to a failure of mechanisms that keep the levels of damaged or misfolded proteins under control, and this is thought to cause harm and contribute to degenerative aging. In most cases researchers are still lacking a full understanding of the mechanisms involved, however. At the very least having solid clumps and fibrils present where they shouldn't exist can disrupt tissue integrity or even cause larger scale issues such as clogging blood vessels.

One approach to removing amyloid involves the use of the immune system. Immune therapies direct immune cells to attack and break down a specific target, and much of the innovation in their use as a therapy to remove amyloid is happening in the Alzheimer's research community. That condition is associated with amyloid beta, but we can hope that any successful therapies will prove adaptable to other forms of amyloid and thus applicable to human rejuvenation.

Alzheimer's disease (AD) is the most common dementia in the industrialized world, with prevalence rates well over 30% in the over 80-years-old population. AD is strongly associated with Amyloid-beta (Abeta) protein aggregation, which results in extracellular plaques in the brain, and according to the amyloid cascade hypothesis appeared to be a promising target for the development of AD therapeutics.

Within the past decade convincing data has arisen positioning the soluble prefibrillar Abeta-aggregates as the prime toxic agents in AD. However, different Abeta aggregate species are described but their remarkable metastability hampers the identification of a target species for immunization. Passive immunotherapy with monoclonal antibodies (mAbs) against Abeta is in late clinical development but recently the two most advanced mAbs, Bapineuzumab and Solanezumab, targeting an N-terminal or central epitope, respectively, failed to meet their target of improving or stabilizing cognition and function.

Preliminary data from off-label treatment of a small cohort for 3 years with intravenous polyclonal immunoglobulins (IVIG) that appear to target different conformational epitopes indicate a cognitive stabilization. Thus, it might be the more promising strategy reducing the whole spectrum of Abeta-aggregates than to focus on a single aggregate species for immunization.

Link: http://www.immunityageing.com/content/10/1/18/abstract