Fight Aging!

Cytomegalovirus (CMV) is one of the less immediately harmful members of the family of herpesviruses. It is very prevalent: most people have it in their system by the time they are old, but probably never even noticed, as the symptoms for a healthy individual are essentially nonexistent. Nonetheless like all herpesviruses CMV is very successful at remaining within the body after initial exposure, establishing a life-long infection despite the best efforts of the immune system to get rid of it. The recurring campaigns waged against CMV by your immune cells appear to have a long-term cost: we have evolved to support a given number of immune cells as adults, and as ever more of those immune cells become specialized to a specific pathogen, such as CMV, there is ever less space left in the inventory for cells that can tackle new threats or keep up with all the other jobs of the immune system, such as destroying precancerous and senescent cells.

If you eye the publications of an open access journal like Immunity and Ageing, you'll see a steady flow of papers looking at the role of CMV in age-related immune system decline, a fair-sized component of the frailty of old age. There are a range of possible approaches to this problem, but the most direct and potentially effective don't actually involve doing anything about CMV itself. Instead there are proposals to either add large numbers of new, fresh, and capable immune cells to the body or eliminate the CMV-specialized cells to free up space. Both of these approaches are quite near-term: only a a couple of years would be needed to develop a viable prototype therapy from where we are now, were a research group fully funded and tasked with the effort. Both the ability to culture immune cells and the ability to destroy specific cells in the body based on their surface markers are progressing rapidly.

Some research groups are working on a vaccine for CMV - but a successful vaccine won't do much good for those high percentage of adults in much of the world who have been infected for a long time. Their immune systems are already badly misconfigured as a result of the extended exposure. So tackling CMV isn't a good enough approach on its own, as it only stops the very slow pace of ongoing harm.

Here is a paper to suggest that the progressive disarray in the immune system caused by CMV starts early, even while young.

Rudimentary signs of immunosenescence in Cytomegalovirus-seropositive healthy young adults

Ageing is associated with a decline in immune competence termed immunosenescence. In the elderly, this process results in an accumulation of differentiated 'effector' phenotype memory T cells, predominantly driven by Cytomegalovirus (CMV) infection.

Here, we asked whether CMV also drives immunity towards a senescent profile in healthy young adults. One hundred and fifty-eight individuals (age 21 ± 3 years, body mass index 22.7 ± 2.7) were assessed for CMV serostatus, the numbers/proportions of CD4+ and CD8+ late differentiated/effector memory cells, plasma interleukin-6 (IL-6) and antibody responses to an in vivo antigen challenge (half-dose influenza vaccine). Thirty percent (48/158) of participants were CMV+.

A higher lymphocyte and CD8+ count and a lower CD4/CD8 ratio were observed in CMV+ people. Eight percent (4/58) of CMV+ individuals exhibited a CD4/CD8 ratio of less than 1.0, whereas no CMV- donor showed an inverted ratio. The numbers of late differentiated/effector memory cells were ~fourfold higher in CMV+ people. Plasma IL-6 was higher in CMV+ donors and showed a positive association with the numbers of CD8+CD28- cells. Finally, there was a significant negative correlation between [vaccine response and the levels of CMV particles present]. This reduced vaccination response was associated with greater numbers of total late differentiated/effector memory cells.

This study observed marked changes in the immune profile of young adults infected with CMV, suggesting that this virus may underlie rudimentary aspects of immunosenescence even in a chronologically young population.

There has been interest in extending increasing telomerase expression as a means to slow aging for some years. The available tools other than gene therapy are sparse on the ground, however. Telomerase extends telomere length, the caps of repeating DNA sequences at the ends of chromosomes that shorten with each cell division. Telomerase may have other roles that more directly impact aging, however, such as an influence on mitochondrial function.

Shorter telomeres in at least some tissues correlate with stress and ill health and aging, but this is a very dynamic system - average telomere length can change in either direction on a short time scale. It is far from clear that progressively shorter telomere length is a cause of aging rather than just a reflection of other changes and damage, and the same goes for natural variations in levels of telomerase in the body. While increasing expression of telomerase is shown to extend life in mice, that may or may not have anything to do with telomere length, and mouse telomerase biology is quite different from that of humans.

So all this said, it was only a matter of time before researchers evaluated all the existing approved drugs for treatment of age-related conditions to see if any of them altered telomerase activity. There are regulatory incentives to beware of here, however, in that it is much cheaper for research institutions to try to find marginal new uses of already approved drugs than to work on new and radically better medical technologies that would then have to go through the exceedingly and unnecessarily expensive approval process. So don't expect anything of great practical use to result from this:

Not only do statins extend lives by lowering cholesterol levels and reducing the risks of cardiovascular disease, but new research [suggests] that they may extend lifespans as well. Specifically, statins may reduce the rate at which telomeres shorten, a key factor in the natural aging process. This opens the door for using statins, or derivatives of statins, as an anti-aging therapy. "By telomerase activation, statins may represent a new molecular switch able to slow down senescent cells in our tissues and be able to lead healthy lifespan extension."

To make this discovery, Paolisso and colleagues worked with two groups of subjects. The first group was under chronic statin therapy, and the second group (control), did not use statins. When researchers measured telomerase activity in both groups, those undergoing statin treatment had higher telomerase activity in their white blood cells, which was associated with lower telomeres shortening along with aging as compared to the control group. This strongly highlights the role of telomerase activation in preventing the excessive accumulation of short telomeres.

"The great thing about statins is that they reduce risks for cardiovascular disease significantly and are generally safe for most people. The bad thing is that statins do have side effects, like muscle injury. But if it is confirmed that statins might actually slow aging itself - and not just the symptoms of aging - then statins are much more powerful drugs than we ever thought."

Link: http://www.eurekalert.org/pub_releases/2013-08/foas-sms082913.php

Building patches for damaged hearts is a popular implementation in tissue engineering at the moment: it's an achievable stepping stone on the way to more complex goals, such as the creation of entire organs starting from only a patient's stem cells, something that still lies in the future. Progress towards a long-term goal in any field requires useful intermediary products, as they help pull in the greater support and funding needed for the next phase of research and development.

When heart cells die from lack of blood flow during a heart attack, replacing those dead cells is vital to the heart muscle's recovery. But muscle tissue in the adult human heart has a limited capacity to heal, which has spurred researchers to try to give the healing process a boost. Various methods of transplanting healthy cells into a damaged heart have been tried, but have yet to yield consistent success in promoting healing.

Now, [researchers] have developed a patch composed of structurally modified collagen that can be grafted onto damaged heart tissue. Their studies in mice have demonstrated that the patch not only speeds generation of new cells and blood vessels in the damaged area, it also limits the degree of tissue damage resulting from the original trauma. The key [is] that the patch doesn't seek to replace the dead heart-muscle cells. Instead, it replaces the epicardium, the outer layer of heart tissue, which is not muscle tissue, but which protects and supports the heart muscle, or myocardium.

The epicardium - or its artificial replacement - has to allow the cell migration and proliferation needed to rebuild damaged tissue, as well as be sufficiently permeable to allow nutrients and cellular waste to pass through the network of blood vessels that weaves through it. The mesh-like structure of collagen fibers in the patch has those attributes, serving to support and guide new growth. Because the patch is made of acellular collagen, meaning it contains no cells, recipient animals do not need to be immunosuppressed to avoid rejection. With time, the collagen gets absorbed into the organ.

Link: http://www.eurekalert.org/pub_releases/2013-08/sumc-scp082613.php

Mammalian (or mechanistic, depending on who you ask) target of rapamycin (mTOR) is the most likely candidate for the next round of billion-dollar research funding devoted to the search for drugs that can slow aging. It will be a repeat of the overhyped and ultimately largely futile interest in sirtuin research, which generated knowledge but nothing of real practical application, except that this time there is far more compelling evidence that manipulation of mTOR actually extends life in laboratory animals. Though as always, there are those who believe that this is not in fact the case - that mTOR alteration only reduces cancer risk, rather than impacting the processes of aging per se. Just as resveratrol and resveratrol-derivatives are the compounds of choice for those investigating sirtuin biology, so rapamycin and rapamycin-derivatives are the compounds of choice for research groups focused on manipulating mTOR and its related signaling networks. I would imagine that we're in for another decade or so of overhyped claims and public and research community interest in what is in fact an inefficient, expensive, and time-consuming path towards only slightly extending healthy life.

Drugs to slow aging through alterations to metabolism are not the path to radical life extension. Slowing aging does nothing for people already old. The research community should focus instead on rejuvenation through therapies that repair and remove the cellular damage that causes aging, an approach that can actually meaningfully help the aged when realized. For all that rejuvenation is the obviously superior research strategy, however, it's taking time to convince the world of that truth. Time spent on trying to slow aging is little different in outcome to time spent investigating the details of aging but choosing to do nothing about it: a few years here and there, and nothing that is as effective as simple exercise and calorie restriction. There's no such thing as useless knowledge in the long term, but we already know enough to work effectively on human rejuvenation.

The new study quoted below will no doubt bolster the prospects of those groups presently raising funds for attempts to slow aging or further develop drug candidates derived from rapamycin. While looking at the results, however, you might compare them with plain old calorie restriction in mice, something that can produce twice the extension of healthy life shown here.

Mutant Mice Live Longer

MTOR is a kinase involved in myriad cellular processes, from autophagy to protein synthesis. Genetic studies of TOR in other organisms, such as yeast and flies, have implicated a role for the enzyme in lifespan. In mammals, however, mTOR is required for survival, making a knockout mouse model unfeasible. So the National Heart, Lung and Blood Institute's Toren Finkel and his colleagues decided to use a mouse in which transcription was only partially disrupted, reducing the levels of mTOR to about 25 percent of the normal amount.

All else being equal, the researchers found that normal mice typically lived 26 months, while those with less mTOR survived around 30 months. Finkel said the increase in lifespan was greater than other researchers have seen using the immunosuppressant rapamycin to inhibit mTOR. It's possible that having mTOR reduced beginning in the womb, rather than at middle age, could explain the disparity. Additionally, this new mutant affected the levels of both forms of mTOR - mTORC1 and mTORC2 complexes - rather than preferentially impacting one, as rapamycin would.

The paper on this research is open access, so head on over and take a look. I think you'll find it interesting. In particular note the author's cautions regarding the size of the life extension effect and the life span of the control mice in the discussion section: the number of mice used isn't large, and it's possible that the controls were just randomly a slightly short-lived group.

Increased Mammalian Lifespan and a Segmental and Tissue-Specific Slowing of Aging after Genetic Reduction of mTOR Expression

We analyzed aging parameters using a mechanistic target of rapamycin (mTOR) hypomorphic mouse model. Mice with two hypomorphic (mTORΔ/Δ) alleles are viable but express mTOR at approximately 25% of wild-type levels. These animals demonstrate reduced mTORC1 and mTORC2 activity and exhibit an approximately 20% increase in median survival. While mTORΔ/Δ mice are smaller than wild-type mice, these animals do not demonstrate any alterations in normalized food intake, glucose homeostasis, or metabolic rate. Consistent with their increased lifespan, mTORΔ/Δ mice exhibited a reduction in a number of aging tissue biomarkers. Functional assessment suggested that, as mTORΔ/Δ mice age, they exhibit a marked functional preservation in many, but not all, organ systems. Thus, in a mammalian model, while reducing mTOR expression markedly increases overall lifespan, it affects the age-dependent decline in tissue and organ function in a segmental fashion.

The immune system declines greatly with aging, and poor immune response is an important component of age-related frailty: old people become vulnerable to infections that the young can shrug off with ease. So we might expect to see that long-lived people have better immune systems, and that whatever underlying mechanisms cause that difference are to some degree inherited.

People may reach the upper limits of the human life span at least partly because they have maintained more appropriate immune function, avoiding changes to immunity termed "immunosenescence." Exceptionally long-lived people may be enriched for genes that contribute to their longevity, some of which may bear on immune function. Centenarian offspring would be expected to inherit some of these, which might be reflected in their resistance to immunosenescence, and contribute to their potential longevity. We have tested this hypothesis by comparing centenarian offspring with age-matched controls. We report differences in the numbers and proportions of both CD4+ and CD8+ early- and late-differentiated T cells, as well as potentially senescent CD8+ T cells, suggesting that the adaptive T-cell arm of the immune system is more "youthful" in centenarian offspring than controls. This might reflect a superior ability to mount effective responses against newly encountered antigens and thus contribute to better protection against infection and to greater longevity.

The goal of future medicine is to make inherited differences of this nature irrelevant. There are a number of promising approaches that may remove much of the age-related decline of immune function: regrow the atrophied thymus, where immune cells are cultured; create new immune cells in the clinic and infuse them regularly into older people; destroy the population of over-specialized memory cells that exist in the elderly, thus freeing up space for effective immune cells that can combat new threats.

Link: http://www.ncbi.nlm.nih.gov/pubmed/23974207

Researchers are managing to grow larger masses of tissue from stem cells of late, with more of the structure of the full organ they came from. See, for example, recent work on liver tissue engineering. This is a small step on the way towards full organ regrowth, and will probably be of greatest immediate benefit to further research, testing of therapies, and the like, as three-dimensional engineered tissues of this sort behave much more like the real thing. The brain is of course an organ just like all the others, grown from a genetic blueprint from a selection of cells - so we should expect to see the same progress here as we see for hearts and livers. It is even conceivable that less vital portions of the brain could be replaced or renewed by transplant or regrowth in the future, as not every part of the brain is essential to either storage of the data of the mind or maintenance of life.

Researchers found that immature brain cells derived from stem cells self-organize into brain-like tissues in the right culture conditions. The "cerebral organoids," as the researchers call them, grew to about four millimeters in size and could survive as long as 10 months. For decades, scientists have been able to take cells from animals including humans and grow them in a petri dish, but for the most part this has been done in two dimensions, with the cells grown in a thin layer in petri dishes. But in recent years, researchers have advanced tissue culture techniques so that three-dimensional brain tissue can grow in the lab. The new report [demonstrates] that allowing immature brain cells to self-organize yields some of the largest and most complex lab-grown brain tissue, with distinct subregions and signs of functional neurons.

[This] is the latest advance in a field focused on creating more lifelike tissue cultures of neurons and related cells for studying brain function, disease, and repair. With a cultured cell model system that mimics the brain's natural architecture, researchers would be able to look at how certain diseases occur and screen potential medications for toxicity and efficacy in a more natural setting.

Other groups are developing three-dimensional brain tissue cultures with the hopes of treating degenerative diseases or brain injury. [One set of researchers] has developed a three-dimensional neural culture to study brain injury, with the goal of identifying biomarkers that could be used to diagnose brain injury and potential drug targets for medications that can repair injured neurons. "It's important to mimic the cellular architecture of the brain as much as possible because the mechanical response of that tissue is very dependent on its 3-D structure."

Link: http://www.technologyreview.com/news/518716/researchers-grow-3-d-human-brain-tissues/

Researchers are making strides in uncovering the low-level details of how memory operates in mammalian brains, just as they are making strides in all areas of biology. Sometimes the process of discovery comes hand in hand with a demonstration of utility, as is the case here. Putting to one side the consequences of an Alzheimer's-like build up of amyloid deposits and its associated neural dysfunction, the research quoted below demonstrates that the rest of the decline in memory function due to old age in mice can be mostly reversed by increasing the levels of one particular protein. This is very interesting, as it suggests that the processes of memory are not greatly inhibited by most of the forms of cellular damage that causes aging, at least in mice, and that this portion of mental decline occurs due to one of the epigenetic responses to that damage.

We might well ask why this came to pass in the course of evolutionary adaptation, but any sort of theorizing on my part would be very speculative at this point, following the party line on antagonistic pleiotropy in the context of aging.

A Major Cause of Age-Related Memory Loss Identified

A team of Columbia University Medical Center (CUMC) researchers [has] found that deficiency of a protein called RbAp48 in the hippocampus is a significant contributor to age-related memory loss and that this form of memory loss is reversible. The hippocampus, a brain region that consists of several interconnected subregions, each with a distinct neuron population, plays a vital role in memory. Studies have shown that Alzheimer's disease hampers memory by first acting on the entorhinal cortex (EC), a brain region that provides the major input pathways to the hippocampus. It was initially thought that age-related memory loss is an early manifestation of Alzheimer's, but mounting evidence suggests that it is a distinct process that affects the dentate gyrus (DG), a subregion of the hippocampus that receives direct input from the EC.

The researchers began by performing microarray (gene expression) analyses of postmortem brain cells from the DG of eight people, ages 33 to 88, all of whom were free of brain disease. The team also analyzed cells from their EC, which served as controls since that brain structure is unaffected by aging. The analyses identified 17 candidate genes that might be related to aging in the DG. The most significant changes occurred in a gene called RbAp48, whose expression declined steadily with aging across the study subjects. To determine whether RbAp48 plays an active role in age-related memory loss, the researchers turned to mouse studies.

When the researchers genetically inhibited RbAp48 in the brains of healthy young mice, they found the same memory loss as in aged mice, as measured by novel object recognition and water maze memory tests. When RbAp48 inhibition was turned off, the mice's memory returned to normal. The researchers also did functional MRI (fMRI) studies of the mice with inhibited RbAp48 and found a selective effect in the DG, similar to that seen in fMRI studies of aged mice, monkeys, and humans. This effect of RbAp48 inhibition on the DG was accompanied by defects in molecular mechanisms similar to those found in aged mice. The fMRI profile and mechanistic defects of the mice with inhibited RbAp48 returned to normal when the inhibition was turned off.

In another experiment, the researchers used viral gene transfer and increased RbAp48 expression in the DG of aged mice. "We were astonished that not only did this improve the mice's performance on the memory tests, but their performance was comparable to that of young mice."

It seems unlikely that what is going on under the hood is simple, even as the result of a single gene change. Researchers still can't fully and comprehensively explain any of the forms of life extension achieved through single gene manipulations, and some of those have been known for more than fifteen years. Altered levels of a single protein can trigger all sorts of sweeping changes in metabolism. I predict that much of the next decade will pass before even a rough sketch of what is going on here is assembled. Fortunately, full understanding isn't required to demonstrate the potential for therapies - it just improves the odds of producing a feasible, useful medical technology.

Here's the paper for those who like to see the original sources:

Molecular Mechanism for Age-Related Memory Loss: The Histone-Binding Protein RbAp48

To distinguish age-related memory loss more explicitly from Alzheimer's disease (AD), we have explored its molecular underpinning in the dentate gyrus (DG), a subregion of the hippocampal formation thought to be targeted by aging. We carried out a gene expression study in human postmortem tissue harvested from both DG and entorhinal cortex (EC), a neighboring subregion unaffected by aging and known to be the site of onset of AD. Using expression in the EC for normalization, we identified 17 genes that manifested reliable age-related changes in the DG. The most significant change was an age-related decline in RbAp48, a histone-binding protein that modifies histone acetylation.

To test whether the RbAp48 decline could be responsible for age-related memory loss, we turned to mice and found that, consistent with humans, RbAp48 was less abundant in the DG of old than in young mice. We next generated a transgenic mouse that expressed a dominant-negative inhibitor of RbAp48 in the adult forebrain. Inhibition of RbAp48 in young mice caused hippocampus-dependent memory deficits similar to those associated with aging, as measured by novel object recognition and Morris water maze tests. Functional magnetic resonance imaging studies showed that within the hippocampal formation, dysfunction was selectively observed in the DG, and this corresponded to a regionally selective decrease in histone acetylation.

Up-regulation of RbAp48 in the DG of aged wild-type mice ameliorated age-related hippocampus-based memory loss and age-related abnormalities in histone acetylation. Together, these findings show that the DG is a hippocampal subregion targeted by aging, and identify molecular mechanisms of cognitive aging that could serve as valid targets for therapeutic intervention.

Researchers have been making good progress in recent years on understanding the mechanisms underlying Parkinson's disease. The condition progresses due to the destruction of a vital set of dopamine-generating neurons in the brain. Like many late-onset conditions, it appears that the root causes of this cell death are an exaggerated form of the harm that falls upon all of us with advancing age. Where Parkinson's has genetic influences, those influences appear to reduce the ability of these cells to maintain themselves against the accumulated damage of aging, hence leading to a faster degeneration and an earlier appearance of the condition. So it is quite possible that one of the outcomes of Parkinson's research will be the understanding necessary to boost the ability of central nervous system cells to maintain themselves in everyone, not just those who are failing more rapidly due to a poor roll of the dice in the genetic lottery.

[Researchers] have brought new clarity to the picture of what goes awry in the brain during Parkinson's disease and identified a compound that eases the disease's symptoms in mice. One of their findings was that the function of an enzyme called parkin, which malfunctions in the disease, is to tag a bevy of other proteins for destruction by the cell's recycling machinery. This means that nonfunctional parkin leads to the buildup of its target proteins, and [researchers] are exploring what roles these proteins might play in the disease.

[Researchers created] mice whose genes for a protein called AIMP2 could be switched into high gear. AIMP2 is one of the proteins normally tagged for destruction by parkin, so the genetically modified mice enabled the research team to put aside the effects of defective parkin and excesses of other proteins and look just at the consequences of too much AIMP2. The consequences were that the mice developed symptoms similar to those of Parkinson's as they aged, the group found. As in Parkinson's patients, the brain cells that make the chemical dopamine were dying.

AIMP2 was activating a self-destruct pathway called parthanatos, [named for the] poly(ADP-ribose), or "PAR," and the Greek word thanatos, which means "messenger of death." [Researchers] had previously seen parthanatos set off after events like traumatic injuries or stroke - not by chronic disease. AIMP2 triggered parthanatos by directly interacting with a protein called PARP1, which was long thought to respond only to DNA damage - not to signals from other proteins.

[The researchers] already knew of compounds drug companies had designed to block this enzyme. Such drugs are already in the process of being tested to protect healthy cells during cancer treatment. Crucially, two of these compounds can cross over the blood-brain barrier that keeps many drugs from affecting brain cells. The research team used a compound that blocks PARP1. "Not only did the compound protect dopamine-making neurons from death, it also prevented behavioral abnormalities similar to those seen in Parkinson's disease."

Link: http://www.eurekalert.org/pub_releases/2013-08/jhm-run082013.php

Much of the future technology required for rejuvenation of the old involves repairing or cleaning out small-scale protein structures and components in and around cells. Given this, it is worth keeping an eye on the field of synthetic biology, wherein researchers strive to understand, alter, and recreate the low-level machinery of the cell:

Engineering began as an outgrowth of the craftwork of metallurgical artisans. In a constant quest to improve their handiwork, those craftsmen exhaustively and empirically explored the properties - alone and in combination - of natural materials. Today, there is a parallel progression unfolding in the field of synthetic biology, which encompasses the engineering of biological systems from genetically encoded molecular components. The first decade or so of synthetic biology can be viewed as an artisanal exploration of subcellular material. Much as in the early days of other engineering disciplines, the field's focus has been on identifying the building blocks that may be useful for constructing synthetic biological circuits - and determining the practical rules for connecting them into functional systems.

[One] field that now seems poised to undergo a revolution by the forward engineering of cells is biomedicine. Cells naturally perform therapeutic tasks in the body - immune cells identify and remove pathogens, for example - and unlike drugs or molecules, cells can perform complex functions, such as sensing their environments or proliferating. Indeed, patient-specific immune cells are already being genetically engineered with receptors called chimeric antigen receptors (CARs) that allow them to target and destroy tumors in the body. Synthetic circuits and approaches could be used to further enhance these cancer-fighting functions and/or make these cell-based therapies safer. Similar approaches could be envisioned for endowing cells with sense-and-response capabilities to detect and mediate a number of other dysfunctions and pathologies. Promising opportunities for cell-based therapeutics also include patient-specific stem cells for regenerative medicine and microbiome engineering to treat gastrointestinal diseases.

What's more, all of these exciting efforts are occurring simultaneously with our now unprecedented ability to make modifications to the genomes of cells. Using targeting tools, such as zinc fingers, TALEs, and CRISPR/Cas, researchers can now edit specific genes within a genome with very high precision. For example, we can - and do, in the form of gene therapy - use these tools to inactivate genes known to be involved in disease progression or in pathogen life cycles. We can also use them to introduce synthetic circuits into precise locations within a variety of genomes, including in human cells - a feat that would have been impossible less than a decade ago. We can even think about de novo designing and sculpting of genomes to have desirable properties.

Link: http://www.the-scientist.com/?articles.view/articleNo/36724/title/Engineering-Life/

Laboratory mice are little cancer factories in comparison to humans, and so any mechanism that reduces cancer risk is going to extend life expectancy in a study group. That's one of many reasons why it is a good idea to pay more attention to research that shows a gain in maximum life extension rather than just mean life span extension. There is some debate over whether reducing cancer risk counts as an anti-aging therapy: the argument in favor suggests that since cancer is an age-related condition, risk rising to a plateau with advancing age, and since aging can be defined as increasing risk of mortality, of course reducing incidence of cancer counts as an anti-aging treatment. On the other side of the fence, there is the tendency of the research community to carve away named diseases from aging as new knowledge arises, and talk about treating those diseases rather than treating aging. See, for example, sarcopenia as the comparatively new designation for age-related loss of muscle mass and strength.

This seems to come down to how well researchers understand a given method of extending life in laboratory animals. No idea how it works, and the older individuals in the study are looking healthier? Then suggest that it is a slowing of aging. If, on the other hand, the precise mechanisms of action can be identified and have to do with cancer, then there is a reluctance to talk about the pace of aging. In this we might see some of the consequences of the remaining divisions and uncertainties over what exactly aging is, how it is caused, and how it progresses at the level of cells, cellular machinery, and biological systems.

An example of this sort of debate showed up recently in connection to rapamycin. Reputable researchers have run sizable studies on mouse life span under treatment with rapamycin: some conclude that rapamycin definitely slows aging, while others conclude that the effect on life span is due to reduced cancer risk, and yet more argue that there is no real difference in this case between life extension and reduced cancer risk as it all stems from the same underlying collection of mechanisms.

I can't say as I have a strong opinion on this topic insofar as it touches on rapamycin: research into drugs to modestly slow aging isn't the future of human longevity. Rather it is a sidebar to learning more about the operation of mammalian biology and how it adapts to various circumstances, such as calorie restriction and aging. But on this subject, I noticed a recent paper on a less well studied longevity-enhancing genetic alteration in which the authors also postulate that the mechanism is reduced cancer risk:

Reduced Malignancy as a Mechanism for Longevity in Mice with Adenylyl Cyclase Type 5 (AC5) Disruption

Disruption of adenylyl cyclase type 5 (AC5) knockout (KO) is a novel model for longevity. Since malignancy is a major cause of death and reduced lifespan in mice, the goal of this investigation was to examine the role of AC5KO in protecting against cancer. There have been numerous discoveries in genetically engineered mice over the past several decades, but few have been translated to the bedside. One major reason is that it is difficult to alter a gene in patients, but rather a pharmacological approach is more appropriate.

The current investigation employs a parallel construction to examine the extent to which inhibiting adenylyl cyclase type 5 (AC5), either in a genetic knockout (KO) or by a specific pharmacological inhibitor protects against cancer. This study is unique, not only because a combined genetic and pharmacological approach is rare, but also there are no prior studies on the extent to which AC5 affects cancer.

We found that AC5KO delayed age-related tumor incidence significantly, as well as protecting against mammary tumor development, [which] can explain why AC5KO is a model of longevity. In addition, an FDA approved anti-viral agent, adenine 9-β-D-arabinofuranoside (Vidarabine or AraAde), which specifically inhibits AC5, reduces [lung and melanoma] tumor growth. Thus, inhibition of AC5 is a previously unreported mechanism for prevention of cancers associated with aging, and which can be targeted by an available pharmacologic inhibitor, with potential consequent extension of life span.

Researchers here spur greater regeneration following injury by broadcasting on one of the channels used for communication between cells. This is a form of cellular manipulation that will become more subtle and powerful in the years ahead as researchers gain a greater understanding of these channels and the messages they carry:

Exosomes are endosomal origin small-membrane vesicles with a size of 40 to 100 nm in diameter. They are generated by many cell types and contain functional messenger RNAs and micro RNAs (miRNAs), as well as proteins. Exosomes are well suited for small functional molecule delivery and increasing evidence indicates that they have a pivotal role in cell-to-cell communication. Recent studies indicate that exosomes and microvesicles derived from multipotent mesenchymal stromal cells (MSCs) have therapeutic promise in cardiovascular, liver, and kidney diseases. Mesenchymal stromal cells decrease neurologic deficits in rodents after stroke by increasing neurite remodeling, neurogenesis, and angiogenesis.

We have previously demonstrated that functional miRNAs are transferred between MSCs and neural cells via exosomes, and that exosome-encapsulated transfer of miRNAs promotes neurite remodeling and functional recovery of stroke in rat. These data suggest that MSC-generated exosomes enhance the stroke recovery process. Thus, it is reasonable to test the hypothesis that exosomes alone when systemically administered to an animal with stroke improve functional outcome, with therapeutic benefit reflecting that observed with systemically administered MSCs. As a proof-of-principle study, we administer cell-free exosomes generated by MSCs to rats subjected to middle cerebral artery occlusion (MCAo) and investigate functional recovery as well as the mechanisms that underlie it. Our results suggest that intravenous administration of cell-free MSC-generated exosomes post stroke improves functional recovery [and] represents a novel treatment for stroke.

Link: http://dx.doi.org/10.1038/jcbfm.2013.152

A number of lines of research aim to find the basis for human therapies in lower animals that happen to have more favorable outcomes in aging as a result of their genetics and metabolism. Here is one example:

Sarcopenia and dynapenia pose significant problems for the aged, especially as life expectancy rises in developed countries. Current therapies are marginally efficacious at best, and barriers to breakthroughs in treatment may result from currently employed model organisms. Here, we argue that the use of indeterminate-growing teleost fish in skeletal muscle aging research may lead to therapeutic advancements not possible with current mammalian models.

Evidence from a comparative approach utilizing the subfamily Danioninae suggests that the indeterminate growth paradigm of many teleosts arises from adult muscle stem cells with greater proliferative capacity, even in spite of smaller progenitor populations. We hypothesize that paired-box transcription factors, Pax3/7, are involved with this enhanced self-renewal and that prolonged expression of these factors may allow some fish species to escape, or at least forestall, sarcopenia/dynapenia. Future research efforts should focus on the experimental validation of these genes as key factors in indeterminate growth, both in the context of muscle stem cell proliferation and in prevention of skeletal muscle senescence.

Link: http://www.frontiersin.org/Genetics_of_Aging/10.3389/fgene.2013.00159/full

Researchers around the world are examining the effects of calorie restriction in many different species, and have been for years. In near all species reducing calorie intake while maintaining optimal levels of vital nutrients extends life and provides numerous health benefits. Spectacular improvements in general health and lowered risk of disease are observed in human practitioners, far more than any presently available medical technology can offer a basically healthy individual, but the jury is still out on the degree to which calorie restriction can extend maximum life span in our species and other longer-lived primates. In part this is due to a lack of data: it takes a long time to run such a study when the only reliable way to measure life extension is to wait and see, and there is little in the way of large sets of historical data to mine. Researchers currently expect calorie restriction to extend human life by only a few years, and the historical absence of evidence bears this out: if calorie restriction with adequate nutrition could significantly extend human life - such as by the 40% seen in laboratory mice - then our ancestors would have found out a long time ago, and at the very least within the last few hundred years of more advanced technology and greater wealth.

Investigations into the biology of calorie restriction induced health and longevity are really only a sideshow in the grand scheme of longevity science. Radical life extension can only arrive from rejuvenation biotechnologies - therapies that can repair the low-level biological damage that causes aging. If you restrict your calories you can expect to have a much healthier life, on average, than would otherwise be the case, something that has great merit in and of itself. But don't expect it to add decades to your overall life span, because it probably won't. For that sort of result, you need to look to the Strategies for Engineered Negligible Senescence (SENS) or other similar programs aiming for new medical technologies to reverse the root causes of aging.

Nonetheless, it will be interesting to see how researchers reconcile the fact that short-term health benefits due to calorie restriction are large and similar in mice and humans, yet calorie restricted mice live for much longer, while humans probably don't. Here are a few recent papers from the breadth of ongoing research into the effects of a lower calorie intake on aging and longevity:

Long-term calorie restriction decreases metabolic cost of movement and prevents decrease of physical activity during aging in the rhesus monkeys

Short-term (less than 1 year) calorie restriction (CR) has been reported to decrease physical activity and metabolic rate in humans and non-human primate models; however, studies examining the very long-term (greater than 10 year) effect of CR on these parameters are lacking. The objective of this study was to examine metabolic and behavioral adaptations to long-term CR longitudinally in rhesus macaques.

Eighteen (10 male, 8 female) control (C) and 24 (14 male, 10 female) age matched CR rhesus monkeys between 19.6 and 31.9 years old were examined after 13 and 18 years of moderate adult-onset CR. Energy expenditure (EE) was examined by doubly labeled water (DLW; TEE) and respiratory chamber (24h EE). Physical activity was assessed both by metabolic equivalent (MET) in a respiratory chamber and by an accelerometer. Metabolic cost of movements during 24h was also calculated. Age and fat-free mass were included as covariates.

Adjusted total and 24h EE were not different between C and CR. Sleeping metabolic rate was significantly lower, and physical activity level was higher in CR than in C independent from the CR-induced changes in body composition. The duration of physical activity above 1.6 METs was significantly higher in CR than in C, and CR had significantly higher accelerometer activity counts than C. Metabolic cost of movements during 24h was significantly lower in CR than in C. The accelerometer activity counts were significantly decreased after seven years in C animals, but not in CR animals. The results suggest that long-term CR decreases basal metabolic rate, but maintains higher physical activity with lower metabolic cost of movements compared with C.

Molecular signatures of mammalian hibernation: comparisons with alternative phenotypes

Mammalian hibernators display phenotypes similar to physiological responses to calorie restriction and fasting, sleep, cold exposure, and ischemia-reperfusion in non-hibernating species. Whether biochemical changes evident during hibernation have parallels in non-hibernating systems on molecular and genetic levels is unclear.

We identified the molecular signatures of torpor and arousal episodes during hibernation using a custom-designed microarray for the Arctic ground squirrel (Urocitellus parryii) and compared them with molecular signatures of selected mouse phenotypes. Our results indicate that differential gene expression related to metabolism during hibernation is associated with that during calorie restriction and that the nuclear receptor protein PPARα is potentially crucial for metabolic remodeling in torpor. Sleep-wake cycle-related and temperature response genes follow the same expression changes as during the torpor-arousal cycle. Increased fatty acid metabolism occurs during hibernation but not during ischemia-reperfusion injury in mice and, thus, might contribute to protection against ischemia-reperfusion during hibernation.

SIRT1 but not its increased expression is essential for lifespan extension in caloric restricted mice

The SIRT1 deacetylase is one of the best-studied potential mediators of some of the anti-aging effects of calorie restriction (CR); but its role in CR-dependent lifespan extension has not been demonstrated. We previously found that mice lacking both copies of SIRT1 displayed a shorter median lifespan than wild type mice on an ad libitum diet. Here we report that median lifespan extension in CR heterozygote SIRT1+/- mice was identical (51%) to that observed in wild type mice but SIRT1+/- mice displayed a higher frequency of certain pathologies. Although larger studies in different genetic backgrounds are needed, these results provide strong initial evidence for the requirement of SIRT1 for the lifespan extension effects of CR, but suggest that its high expression is not required for CR-induced lifespan extension.

Maintenance of cellular ATP level by caloric restriction correlates chronological survival of budding yeast

The free radical theory of aging emphasizes cumulative oxidative damage in the genome and intracellular proteins due to reactive oxygen species (ROS), which is a major cause for aging. Caloric restriction (CR) has been known as a representative treatment that prevents aging; however, its mechanism of action remains elusive. Here, we show that CR extends the chronological lifespan (CLS) of budding yeast by maintaining cellular energy levels. CR reduced the generation of total ROS and mitochondrial superoxide; however, CR did not reduce the oxidative damage in proteins and DNA. Subsequently, calorie-restricted yeast had higher mitochondrial membrane potential (MMP), and it sustained consistent ATP levels during the process of chronological aging. Our results suggest that CR extends the survival of the chronologically aged cells by improving the efficiency of energy metabolism for the maintenance of the ATP level rather than reducing the global oxidative damage of proteins and DNA.

In past years researchers have shown that introducing young cells and cell signaling into old individuals via transplant or parabiosis improves some measures of health and reduces some measures of aging. Research here generally focuses on stem cells and the mechanisms by which stem cell activity declines with age: there appears to be a strong signaling component to this decline, presumably a part of the evolved response to accumulating damage in tissues, a way to minimize cancer risk from damaged cells at the cost of failing tissue maintenance and faster aging. So stem cells remain capable of tissue maintenance, but increasingly refrain.

Here researchers are transplanting a significant fraction of bone marrow rather than using the easier approach of blood transfusions to investigate these effects. They find a modest increase in remaining life expectancy for the old mice receiving bone marrow from young donors, but it is worth noting that this was a small group of animals, and a procedure with a high failure rate at this point - this is an early exploratory proof of concept, preliminary to a more rigorous study:

Tissue renewal is a well-known phenomenon by which old and dying-off cells of various tissues of the body are replaced by progeny of local or circulating stem cells (SCs). An interesting question is whether donor SCs are capable to prolong the lifespan of an aging organism by tissue renewal. In this work, we investigated the possible use of bone marrow (BM) SC for lifespan extension. To this purpose, chimeric C57BL/6 mice were created by transplanting BM from young 1.5-month-old donors to 21.5-month-old recipients. Transplantation was carried out by means of a recently developed method which allowed to transplant without myeloablation up to [about] 25% of the total BM cells of the mouse. As a result, the mean survival time, counting from the age of 21.5 months, the start of the experiment, was +3.6 and +5.0 (±0.1) months for the control and experimental groups, respectively, corresponding to a 39 ± 4% increase in the experimental group over the control.

The oldest transplanted animal lived 3 weeks longer than the oldest control animal. However we cannot calculate the maximal lifespan here, since it is, by definition, the mean lifespan of the most long-lived 10% of each group. In our small group, 10% would be less than one mouse. So, the investigation of an influence of BMT on maximal lifespan is the task for future work.

The obtained positive influence of BMT on the mean lifespan in our work is underestimated because of transplantation complications (including the occlusion of vessels) from which, obviously, suffered not only the two mice that died during transplantation and were excluded from the statistics, but also those that survived, though to a lesser degree. We expect a greater difference in lifespan between control and experimental groups by (i) the use of high-quality commercial filters for purification of transplanted material from cell aggregates and (ii) the use of more accurate controls injected with old BM (in this work the control animals did not get the parallel invasive treatment because of the absence of additional 20 months old animals to produce old BM for control transplantation).

Link: http://www.frontiersin.org/Genetics_of_Aging/10.3389/fgene.2013.00144/full

The genomics X Prize had only a slight connection to aging research: the goal was to sequence the genomes of 100 centenarians at a small cost, and add that knowledge to the present state of understanding regarding the genetics of human longevity. That result would have been a side-effect of spurring work in low-cost sequencing. But sequencing is advancing rapidly regardless, there was no great public interest in the prize, and greater understanding of the genetics underlying natural variations in longevity is not the path to greatly extending human life. The research community will meaningfully extend healthy life spans through rejuvenation, by repairing the already known root causes of aging, not by altering human genes to slow down aging.

So all in all, I think that this prize was a poor choice at the outset: the goal not radical enough, and focused on an area of research and development that was already in a state of rapid progress, and with too much funding available for a research prize to be effective.

Mere weeks before its official start, the genomics X Prize - intended to spur a revolution in fast, cheap and accurate human-genome sequencing - has been abruptly cancelled. Peter Diamandis, chair of the X Prize Foundation in Playa Vista, California, says the Archon Genomics X Prize has been abandoned because it was outpaced by innovation.

Announced seven years ago, the prize asked companies to design devices that could sequence 100 human genomes in 30 days or less, with additional requirements for accuracy and cost. Today, companies are routinely sequencing human genomes for less than the $10,000 per genome the prize originally required. But the full picture is more complex. Yes, the cost of genome sequencing has plummeted, which explains why the prize had dropped its cost goal to $1000 per genome. But current technologies are still some way from meeting the revised goal for accuracy: making only one error per million DNA bases sequenced.

Genomics pioneer Craig Venter, who conceived the prize, is disappointed that companies and scientists "seem to have little or no interest in meeting the demanding goals we set up". Indeed, only two teams had entered. Given that the genome-sequencing industry has annual revenues in the billions of dollars, it is perhaps no surprise that a $10 million prize did not prove a huge incentive. In the long term, though, Venter argues that concentrating on speed and cost over accuracy is misguided. "I think for the future, it's an absolute mistake," he says.

Clifford Reid, who heads Complete Genomics of Mountain View, California, one of the leading companies in the field, agrees. But he is confident that accuracy will improve, whether or not there's an X Prize on the table. "The market forces are in the process of changing from meeting the needs of the research community to the needs of medicine," says Reid.

Link: http://www.newscientist.com/article/dn24105-x-prize-for-genomes-cancelled-before-it-begins.html

The 2045 Initiative is a fairly young but comparatively well-backed effort to generate more support for and technological progress towards non-biological means of human life extension: artificial bodies, and ultimately artificial brains, built to be far more resilient and maintainable than our present evolved equipment. There is some debate over whether this is an efficient course in comparison to medical research, but that end of the futurist community already primarily interested in strong artificial intelligence seem to like where this is going.

There is a lot of fascinating groundwork in reverse-engineering the human brain presently under way, and it's clear that neuroscience is going to become an interesting place to be over the next few decades. However, I remain unconvinced that any of this is going to help us get over the initial hurdles to extending human longevity, meaning the frailty and short life span of the human body and physical structures that support the mind, soon enough to matter. Artificial intelligence and human minds running on machinery will certainly come to pass, and I will be surprised if the latter fails to happen in the laboratory prior to 2050 given the pace at which available processing power is growing. However, and this is important, over that time scale most of us doing the writing and the reading here and now are dead without some means of medical treatment for aging. This is one of the reasons why I pay less attention to neuroscience and mind-machine interface development than I do to repair biotechnologies for the causes of aging.

The Global Futures 2045 conference series is a part of the 2045 Initiative advocacy, and the most recent event took place a couple of months ago. I noted some of the media reports at the time. A two part report published earlier this month is quoted below and focuses more on the presentations than did past articles in the popular press, which I think is a good thing.

The world according to Itskov: Futurists convene at GF2045 (Part 1)

The development of brain-computer interfaces (BCIs) to allow paralyzed individuals to control various external prosthetic devices, such as a remote robotic arm, was another key topic at GF2045. A very recent example of the BCI research Carmena and Maharbiz discussed is Neural Dust: An Ultrasonic, Low Power Solution for Chronic Brain-Machine Interfaces. The theoretical pre-print paper proposes neural dust - thousands of ultra-miniaturized, free-floating, independent sensor nodes that detect and report local extracellular electrophysiological data - with neural dust power and communication links established through a subcranial interrogator. With the purpose being to enable "massive scaling in the number of neural recordings from the brain while providing a path towards truly chronic BMI," the researchers' goal is "an implantable neural interface system that remains viable for a lifetime."

In Making Minds Morally: the Research Ethics of Brain Emulation, Dr. Anders Sandberg - a Computational Neuroscientist, and James Martin Research Fellow at the Future of Humanity Institute at Oxford University, and Research Associate at the Oxford Neuroethics Center - addressed the social and ethical impact of cognitive enhancement and whole brain emulation. "We want to get to the future," Sandberg said in his talk, "but that implies that the future had better be a good place. Otherwise, there wouldn't be a point in getting there - but that would mean in turn that the methods we're going to use to get to the future had better be good as well."

The world according to Itskov: Futurists convene at GF2045 (Part 2)

Dr. Theodore Berger gave the most groundbreaking presentation of the Congress - one that also received a standing ovation. In Engineering Memories: A Cognitive Neural Prosthesis for Restoring and Enhancing Memory Function, Berger discussed his extraordinary research in the development of biomimetic models of hippocampus to serve as neural prostheses for restoring and enhancing memory and other cognitive functions. Berger and his colleagues have successfully replaced the hippocampus - a component of the cortex found in humans and other vertebrates that transforms short-term memory into long-term memory - with a biomimetic VLSI (Very Large-Scale Integrated circuit) device programmed with the mathematical transformations performed by the biological hippocampus.

Dr. Randal Koene, neuroscientist, neuroengineer and science director of the 2045 Initiative, has been focusing on the functional reconstruction of neural tissue since 1994. In his Whole Brain Emulation: Reverse Engineering A Mind presentation and soon-to-be published book with the same title, Koene describes the process of progressing from our current condition to a possible substrate-independent mind achieved by whole brain emulation and cites a wide range of research, including the work of fellow GF2045 presenters.

A conservative view of what lies ahead for Alzheimer's disease (AD) research sees incremental progress resulting from new and better investigative biotechnologies:

In the recently published work "The Biology of Alzheimer Disease" (2012), most of what is known about AD today is described in detail. The book culminates in a chapter called Alzheimer Disease in 2020, where the editors extol "the remarkable advances in unraveling the biological underpinnings of Alzheimer disease...during the last 25 years," and yet also recognize that "we have made only the smallest of dents in the development of truly disease modifying treatments." So what can we reasonably expect over the course of the next 7 years or so? Will we bang our heads against the wall of discovery, or will there be enormous breakthroughs in identification and treatment of AD?

Though a definitive diagnosis of AD is only possible upon postmortem histopathological examination of the brain, a thorough review of the book leads me to believe that the greatest progress currently being made is in developing assays to diagnose AD at earlier stages. It is now known that neuropathological changes associated with AD may begin decades before symptoms manifest. This, coupled with the uncertainty inherent in a clinical diagnosis of AD, has driven a search for diagnostic markers. Two particular approaches have shown the most promise: brain imaging and the identification of fluid biomarkers of AD.

The authors anticipate that advances in whole-genome and exome sequencing will lead to a better understanding of all of the genes that contribute to overall genetic risk of AD. Additionally, improved ability to sense and detect the proteins that aggregate in AD and to distinguish these different assembly forms and to correlate the various conformations with cellular, synaptic, and brain network dysfunction should be forthcoming in the next few years. Lastly, we will continue to improve our understanding of the cell biology of neurodegeneration as well as cell-cell interactions and inflammation, providing new insights into what is important and what is not in AD pathogenesis and how it differs across individuals, which will lead, in turn, to improved clinical trials and treatment strategies.

Link: http://www.alcor.org/magazine/2013/08/21/alzheimer-disease-in-2020/

The modern movements of transhumanism and support for longevity science have deep roots: you can find early expressions of the ideas of human enhancement and overcoming natural limits on our biology in a range of writings from past centuries. These ideas became more commonplace and more complex over time as the prospects for technology caught up with our desires:

Immanuel Kant (1724-1804) was an 18th century philosopher, one of the earliest philosophers belonging to the enlightenment tradition, and often considered the father of German Idealism. Kant is remembered today more for his moral philosophy than his contributions to metaphysics and epistemology (Rohlf 2010). His contributions to the field of life-extension, however, remain almost completely unexplored, despite the fact that certain claims made in his Theory of Ethics arguably qualify him as a historical antecedent of the contemporary social movement and academic discipline of life-extension.

Marquis du Condorcet (1743-1794), another historical antecedent the modern longevity movement, appears to have originated the "idea of progress" in the context of the enlightenment, which became an ideological cornerstone of the enlightenment tradition. In Sketch for a Historical Picture of the Progress of the Human Mind, Condorcet not only conceives of the idea of progress in perhaps the first form it would take within the enlightenment tradition, but also explicates its link to indefinite life-extension, which was not an existing movement or academic discipline at the time of his writing:

"Would it be absurd now to suppose that the improvement of the human race should be regarded as capable of unlimited progress? That a time will come when death would result only from extraordinary accidents or the more and more gradual wearing out of vitality, and that, finally, the duration of the average interval between birth and wearing out has itself no specific limit whatsoever? No doubt man will not become immortal, but cannot the span constantly increase between the moment he begins to live and the time when naturally, without illness or accident, he finds life a burden?"

It is this very notion of infinite progress towards endlessly-perfectible states, carried forward after Condorcet by Kant and other members of the enlightenment tradition, that also underlies Kant's own ties to the contemporary field of life-extension. Kant's claim, made in his Theory of Ethics, that to retain morality we must have comprehensively unending lives - that is, we must never, ever die - I will argue qualifies him as a historical antecedent of the contemporary life-extension movement.

Link: http://hplusmagazine.com/2013/08/21/immanuel-kant-morality-necessitates-immortality/

Aging is damage: it is the accumulation of broken and obstructed protein machinery and nanoscale structures inside and around our cells. Living beings come with many varied repair systems, so the processes by which damage grows and eventually overwhelms those repair systems is far from straightforward. In that sense aging isn't like the wearing of stone by the weather, or the failure of a non-repairing mechanical system like a car - but it's still all about damage. At the highest level the same mathematical models of damage and component loss that work just fine as aids to understanding failure in complex non-repairing systems like electronics also work just fine for aging.

Every so often a research group feels the need to publicize work in which they damage mice or other laboratory species in ways that cause them to live shorter lives. There are many very subtle ways to alter genes, such as those involved in DNA repair, that produce what is arguably accelerated aging. (Though not everyone thinks that these forms of life span reduction are in fact accelerated aging, but that's a debate for another time and place). The point here is that I think you have to beware of taking it at face value that these research results are relevant to normal aging, or relevant to extending healthy life. You can damage mice with a hammer if you so choose, and it will certainly shorten their life spans, but examining the results won't tell you anything about aging. Similarly, it's the case that near all of the possible ways of interfering in mouse biology via genes and metabolic operation in order to reduce life span are just as irrelevant.

Here is an example of this sort of thing: researchers are producing mice with additional damage in their mitochondria, a component of cellular biology known to be important in all sorts of metabolic processes, and considered to be important in aging, and showing that these mice don't live as long. I don't think that the authors can show that they've proved much of relevance to aging with this study as constructed, however, for the reasons noted above.

Mutations of mitochondrial DNA can hasten offspring's ageing process

In ageing research, mitochondria have been scrutinized by researchers for a long time already. The mitochondria in a cell contain thousand of copies of a circular DNA genome. These encode, for instance, proteins that are important for the enzymes of the respiratory chain. Whereas the DNA within the nucleus comes from both parents, the mitochondrial DNA (mtDNA) only includes maternal genes, as mitochondria are transmitted to offspring via the oocyte and not via sperm cells. As the numerous DNA molecules within a cell's mitochondria mutate independently from each other, normal and damaged mtDNA molecules are passed to the next generation.

To examine which effects mtDNA damage exerts on offspring, researchers used a mouse model. Mice that inherited mutations of mtDNA from their mother not only died quicker compared to those without inherited defects, but also showed premature ageing effects like reduced body mass or a decrease in male's fertility. Moreover, these rodents were prone to heart muscle disease.

As the researchers discovered, mutations of mtDNA not only can accelerate ageing but also impair development: In mice that, in addition to their inherited defects, accumulated mutations of mtDNA during their lifetime, researchers found disturbances of brain development. They conclude that defects of mtDNA that are inherited and those that are acquired later in life add up and finally reach a critical number.

To show relevance, you really need to demonstrate life extension - meaning repair mechanisms for mitochondrial DNA rather than damage mechanisms should be the focus. To shorten life spans through various forms of damage is unlikely to provide anything more than hints and inference when it comes to ways to extend life.

Long term calorie restriction lowers the risk of cancer in addition to extending life in laboratory animals. Here researchers show that short term calorie restriction appears to augment the effectiveness of treatments for an existing cancer:

While previous studies suggest a connection between caloric intake and the development of cancer, scientific evidence about the effect of caloric intake on the efficacy of cancer treatment has been rather limited to date. When humans and animals consume calories, the body metabolizes food to produce energy and assist in the building of proteins. When fewer calories are consumed, the amount of nutrients available to the body's cells is reduced, slowing the metabolic process and limiting the function of some proteins. These characteristics of calorie restriction have led researchers to hypothesize that reducing caloric intake could potentially help inhibit the overexpression of the protein Mcl-1, an alteration associated with several cancers.

Researchers conducted a series of experiments in mice developing lymphoma resembling Burkitt's lymphoma and diffuse large B-cell lymphoma, two human cancers of the white blood cells. The team began by separating the mice into two categories: those who would receive a regular diet and those who would receive a reduced-calorie diet (75 percent of normal intake) for the duration of the experiment. After the mice consumed either a regular or a reduced-calorie diet for one week, researchers then further divided the mice into four groups according to the treatment they would receive for the following 10 days. Of the two groups of mice that received a normal diet, one (the control group) did not receive treatment and the other received treatment with an experimental targeted therapy, ABT-737, designed to induce cancer cell death. Of the two groups of mice who received a reduced-calorie diet, one did not receive treatment and the other received ABT-737. On day 17 of the experiment, both treatment and calorie restriction ended, and mice had access to as much food as they desired.

Investigators observed that neither treatment with ABT-737 nor calorie restriction alone increased the survival of mice over that of the other mice; however, the combination of ABT-737 and calorie restriction did. Median survival was 30 days in the control group that received a regular diet and no treatment, 33 days in mice that received a regular diet and treatment with ABT-737, 30 days in mice that received a reduced-calorie diet without treatment, and 41 days in mice that received a reduced-calorie diet and treatment with ABT-737. Shortly after this experimental period, investigators also observed that the combination of calorie restriction and ABT-737 reduced the number of circulating lymphoma cells in the mice, suggesting that the combination sensitized the lymphoma cells to treatment.

Link: http://hematology.org/News/2013/10958.aspx

The blindness of age-related macular degeneration is linked to the build up of lipofuscin in cells, a hardy collection of metabolic waste products that the body cannot effectively break down. Lipofuscin accumulates to cause progressive failure of the cellular recycling and maintenance mechanisms known as autophagy - this is due to failing lysosomes, a part of the autophagic machinery which becomes increasingly clogged and bloated by lipofuscin.

Macular degeneration is one of the better known manifestations of this process, but it happens in long-lived cells throughout the body. The SENS proposals for rejuvenation therapies include the use of bacterial enzymes to break down the components of lipofusin, so as to restore autophagy and remove this contribution to degenerative aging. The open access research into autophagy and macular degeneration quoted below supports the SENS view on how best to proceed:

A new [study] changes our understanding of the pathogenesis of age-related macular degeneration (AMD). The researchers found that degenerative changes and loss of vision are caused by impaired function of the lysosomal clean-up mechanism, or autophagy, in the fundus of the eye. The results open new avenues for the treatment of the dry form of AMD, which currently lacks an efficient treatment.

AMD is a storage disease in which harmful protein accumulations develop behind the retina. These accumulations are indicative of the severity of the disease. As the disease progresses, retinal sensory cells in the central vision area are damaged, leading to loss of central vision. The cell biological mechanisms underlying protein accumulations remain largely unknown.

For the first time ever, the present study showed that AMD is associated with impaired lysosomal autophagy, which is an important clean-up mechanism of the fundus of the eye. This renders the cells in the fundus of the eye unable to dispose of old, deformed or otherwise faulty proteins, which, in turn, leads to the development of protein accumulations and loss of vision. The study can be regarded as a breakthrough, as the results change our understanding of the pathogenesis of AMD and also open new avenues for the treatment of the dry form of AMD. Drugs inhibiting the impairment of autophagy could possibly even stop the progression of AMD.

Link: http://dx.doi.org/10.1371/journal.pone.0069563

Stem cell research forges ahead these days on too many fronts to keep up with more than the high points. It's still enormously, unnecessarily expensive and time consuming to bring perfectly serviceable cell therapies into clinical practice in the US, so the medical tourism market continues to grow. The bulk of practical experience in the use of early stage stem cell therapies is at this point distributed to less regulated parts of the world, I believe. Work in the laboratory continues to advance in leaps and bounds, meanwhile, ever further ahead of what government regulators are willing to let pass their increasingly ridiculous testing processes. Researchers are moving closer to using stem cells to build useful amounts of tissue, and in programming stem cells to behave as we'd like them to behave: more active involvement in tissue regeneration, for example. There is a still a great deal yet to learn about how stem cells are programmed, however.

Here is a selection of recent news, a cross section of the average state of progress in stem cell research and the business of moving discoveries into clinical practice.

Stem Cells Market Will Reach USD 119.51 Billion in 2018

The market growth is majorly attributed to therapeutic research activities led by government support worldwide owing to the growing number of patients with chronic diseases across the globe. In addition, rising awareness of regenerative treatment options and growing importance of stem cell banking services are also fostering the growth of the market. Apart from these, development of medical tourism hubs in developing nations such as India and China and in turn migration of patients from developed nations such as the U.S. and Europe for quality treatment at significantly lower prices will also serve the market as a driver especially for the Asian stem cells market.

Adult stem cells held majority share of the overall stem cells market in 2011 at over 80%. This is due to less laborious procedure of harvesting, and less probability of contamination during expansion and sub-culture of adult stem cells. However, fewer post-transplant complications and lesser risk of graft vs. host reaction from the recently introduced induced pluripotent stem cells will lead to its rapid inclusion in research activities and help the global induced pluripotent stem cells market to grow at a relatively faster [rate] during the forecast period.

Egg engineers

Starting with the skin cells of mice in vitro, [Katsuhiko Hayashi] created primordial germ cells (PGCs), which can develop into both sperm and eggs. To prove that these laboratory-grown versions were truly similar to naturally occurring PGCs, he used them to create eggs, then used those eggs to create live mice. He calls the live births a mere 'side effect' of the research, but that bench experiment became much more, because it raised the prospect of creating fertilizable eggs from the skin cells of infertile women. And it also suggested that men's skin cells could be used to create eggs, and that sperm could be generated from women's cells.

Heart's own stem cells offer hope for new treatment of heart failure

[Researchers] have for the first time highlighted the natural regenerative capacity of a group of stem cells that reside in the heart. This new study shows that these cells are responsible for repairing and regenerating muscle tissue damaged by a heart attack which leads to heart failure. The study [shows] that if the stem cells are eliminated, the heart is unable to repair after damage. If the cardiac stem cells are replaced the heart repairs itself, leading to complete cellular, anatomical and functional heart recovery, with the heart returning to normal and pumping at a regular rate. Also, if the cardiac stem cells are removed and re-injected, they naturally 'home' to and repair the damaged heart, a discovery that could lead to less-invasive treatments and even early prevention of heart failure in the future.

Developmental On-Switch: Substances That Convert Body Cells Back Into Stem Cells Initially Activate All Genes in the Embryo

[Working with zebrafish] researchers have demonstrated for the first time why the molecular cocktail responsible for generating stem cells works. Sox2 and Oct4 are proteins whose effect on cells resembles that of an eraser: They remove all of the cell's previous experiences and transform it into a so-called pluripotent stem cell. The Oct4 protein in the zebrafish embryo, which is initially provided by the mother, is responsible for switching on the embryo's genes for the first time, thus initiating the animal's independent development.

Using the regulatory network discovered in the zebrafish, developmental biologists can now study how particular cell types in the body are created from stem cells and what makes them stable. Scientists require reliable processes for forming stable tissue before it can be used for applications in medicine.

Shining Stem Cells Reveals How Our Skin Is Maintained

Until now, the belief was that the skin's stem cells were organized in a strict hierarchy with a primitive stem cell type at the top of the hierarchy, and that this cell gave rise to all other cell types of the skin. However, our results show that there are differentiated levels of stem cells and that it is their close micro-environment that determines whether they make hair follicles, fat- or sweat glands.

Our data completes what is already known about the skin and its maintenance. Researchers have until now tried to fit their results into the old model for skin maintenance. However, the results give much more meaning when we relate them to the new model that our research proposes. We have marked the early skin stem cell with shining proteins in order to map stem cell behaviour in the outer layer of the skin. The stain is inherited by the daughter cells, so that we can trace their origin and make a family tree. The fine details of the family tree can be used to infer the stem cell's role in normal maintenance of the skin, as well as in wound healing.

The FDA has in recently years tried to shut down US clinics offering very simple forms of autologous stem cell therapy, those that do very little in the way of refining or altering or culturing the patient's cells, but these services are spreading nowadays. There was a ruling last year in which the FDA, for a change, decided not to continue to block new forms of therapy. There are of course no apologies for the costs incurred by groups like Regenerative Sciences due to government legal actions taken against their practices. So perhaps there is a useful erosion of FDA authority at this point and in this matter - more of that can only be a good thing. I would imagine that this has a lot to do with the ubiquitous availability of these therapies outside the US: competition and regulatory arbitrage between regions is the only thing that will generate sufficient pressure to make the FDA and other portions of the US medical regulation edifice back down.

Using body's own stem cells can help postpone knee replacement

"Knee replacements typically last 10 to 15 years on average," said Welsh. "If you're somebody in your 40-50s that has to have a knee replacement, and that's your only option, then you're having a big revision surgery in your 60s or 70s when your health may be starting to fail." So what to do? Welsh recommended a far less invasive procedure called stem cell knee injection. Welsh takes stem cells from the patient's own body that are generally found in the pelvis. Those stem cells are removed with a syringe and placed into a centrifuge where they're spun and mixed together for 15 minutes. Welsh then injects the stem cells into the knee.

"There was absolutely no pain involved in taking the stem cells out of my hip and putting them into my knee," said Hall.

"The benefit is we can postpone that knee replacement surgery hopefully for many years if we can truly regenerate cartilage," said Welsh.

"I know that it's working because I'm already exercising," said Hall. "I am so excited about feeling healthy again."

Stem Cells to the Rescue: Relieving Throbbing Joint Pain

Emory Orthopedic Specialists take the stem cells from a patient's own bone marrow, process them, and inject them back into the patients' joint, causing the pain to go away. "We have also seen regeneration of cartilage," Dr. Mason said. Patients are able to walk or drive immediately after the procedure and should experience significant overall improvement within six weeks.

"The implant was a little intense for a few seconds, nothing you couldn't deal with. It was a whole lot less painful than a root canal," Lunsford said. Out of 50 patients, only one needed surgery. "We basically turbo charged that site to heal itself and so far so good," Lunsford said.

Stem cell injections are being used mainly in the larger joints: knees, hips, and shoulders. However, because this treatment is so new, doctors don't know how long it will last. After three to four years patients will need to have another injection, or the replacement surgery, and because of that most health insurance plans will not cover it.

When investigating aging and longevity through comparing the biology of different species, one place to start is with the few species that are unusually long-lived in comparison to similarly-sized neighboring species. Hence the study of naked mole rats, which live nine times as long as other small rodents. Bats are also of interest, as they live much longer than other small active mammals. Digging into their biochemistry might tell researchers more about how the operation of mammalian metabolism determines longevity and the pace of aging. The results here, for example, may reinforce the role of growth hormone receptor (GHR) in the pace of aging:

Bats are among the most successful groups of animals. They account for ~20% of mammalian species, are the only mammals that have evolved powered flight, and are among the few animals that echolocate. Bats are also among the smallest of mammals, but are unusually long-lived, thus challenging the observed positive correlation between body mass and maximum lifespan. The Brandt's bat (Myotis brandtii) holds the record with regard to lifespan among the bats. Its reported maximal lifespan of at least 41 years also makes it the most extreme mammal with regard to disparity between body mass and longevity.

Here we report sequencing and analysis of the Brandt's bat genome and transcriptome, which suggest adaptations consistent with echolocation and hibernation, as well as altered metabolism, reproduction and visual function. Unique sequence changes in growth hormone and insulin-like growth factor 1 receptors are also observed. The data suggest that an altered growth hormone/insulin-like growth factor 1 axis, which may be common to other long-lived bat species, together with adaptations such as hibernation and low reproductive rate, contribute to the exceptional lifespan of the Brandt's bat.

It is prudent to ask whether the changes in the GHR/IGF1 axis in the Brand's bat contribute to the animal's long lifespan, its small body size or both. Although it is appreciated that other genes have been altered during the ~82 million years of bat evolution, we suggest that the changes observed in GHR and IGF1R contribute to the longevity and dwarfism-like phenotype of the Brandt's bat. Moreover, M. brandtii may mirror GHR dysfunction in mice and humans, and possibly insulin signalling in long-lived nematodes.

Link: http://dx.doi.org/10.1038/ncomms3212

Many lower animals are capable of regenerating from near any injury, and in some species researchers struggle to find any signs that they are subject to degenerative aging. These are not complex creatures, however. Lacking a central nervous system or a brain and other complex organs implies the ability to be resilient and regrow tissues to a degree that a complex organism simply cannot match. This point was raised in comments on the possible agelessness of hydra, but there are other similar lower animals:

Hydractinia echinata has the power to regenerate any lost body part, can clone itself, does not age biologically, [and] "in theory - lives forever. Hydractinia has some stem cells which remain at an embryonic-like stage throughout its life. It sounds gruesome, but if it has its head bitten off, it simply grows another one within a few days using its embryonic or 'pluripotent' stem cells. So the potential for research is immense."

[Researchers have] discovered an unknown link between 'heat-shock' proteins and a cell-signalling pathway, known as Wnt signalling, in Hydractinia stem cells. "These two cellular signalling mechanisms are known to play important roles in development and disease, so they have been widely, though separately, studied. We have shown that they talk to each other, providing a new perspective for all scientists in this field. We found the link coincidentally - we weren't looking for it." Both the heat-shock proteins and Wnt signalling are known to be associated with cancer and cell growth. Hydractinia stem cells should be "very similar to their human counterparts and studying them may provide information on human stem cells."

"So why don't humans keep their pluripotent cells as adults? It's a good question. Keeping them in a complex body like ours is probably too dangerous, as they can easily form cancer. It's not so much a problem in simple animals - they would probably cut a cancer off. The price to become complex is to lose the ability to be immortal."

The great difference between a simple and a complex organism means that there may be little beyond knowledge to be extracted from these studies. We have evolved to lose regenerative capacity for reasons that probably have to do with the complexity of our structure - researchers can't simply port over the biology of lower animals to let our stem cells run rampant and expect positive results to follow. Improving human regeneration is something that will have to be carefully steered and controlled, as is the case in research presently taking place in the stem cell scientific community.

Link: http://www.irishtimes.com/news/science/immortal-irish-marine-animal-provides-hope-for-research-into-ageing-1.1500113

The protein C1q is related to the processes of Wnt signaling, a name which might be more familiar to those who follow research into the molecular biochemistry and genetics of aging. Wnt shows up in all sorts of areas related to development and regeneration, and a range of research groups are investigating this area of biology. Levels of C1q increase with aging, and genetic engineering to remove C1q in mice was shown to be beneficial, producing an increase in regenerative capacity:

We here report that complement C1q activates canonical Wnt signaling and promotes aging-associated decline in tissue regeneration. Serum C1q concentration is increased with aging, and Wnt signaling activity is augmented during aging in the serum and in multiple tissues of wild-type mice, but not in those of C1qa-deficient mice. ... Skeletal muscle regeneration in young mice is inhibited by exogenous C1q treatment, whereas aging-associated impairment of muscle regeneration is restored by C1s inhibition or C1qa gene disruption.

More recent research now shows that eliminating C1q also reduces the mental decline associated with aging in mice. This might operate through similar underlying mechanisms to those that improve muscle regeneration, such as by a boost to the ability to generate new neurons and maintain neural tissue and blood vessels in the brain in better functioning condition.

A Dramatic Increase of C1q Protein in the CNS during Normal Aging

The decline of cognitive function has emerged as one of the greatest health threats of old age. Age-related cognitive decline is caused by an impacted neuronal circuitry, yet the molecular mechanisms responsible are unknown. C1q, the initiating protein of the classical complement cascade and powerful effector of the peripheral immune response, mediates synapse elimination in the developing central nervous system.

Here we show that C1q protein levels dramatically increase in the normal aging mouse and human brain, by as much as 300-fold. This increase was predominantly localized in close proximity to synapses and occurred earliest and most dramatically in certain regions of the brain, including some but not all regions known to be selectively vulnerable in neurodegenerative diseases, i.e., the hippocampus, substantia nigra, and piriform cortex.

C1q-deficient mice exhibited enhanced synaptic plasticity in the adult and reorganization of the circuitry in the aging hippocampal dentate gyrus. Moreover, aged C1q-deficient mice exhibited significantly less cognitive and memory decline in certain hippocampus-dependent behavior tests compared with their wild-type littermates.

There is presently some debate over whether or not rapamycin actually slows aging - based on rigorous studies some researchers say yes, say no, it extends life in mice but only by reducing cancer risk. Rapamycin and various derivatives under development are presently the longevity enhancing drug candidates best supported by the evidence in laboratory mice, so there is probably a lesson to be learned here in regards to the soundness of the whole strategy of trying to slow aging via metabolic manipulation.

The researcher quoted here is a vocal proponent of one of the programmed theories of aging (the hyperfunction theory), so bear that in mind while reading his defense of rapamycin. His view is that it is absolutely the case that aging can be significantly impacted by intervening in genetic programs thought to be driving it, and suitable drugs are the first step on that road. This is the reverse of other side of the aging research community who see aging as caused by accumulated damage, and the accompanying metabolic changes as a reaction to that damage rather than its cause. Nonetheless there are some interesting arguments made here:

Making headlines, a thought-provocative paper by Neff, Ehninger and coworkers claims that rapamycin extends life span but has limited effects on aging. How is that possibly possible? And what is aging if not an increase of the probability of death with age. I discuss that the JCI paper actually shows that rapamycin slows aging and also extends lifespan regardless of its direct anti-cancer activities.

Found by chance on the mystical Easter island, the anti-aging drug rapamycin gave birth to numerous myths. This time, it is claimed that rapamycin prolongs lifespan and prevents aging-associated changes by aging-independent mechanisms, not by affecting aging itself. But what is then aging itself. Aging is an exponential increase of the probability of death with age. No one has died from health or without a cause. Most elderly humans die from age-related diseases, which are also called "natural causes", if a precise diagnosis is unnecessary. In mammals, death from aging means death from age-related diseases. Not only humans and other mammals but also aging worms and flies die from pathologies.

Age-related diseases are biomarkers of aging. The most common are cardiovascular diseases (associated with atherosclerosis, hypertension and cardiac hypertrophy), cancer, diabetes (and other complications of metabolic syndrome), Alzheimer and Parkinson diseases, macular degeneration and so on. Many manifestations of aging are not considered as diseases because they either develop in everyone (e.g. female menopause. The distinction is arbitrarily. For example, cancer-prone transgenic mice can exclusively die from cancer but still cancer is a disease.

Aging processes do not spring from nothing. They are continuations of normal cellular, tissue, organ and system functions in young animals. Unless miracle is possible, rapamycin must affect the same processes in old and young animals. And it does. Rapamycin extends life span independently of its anti-cancer effect and prevents cancer by slowing down aging. If rapamycin indeed prevents cancer by slowing aging (not by killing cancer cells), the prevention must be started before cancer is initiated. In other words, if rapamycin treatment is started too late in life, then its anti-cancer effect will be blunted. This was shown in cancer-prone p53+/- mice. The same was shown by Neff et al: rapamycin did not prevent cancer when the treatment was started at middle and old age. Thus, the JCI study confirms the notion that rapamycin delays cancer by slowing aging. Anti-cancer effects simply cannot be responsible for life extension by rapamycin.

Link: http://impactaging.com/papers/v5/n8/full/100591.html

David Sinclair of Sirtris leads research on a few lines of calorie restriction mimetic drug development based on sirtuins that I don't think have a hope of significantly impacting human aging. This is a part of a broader field, that of metabolic manipulation to slow aging, that I also don't think has much of a chance to significantly impact human aging within our lifetimes. Nonetheless, Sinclair is an optimist on the future of this field - which is understandable, given his choice to pursue it, but by this point, with a lot of sunk costs and little to show for it, there may be an element of talking up his position as well.

We can expect to see people live to 120 and beyond within our lifetime, a geneticist has told Insight. Harvard University's Professor David Sinclair is working on a 'cure for ageing' and believes modern medicine can significantly extend the human lifespan. "I think there will be a world where people can look forward to living at least beyond 100, and it will be not uncommon where people can live to 120. Every time we say that there's a natural limit, we develop technology to push us further."

Simple organisms, even yeast cells and fruit flies, have 'longevity genes' that can be switched on by low calorie diets and exercise, says Professor Sinclair. When these genes are 'switched on', they can protect the organism and help them live longer. "We have many of these genes in our bodies and we're just starting to learn that they do help us live longer and healthier."

Sinclair also tells Insight there are drugs already in clinical trials and, so far, they seem to be safe and showing early signs of success. "Instead of just lowering your cholesterol this pill would prevent Alzheimer's disease, lung diseases, bowel diseases, dementia, a whole list of diseases... That's what we're able to do in mice so far. The question is: can we do that in people, and how soon? No matter how much we say that it's good for you to be thin and to exercise, it doesn't seem to help for most people [to provide the motivation to actually get up and make that effort]. If we could have a simple pill that our doctor would prescribe to take with breakfast, that could help our lifestyle. I'm not saying we should just sit on the couch and get fat and take a pill, that's not the point. But we can supplement what our bodies naturally are doing to help keep us young."

Link: http://www.sbs.com.au/news/article/2013/08/20/insight-pill-cure-ageing

With the recent publication of a fairly high profile survey on radical life extension, there has been more chatter than usual in the media and blogs on the topic of longevity science. That can only be a good thing: the more this subject is discussed, the more people will come to see healthy life extension through medical science as possible, plausible, and desirable. Greater public support is very much needed if we are to see the plausible means of human rejuvenation developed over the next few decades, soon enough to matter for those of us in the middle of life today.

Detailed plans for building therapies to lengthen the healthy human life span already exist, and a few organizations like the SENS Research Foundation are following those plans, but accomplishing this goal soon enough to matter is very much dependent on funding. There is little money for aging research in comparison to its importance to human health, let alone the small fraction of this research devoted to actually doing something about aging rather than just recording its effects or picking apart its mechanisms. Outside the work of the stem cell research community, some of which has relevance to reversal of aging, I'd be surprised to learn that more than $10 million / year is being spent on the foundations of rejuvenation therapies at this time.

(In comparison, efforts to slightly slow aging through drugs have probably consumed a billion dollars or more in the last decade, and with little to show for it. There are good reasons to think that rejuvenation research would be considerable less speculative and costly).

One thing I think that we'll see in the future is a growth in the number of media articles and public discussions that explicitly address one of the most important errors of belief regarding extending human life: people tend to think that medicine will make us older and decrepit for longer, rather than younger and healthier for longer, and this goes a long way towards explaining the lack of interest in extended life in the public at large. But this belief is false, as life extension is youth extension not old age extension. It has to be, because aging is damage at the level of cells and tissue structures, and the only meaningful ways to address aging involve repairing or preventing that damage. Less damage means that you are literally physically younger: less frail, with a lower risk of death, and greater vitality and function of your organs and biological systems.

More often these days I'm seeing media articles talk about this mistaken belief of extended frailty in the context of providing a correction: explaining that, no, researchers are in fact going to prolong youth or attempt to reverse the degenerations of aging by repairing the root causes of frailty and dysfunction. More of this sort of thing helps to lower the barrier presented by mistaken beliefs about longevity, opening the doors to greater growth in the number of people willing to materially support organizations like the SENS Research Foundation and their scientific work aimed at preventing and reversing aging and age-related disease. Here's a recent example of the sort of article I'm talking about:

Science could add decades to the average human lifespan

In a New York City laboratory, a handful of mice are poised to outlive their peers by the human equivalent of 20 years. Not only will they hang around longer, but their extended lives will be fuller. They'll recall maze patterns faster than other elderly mice. Their muscles and tendons will be stronger. Their bones will be denser, their skin more supple.

[Yet in a recent survey] more than two-thirds of Americans gave their "ideal lifespan" as between 79 and 100 years old, with just 8 per cent wanting to hit the century mark. The answers were nearly uniform across the board, with 18- to 29-year-olds being the least likely to idealize living to 100.

Dr. Gloria Gutman, who founded the Gerontology Research Centre at Simon Fraser University, suspects the tepid American response to long life was influenced by the question's lack of clarity on staying healthy. "The average person thinks in the stereotypical point of view that old means decrepit. But if you're looking at it as extending the vitality of living, then why not? If I have my mental and physical capacity, then why wouldn't I want to live to see how my kids are going to spend my money and how my grandchildren are going to turn out? ... None of us wants to be drooling in a nursing home."

At the Strategies for Engineered Negligible Senescence (SENS) Research Foundation in Mountain View, Calif., the thinking is that aging is a disease that can be controlled and "cured" through a variety of "rejuvenation biotechnologies," like a mechanic would keep a vintage car running indefinitely. The foundation spends millions of dollars a year on research to find ways to repair age-related damage to the body. An ongoing project seeks to extract "extracellular junk," malformed proteins that are no longer useful, from the brains of patients with Alzheimer's disease.

"Most people have this idea that aging is natural and sometimes desirable, and the idea that we would come along and defeat aging just doesn't compute," said the foundation's chief scientist, Dr. Aubrey de Grey, who believes aging and death are neither synonymous nor inevitable. Is he really saying immortality is possible? "Of course not, there are always trucks on the road," de Grey said to accentuate his belief that while there are many causes of death, aging does not have to be one of them.

Without aging, and with today's accident rates, we'd live for a thousand years or more. Plenty of time to figure out how to extend our healthy lives indefinitely.

When you read about a topic you know a great deal of in the mainstream media, you'll likely notice many errors and misrepresentations. You won't see that in topics you know less of, but those errors and misrepresentations are still there. A decent writer can make anything sound plausible and look good to someone only casually familiar with a field, even while he is omitting vital information or propagating outright falsehoods - either due to insufficient research or underlying agendas. Accuracy in media is fairly low in the list of priorities as a general rule.

Here is a good long-form example of the state of the art in misrepresentation of longevity science. All sorts of strategic omissions and outright misrepresentations are made on the work of specific scientists and the state of specific lines of research in those areas where I know enough to identify them, so I have to assume they are present elsewhere as well. Yet the piece reads as though a well-researched and constructed popular science article, and there's enough truth in there to float the falsehoods.

This is a time when we can grow human ears on the backs of mice and implant culture-grown lungs into rats. In the near future, specialists say, whenever we need replacement body parts, from blood vessels to bladders, we'll use rejection-proof artificial organs grown in laboratories using our own cells. "By putting in the parts you need, you'll be able to extend life by several decades," explains Anthony Atala, director of the Wake Forest Institute for Regenerative Medicine. "We may even push that up to 120, 130 years."

Bolstered by such promising discoveries, our understanding of aging is changing rapidly. Outside the field of organ regeneration, other genuine life-extending breakthroughs are being made in model test species. In 2011, Nature reported that dying worms yellow with a pigment called Thioflavin T (or Basic Yellow 1) makes them live 60 to 70 percent longer than the norm. There's more. Researchers are currently finding clues to longevity everywhere from Texan bat caves (where biochemists are investigating the role of misfolding proteins in long-lived bats) to the soil of Easter Island (where antifungal microbes known as rapamycin can raise the life expectancy of mice by 30 percent or more). Spermidine, a molecular compound found in human semen as well as grapefruit, has also been proven to significantly prolong the life span of worms, fruit flies, and yeast.

These strange-sounding experiments are yielding findings that could affect our lives. Will longevity research yield breakthroughs leading to immortality? Tinkering with the genes in yeast or roundworms has real effects on longevity in those species; that doesn't mean those genes will perform similarly in humans. And experiments on human cells in vitro do not guarantee similar functioning in vivo.

Link: http://www.salon.com/2013/08/18/live_forever_can_science_deliver_immortality/

This article is long on the human interest and short on scientific specifics, but is nonetheless an interesting look at the present state and potential for immunotherapies for cancer - one form of the coming generation of targeted cell destruction treatments. Therapies that can cure cancer in a fraction of even late stage patients have moved from the laboratory and into early trials in recent years, a progression that will continue and broaden:

Walt [was] in Philadelphia, where he'd come to be a guinea pig in a test of a new kind of cancer treatment. Leukemia had invaded his bone marrow and spread like a stain through his lymph nodes; the traditional options, including chemo and radiation, had failed. He was 58, and his body groaned with tumors potentially weighing as much as seven pounds. Walt needed something radically different if he was going to live. And the treatment he'd been given a few days ago was certainly that.

Over the past several years, a couple of hundred mice had received it, but Walt was only the seventh adult human. (Six men had preceded him, as well as a six-year-old girl.) The treatment wasn't a chemo drug, and it wasn't a vaccine. Instead, doctors at the University of Pennsylvania had tried to make Walt's own body the drug. In an approach known as gene therapy, they'd taken his own immune cells, modified them to give them new powers, and injected them back into his blood.

Scientists don't talk about "curing" cancer. A cure is the hope so great, so seemingly out of reach, that it must never be invoked. They've built a wall around the word. Still, the Penn researchers - as careful as they were, as professionally sober and skeptical - couldn't help but wonder: Was their small experiment the start of something that could one day affect thousands, tens of thousands, more? Was it revealing a secret about the human body that could point the way to treatments for other cancers, not just leukemia? There was no way to know until they gathered more data. They needed to show that the therapy was safe. And they needed to prove that the early patients - the men whose tumors they'd blasted away - weren't flukes.

Which is why so much now depended on Walter Keller. If Walt's condition improved and his tumors diminished, the trial would move forward, and the potential of the Penn therapy - the result of a decades-long quest of scientific passion and discovery - would continue to grow. But if he suffered harm, Penn would have to pause the trial and maybe stop it altogether.

Link: http://www.phillymag.com/articles/carl-june-key-fighting-cancer/

The British Science Festival will be held in Newcastle a few weeks from now. One of the events has Aubrey de Grey of the SENS Research Foundation, advocate and coordinator for rejuvenation research, debating Tom Kirkwood, one of the leading figures in the mainstream faction of the aging research community who think that there isn't much hope for rapid progress to rejuvenation. Those researchers see the best available path forward as one of modestly slowing aging through replication of known metabolic or genetic alterations associated with natural variations in longevity, such as those involved in the response to calorie restriction - but even this will be a long time in realization, a slow grind towards incremental improvements.

I agree with the viewpoint that attempts to safely slow aging in humans will be very hard indeed. Success requires a much greater understanding of metabolism and aging than presently exists, and it's not unreasonable to suggest that decades and many billions of dollars lie between us and even the first prototype drugs to slightly slow aging. However, slowing aging by altering genes and metabolism is not the only approach that can be taken - indeed it's probably the worst of viable scientific approaches to extending healthy life. It's exceedingly costly, produces marginal results, and therapies that can slow ongoing aging are of little to no use for people who are already old and frail.

In this Kirkwood represents the old mainstream of standardized drug discovery and marginal, unambitious process in medicine. De Grey represents the disruptive future of medical technology, his SENS vision and ongoing research being one of a number of entirely new paradigms for health and aging that are winning over an increasing fraction of the research community. The times are changing, and every new wave of development is met by skepticism from those in the mature industries it will replace. We should aim for rejuvenation through periodic repair of cellular damage: it will like take no longer, will quite possibly be cheaper than trying alter ourselves to slow aging, and will be very beneficial for people who are already old when these therapies are introduced.

Life Without Ageing - Two Contrasting Visions Of An Ageing World

EVENT: Life Without Ageing - Two contrasting visions of an ageing world DATE: Monday 9th September TIME: 13.00 - 14.30 VENUE: Fine Art Building Lecture Theatre, Newcastle, UK

Is a cure for ageing within reach in our own lifetimes?

Biomedical gerontologist Dr Aubrey de Grey, Chief Science Officer of the SENS Research Foundation will be joining Professor Tom Kirkwood CBE, Associate Dean for Ageing at Newcastle University to debate a 'Life Without Ageing'. In this event, chaired by Dr Sir Tom Shakespeare, Aubrey de Grey will suggest that a "cure" for ageing is within reach in our own lifetimes, while Tom Kirkwood will argue that such a goal is not only unrealistic but distorts what should be the real research priorities of an ageing world.

Dr de Grey's research proposes that eliminating ageing as a cause of debilitation and death in mankind can be achieved within just a few decades through his proposed 'Strategies for Engineered Negligible Senescence'; a term coined by De Grey in his first book The Mitochondrial Free Radical Theory. Countering this is Professor Kirkwood, a former BBC Reith Lecturer, whose research is around healthy ageing and improving life in old age by looking at the prevention of age associated factors, such as frailty, disability and age related disease, and by helping to change society's attitudes towards ageing.

The tantalising idea of living forever is as old as humanity, but can modern science really hope to consign the ageing process to history? Life Without Ageing promises to be a fascinating insight into modern day ageing research and the opposing visions of an ageing world. At the end of the debate the floor will be opened, giving the audience opportunity to put questions to the speakers and take part in what should be a lively discussion.

If you take a careful look at the festival site page for the debate, you'll see that it's possible to submit questions for the speakers. If you intend to go in person, it looks like registration is required, but it's otherwise a free event.

Technologies derived from rapid prototyping and 3-D printing will likely play an important role in the future of tissue engineering, just as they are coming to do in many fields:

The field of tissue engineering has deployed several fabrication strategies aimed at bringing cells and structure together to generate tissue. Biomaterial scaffolding - which provides structural support and can be formed into biologically relevant shapes - has been combined with cells to generate hybrid 3-D structures for use as tissue surrogates in vitro and in vivo. Protocols have been developed that enable removal of living cells from native tissues, leaving only a natural scaffolding of extracellular matrix, which can then be re-seeded with cells to reconstruct or partially reconstruct 3-D tissues. Another approach to soft tissue reconstruction has been the development of cell-laden hydrogels, which are often cast into a specific shape and placed into a permissive environment in vitro or in vivo that allows maturation and establishment of tissue-specific characteristics. In recent years, with the advancement of 3-D printing technologies for the on-demand fabrication of complex polymer-based objects, efforts have been underway to adapt 3-D printing technologies and engineer bioprinting instruments that can leverage similar 3-D replication concepts and accommodate the incorporation of living cells.

Organovo's NovoGen MMX Bioprinter precisely dispenses "bio-ink" - tiny building blocks composed of living cells - generating tissues layer-by-layer according to user-defined designs. Built for flexibility, the bioprinter enables fabrication of tissues with a wide array of cellular compositions and geometries; side-by-side comparison of multiple tissue prototypes facilitates optimization and selection of specific designs geared toward a particular application. Working within the confines of an object library, bio-ink building blocks of various shapes, sizes and compositions are assembled into architectures that recapitulate the form of native tissue. Tubes, layered sheets and patterned structures have been bioprinted, yielding 3-D tissues that are free of biomaterial scaffolding and characterized by tissue-like microarchitecture, including the development of intercellular junctions and endothelial networks.

In the short-term, 3-D human tissues are being deployed in the laboratory setting as models of human physiology and pathology; cell-based assays are a mainstay of the drug discovery and development process, and multicellular/multitissue systems may serve as more predictive indicators of clinical outcomes. Longer-term applications of 3-D tissue technologies will extend our knowledge of how to build the smallest functional units of a tissue to the fabrication of larger-scale tissues useful for surgical grafts to repair or replace damaged tissues and organs in the body. What are the next steps in the evolution of bioprinting? The first step is scaling up and down - increasing the resolution of specific features while advancing fabrication hardware and techniques to produce larger-scale tissues. The next, enhancing the complexity of designs - building the tool set that enables conceptual or visual inputs to be translated rapidly to executable bioprinting programs that select from a library of bio-ink building blocks to translate the vision into reality.

Link: http://www.rdmag.com/articles/2013/08/3-d-printing-life-science-applications

In recent years researchers have demonstrated a number of ways to improve memory in old laboratory mice. Here is another:

If you forget where you put your car keys and you can't seem to remember things as well as you used to, the problem may well be with the GluN2B subunits in your NMDA receptors. And don't be surprised if by tomorrow you can't remember the name of those darned subunits. They help you remember things, but you've been losing them almost since the day you were born, and it's only going to get worse. An old adult may have only half as many of them as a younger person.

Cognitive decline with age is a natural part of life, and scientists are tracking the problem down to highly specific components of the brain. Separate from some more serious problems like dementia and Alzheimer's disease, virtually everyone loses memory-making and cognitive abilities as they age. The process is well under way by the age of 40 and picks up speed after that. But of considerable interest: It may not have to be that way. "These are biological processes, and once we fully understand what is going on, we may be able to slow or prevent it."

In recent research [scientists] used a genetic therapy in laboratory mice, in which a virus helped carry complementary DNA into appropriate cells and restored some GluN2B subunits. Tests showed that it helped mice improve their memory and cognitive ability. The NMDA receptor has been known of for decades. [It] plays a role in memory and learning but isn't active all the time - it takes a fairly strong stimulus of some type to turn it on and allow you to remember something. The routine of getting dressed in the morning is ignored and quickly lost to the fog of time, but the day you had an auto accident earns a permanent etching in your memory.

Within the NMDA receptor are various subunits, [and] research keeps pointing back to the GluN2B subunit as one of the most important. Infants and children have lots of them, and as a result are like a sponge in soaking up memories and learning new things. But they gradually dwindle in number with age, and it also appears the ones that are left work less efficiently. "The one thing that does seem fairly clear is that cognitive decline is not inevitable. It's biological, we're finding out why it happens, and it appears there are ways we might be able to slow or stop it, perhaps repair the NMDA receptors. If we can determine how to do that without harm, we will."

Link: http://oregonstate.edu/ua/ncs/archives/2013/aug/cognitive-decline-age-normal-routine-%E2%80%93-not-inevitable

The SENS Research Foundation coordinates and conducts research into the baseline technologies needed for human rejuvenation. We age because we become damaged: cells and the structures between cells accumulate broken proteins, waste products, and other forms of harm. The machines of our cells run down, run amok, and run ragged. Eventually that kills us, as damage overwhelms self-repair, but this ugly process of aging to death could be indefinitely postponed given effective means of repairing the forms of damage that are fundamental, those that result from nothing more than the ordinary operation of human metabolism.

SENS stands for the Strategies for Engineered Negligible Senescence, and is a detailed set of theories and supporting evidence regarding which forms of damage and change identified in the old actually cause aging, combined with research plans to develop the foreseeable means to repair these fundamental forms of damage. SENS is a guide to lead us from today, a time in which the research community finally knows enough to be able to lay out a plan like this in detail, to a tomorrow of realized prototype therapies that can rejuvenate old laboratory animals such as mice.

If fully funded to a level of $100 million / year or so, then SENS is a ten to twenty year project, involving the creation of a large new research community and public support to rival that of the cancer research edifice. It might sound like a massive, unobtainable amount of money, but bear in mind that the National Institute on Aging spends ten times amount that as a yearly budget, a single company engaged in not-so-great-in-the-end research on a single type of drug to slightly slow aging sold for $700 million, and neither of those examples offers any great hope of producing meaningful change in the aging process. To a first approximation the NIA are not funding interventions, only investigations, and much of that work is largely irrelevant in comparison to what might be done by ambitious, funded researchers. Such is life: in large-scale institutions mediocrity rules, and ambitious, high risk work that might produce great change is largely going to go unfunded.

At the end of the SENS road we will have the first form of a medical toolkit to reverse aging - an event that could happen in time to help most of those reading this today. Yet there is still little funding for SENS research: a few million dollars a year, derived from community support and philanthropic donors such as Peter Thiel and Aubrey de Grey. This level of funding will have to increase greatly if we are to see the promise of SENS realized.

In advance of the forthcoming SENS6 conference, the SENS Research Foundation has released their 2013 research report, which as always makes for interesting reading.

SENS Research Report 2013 (PDF)

In May of 2012, a 10-year-old girl was suffering in hospital with a blockage in her portal vein - the major blood vessel that brings nutrients from the digestive tract into the liver. Bypassing the risks of transplantation, Swedish doctors engineered the girl a new, custom replacement. Drawing from earlier human successes with engineered tracheas, a donor's blood vessel was stripped of its cells.The resulting scaffold was seeded with stem cells from the girl's bone marrow, and chemical signals were then used to encourage the cells to grow into a functional portal vein. Thanks to the engineered vessel, the girl's blood tests have normalized, and she is now capable of light gymnastics and mile-and-a-half walks.

This groundbreaking achievement is just one example of what can emerge from a few years of rapid progress in animal models and other precedent-setting tissue engineering projects. It is also an example of the type of work SENS Research Foundation is funding with the goal of applying it to a primary problem of aging: the decline of the immune system. Only a few of us will ever need a new portal vein or trachea - but nearly all of us will need a new thymus, which plays an indispensible role in the immune system. The fine structures and functioning cells of the thymus we were born with will slowly degenerate between our teen years and our sixties; as the organ begins to fail with age, we become increasingly vulnerable to influenza and other common infectious diseases. With SRF support, Wake Forest Institute of Regenerative Medicine researchers are now making rapid progress in work to apply the decellularized-recellularized scaffold method to the thymus in animal models. SRF is excited to be spearheading the adaptation of existing techniques to geriatric medicine, where innovation is so sorely needed. But we know that this alone is not enough to address the emerging health crisis posed by age-related disease, which has surpassed infectious disease as the most pressing health problem facing humanity today.

SENS Research Foundation is currently the only research nonprofit pushing the boundaries of the field toward the molecular level, where much of the damage of aging resides. Treating the symptoms of the resulting pathologies can only take us so far, because the body's repair and maintenance mechanisms continue to deteriorate. SRF's unique dedication to identifying and alleviating the damage that long precedes pathology serves as the basis for much of our work. Our longest-running project in this vein targets age-related macular degeneration, the leading cause of blindness in people over the age of 65. Macular degeneration is caused by the accumulation of a toxic byproduct of the visual cycle called A2E, which builds up in the retinal pigment epithelial (RPE) cells responsible for maintaining the light-sensing cells of the eye. We are working to preserve and restore the health of these cells by fortifying them with new, engineered enzymes capable of clearing A2E deposits. In 2012, scientists in our Research Center identified an enzyme (SENS20) that has since demonstrated efficacy in degrading A2E not only in vitro, but in RPE cells administered an A2E "stress test."

These two critical-path projects, as well as the others described in this Research Report, reflect our ongoing mission to transform the way the world researches and treats age-related disease. Our commitment to developing the industry of restorative medicine begins with proof-of-concept work - but ultimately rests upon creating the rejuvenation biotechnologies that can actually cure these diseases. To accomplish this, in addition to funding and conducting more research into the health problems of aging, we must realize a shift in how these health problems are conceptualized. We must move from seeing age-related illnesses as discrete entities to acknowledging that as we grow older, we become progressively more vulnerable to every single age related disease that exists, because we are all accumulating damage at levels no form of medicine can presently touch. When we reimagine aging, we envision a world where the damage preceding pathology is recognized as a treatable condition in and of itself, and addressed accordingly. SRF is delighted to share our progress toward this end in this Research Report. We hope you will join us in taking the tremendous opportunity at hand to set the new standard for twenty-first century medical research and development.

SENS and the SENS Research Foundation are the seed for what will become the core, central pillar of medicine in the decades ahead. Nothing will be as important to health as maintaining youth by periodic repair of cellular damage. Just like antibiotics today, that will be the primary barrier that stands between us and the ubiquitous suffering and mortality that preceded it. The greater the support given to SENS and SENS-like research, the faster we get to that point.

Mitochondria are the power plants of the cell, generating chemical fuel stores that can be used to power cellular processes. They are important in aging, and this has a lot to do with the generation of reactive oxygen species (ROS) that happens as a side-effect of their operation. Researchers have shown that benefits to health and longevity can be realized in laboratory animals by targeting antioxidants to mitochondria in order to soak up some ROS before they cause harm. Other research focuses on repairing the damage that mitochondria inflict upon themselves this way, so as to stop it from contributing to degenerative aging.

There is general agreement that mitochondria play an important role in the aging process, but the role of mitochondrial oxidative stress remains controversial. Most previous work looking at mitochondrial oxidative stress has focused on damage to DNA, proteins, and lipids with age or in response to manipulation of cellular antioxidants. The interaction between oxidative damage and aging has been called into question in recent years by studies demonstrating little effect on aging and lifespan in mice with genetically modified antioxidant systems. A notable exception is the life extension and protection against multiple diseases in mice that express catalase in the mitochondria, which suggests that the cellular location and type of reactive oxygen species is an important factor.

Our laboratory is interested in whether redox inhibition of mitochondrial function contributes to age-related energy deficits in vivo in mouse and human skeletal muscle. [We] tested this hypothesis using a mitochondrial targeted peptide, SS-31, known to reduce mitochondrial H2O2 production.

SS-31 reduced the high mitochondrial H2O2 production from aged permeabilized muscle fibers [but] had no effect on young fibers. In the aged mice, one hour after in vivo treatment with SS-31 the cellular redox status [was] more reduced. This was accompanied by improved mitochondrial [function] in vivo in the skeletal muscle, while there was no effect on the mitochondrial energetics in young skeletal muscle. In addition to the improvements in muscle energetics, one hour and one week of SS-31 treatment resulted in improved muscle performance and increased exercise tolerance, respectively, in the old mice.

This rapid reversal of in vivo energy deficits supports the hypothesis that mitochondrial deficits in aged skeletal muscle are, at least in part, due to reversible redox sensitive inhibition. Thus assessing the role of mitochondrial oxidative stress in aging and disease will require careful attention to changes to the in vivo redox environment and the mechanisms by which these changes can affect cell function.

Link: http://impactaging.com/papers/v5/n8/full/100590.html

The sixth Strategies for Engineered Negligible Senescence conference will be held in September, the latest in a series of conferences devoted to rejuvenation biotechnology, building the means to reverse aging:

The world's leading series of conferences dedicated to the prevention and treatment of the diseases of aging using regenerative medicine will hold its next installment later this year. The conference, entitled "SENS6: Reimagine Aging," will be held from September 3-7, 2013 at Queens' College, Cambridge, UK. As part of the biennial SENS conference series, SENS6 will be presented by SENS Research Foundation (SRF), a biomedical research charity.

"What makes the SENS conferences different is the way they unite experts on every major aspect of aging," said Dr. Aubrey de Grey, SRF's Chief Science Officer. "These conferences are a place where we talk about solutions: repairing the damage that underlies each of these diseases. You won't find that comprehensive, practical approach discussed anywhere else - though, of course, we're doing our best to change that."

Topics covered at the conference will include heart disease, cancer, cellular senescence, age-related dysfunction of lysosomes and mitochondria, and advances in gene delivery. "Based on how far we've already come, as this meeting will show, I'm extremely optimistic about the progress that the scientific community will make in all of these areas in the coming decades," added Dr. de Grey.

The keynote address will be delivered by Harvard's Dr. George Church, a world-leading luminary in genomics. Other top speakers include MIT's Todd Rider, Cambridge's Robin Franklin, Carnegie Mellon's Alan Russell, and the McGowan Institute's Eric Lagasse.

Link: http://sens.org/outreach/outreach-blog/press-release-preeminent-aging-research-conference-takes-aim-all-age-related

Why undertake advocacy aimed at persuading wealthy individuals to support your cause? Well, for one, that's where most of the money is. There is the thought that if you have to go to a certain amount of work to persuade a given individual, then why not aim to persuade the individuals who can afford give more as supporters? Why spend a hundred times the effort to persuade a hundred people if you can obtain a thousand times more in the way of resources and publicity by persuading one?

A Letter to Sergey Brin

Dear Mr. Brin,

I've heard you are interested in the topics of aging and longevity. This is very cool, because fighting for radical life extension is the wisest and most humanitarian strategy. I would like to tell you what needs to be done, but, unfortunately, I haven't got your email address, or any other way to be heard. 100,000 people die from aging-related causes every day, but what makes the situation even worse is that the scientists know how to tackle this problem, but don't have clue how to convey their message to those people, who could change the situation and make the creation of human life extension technologies possible. Therefore, I am simply writing in my blog, hoping, that maybe somehow you will read this letter, or that maybe my friends will give me some advice on how it could be delivered to you, or that maybe someone would send it to you.

I think there's a little broken logic in there somewhere, however. Convincing a millionaire to meaningfully support a cause is a long way distant from talking to the average fellow in the street. Moving up another few levels of wealth, convincing a billionaire is more like holding a significant business negotiation with a company: people who have risen to that level are no longer really sovereign individuals with a bank account, but more akin to tribal leaders, with obligations, councils of advisors, processes to follow, and fiefdoms to defend. Even gaining a moment of attention is a tremendous effort.

From a psychological point of view, there is also the hurdle alluded to in the title of this post. No-one really likes to be told to their face that they need to sort themselves out and devote funds to a specific cause. It creates an instinctively defensive reaction. Further, no wealthy person is without a full slate of obligations, long-term plans, and petitioners already. They have put a great deal of thought and energy into maintaining the processes of their wealth. Why listen to random talking heads who haven't the faintest idea of what it is to take on that work and that responsibility, and why bother to pick out talking head A from talking head B when the likelihood is that they're all full of it? To be wealthy is to have innumerable would-be parasites attracted by the possibility of nibbling away at the edges, and picking out the legitimate causes and honest individuals from the masses is a real challenge. Wealth is a cloud that blinds you in many ways.

This is why I think that while it is certainly tempting to adopt a strategy that consists entirely of persuading high net worth individuals, it's actually far better in the long run to carry though the hard work of persuading as many people as possible, regardless of their wealth and ability to materially support the cause. There is a method to this: what best persuades wealthy individuals and the leaders of funds and companies is (a) social proof and (b) plain old success. The way to open the door to be considered seriously by people who conservatively manage large amounts of money is to already have widespread support: be talked about, have thousands of supporters, have raised millions from the community, have books and films published on the cause, and so on.

Wealth and the wealthy really only follow success on the large scale. They arrive at the point at which they would have been really helpful a few years back, turning up after the long and painful bootstrapping has been accomplished. It is the rare individual, such as Peter Thiel, who makes a serious effort to buck this trend and create greater progress by taking greater risks, by being less conservative, by not following the herd.

I think that knowledge of and support for radical life extension are on the curve that leads to widespread adoption. It's still very early, though: we haven't even really reached the 10% tipping point at which persuasion becomes an avalanche heading into the cultural mainstream. These are the years in which we keep plugging away at persuasion, fundraising, and education - in the knowledge that we are many millions of dollars further ahead of the game, with far more of the most important rejuvenation research underway, albeit on a small scale, than was the case a decade ago. Keep up the work and ten years from now we'll be even further ahead.

Here is an interesting view on the process of final decline and fatal systems failure due to damage and maladaptive responses to damage that occurs at the end of aging:

As we get older we become more likely to get sick and, eventually, die. Although the underlying pathologies and major causes of death in elderly humans have been well documented, much less is known about the events leading to age-related death in the fruit fly Drosophila melanogaster - one of the premier model systems in aging research. What is the underlying pathology that limits the lifespan of a fly? Is it possible to predict when a fly will die based upon a loss of organ function? What accounts for the enormous variation in lifespan amongst individual flies within a population? Recently, we have identified a physiological phenotype preceding death in Drosophila that allows us to identify, in any given population, individuals that will die in the next few days.

In this work, we show that all individuals show an altered control of intestinal permeability a few days prior to death regardless of chronological age. Interestingly, these same individuals also showed a striking increase in the expression of inflammatory markers (antimicrobial peptides, AMPs) as well as systemic metabolic defects, including impaired insulin/insulin-like growth factor signaling (IIS). Importantly, we observed that chronologically age-matched individuals, from the same population, without altered intestinal permeability do not show major changes in these parameters with age. This discovery suggests that, in Drosophila at least, these different phenotypes are tightly linked to one another and to the end of life. Indeed, we could independently identify flies that would die within a few days by selecting for increased AMP expression, and these flies showed systemic metabolic defects, including impaired IIS, and intestinal barrier failure.

One interpretation of these findings, consistent with the 'hyperfunction theory of aging', is that the overactivity of AMPs is driving pathology and directly leading to death. Alternatively, increased AMP expression may represent a benign marker of impending death, which may result, in large part, from other factors such as a loss of intestinal homeostasis and/or systemic metabolic dysfunction.

As well as highlighting an important link between intestinal aging and organismal aging, this work may be telling us something about the very nature of the aging process itself. Our findings support a model where aging is composed of two consecutive phases, a first phase characterized by a growing likelihood of displaying intestinal barrier failure / inflammation / systemic metabolic dysfunction followed by a second phase leading to death. Remarkably, recent work [has] shown that intestinal cell death precedes organismal death in C. elegans, through a calcium-propagated necrotic wave. Furthermore, a chronic state of inflammation and the development of insulin resistance are key hallmarks of human aging and have been linked to multiple age-onset diseases. Therefore, our findings, in Drosophila, may provide insight into the relationships between intestinal homeostasis, systemic aging and disease susceptibility in mammals.

You might consider this in the context of past research that has shown that altering PGC-1 in intestinal tissues only, thereby apparently increasing stem cell activity and improving mitochondrial function in the intestine, is enough to increase life span in flies by up to 50%.

Link: http://impactaging.com/papers/v5/n8/full/100589.html

Researchers here demonstrate a way to greatly increase the number of cancer-targeted viruses that can be safely infused into a patient. By disabling the ability of the virus to self-replicate they prevent it from causing dangerous side-effects:

The researchers used a specific method and dose of UV light to transform regular replicating viruses into unique particles that could no longer replicate and spread, but could still enter cancer cells efficiently, kill them and stimulate a strong immune response against the cancer. These particles were able to kill multiple forms of leukemia in the laboratory, including samples taken from local patients who had failed all other therapies. Normal blood cells were not affected. This novel treatment was also successful in mouse models of leukemia. In fact, 80 per cent of the mice that received the therapy had markedly prolonged survival and 60 per cent were eventually cured, while all of the untreated mice died of their leukemia within 20 days.

Rhabdoviruses (RVs) are currently being pursued as anticancer therapeutics for various tumor types, notably leukemia. However, modest virion production and limited spread between noncontiguous circulating leukemic cells requires high-dose administration of RVs, which exceeds the maximum tolerable dose of the live virus. Furthermore, in severely immunosuppressed leukemic patients, the potential for uncontrolled live virus spread may compromise the safety of a live virus approach.

We hypothesized that the barriers to oncolytic virotherapy in liquid tumors may be overcome by administration of high-dose non-replicating RVs. We have developed a method to produce unique high-titer bioactive yet non-replicating rhabdovirus-derived particles (NRRPs). This is the first successful attempt to eradicate disseminated cancer using non-replicating virus-derived particles, and represents a paradigm shift in the field of oncolytic virus-based therapeutics. Through in silico and in vitro testing, we demonstrate that NRRPs, analogous to live virus, are tumor selective, given that they exploit defects in innate immune pathways common to most tumors. However, this platform is unencumbered by the principle safety concern associated with live virus replication, that is, the potential for uncontrolled viral spread in immunocompromised patients. Indeed, the superior safety margin afforded by the NRRP platform was exemplified by the observation that high-titer intracranial NRRP administration was well tolerated by murine recipients.

Here we establish that NRRPs exhibit both direct cytolytic and potent immunogenic properties in multiple acute leukemia models. A peculiar form of programmed cell death involves the induction of adaptive immune responses against the dying cell. This process, commonly referred to as immunogenic apoptosis, is essential to the efficacy of several current chemotherapeutics and is required for host defense against viral infection including live RVs. Our in vivo results indicate that a similar process is induced by NRRPs and is a driving factor for treatment efficacy.

Link: http://dx.doi.org/10.1038/bcj.2013.23

Decellularization is the process of taking a complex organ or other tissue structure and stripping the cells from it, leaving behind the supporting extracellular matrix. The matrix can then be repopulated by new cells of the appropriate types in order to recreate a functional organ. This is in any case is the end goal of this ongoing line of research: decellularization has been used in recent years to produce tracheas and heart valves for transplantation, populating the tissue with the recipient's own cells so as to eliminate the possibility of rejection.

A trachea is a comparatively simple structure, however. Just as for tissue engineering of organs from scratch, there are hurdles to be overcome in making decellularization a practical option for organs and tissues that are more functional than structural: lungs, livers, hearts, for example While it is certainly the case that decellarization is lot closer to practical application for heart engineering than building a heart from a patient's own stem cells using bioprinting technologies, or other from-scratch strategies, there is work yet to be done. See this latest research, for example, in which a beating mouse heart is produced, but not one that performs well enough to be a transplant candidate:

Decellularized Mouse Heart Beats Again After Regenerating With Human Heart Precursor Cells

For the project, the research team first "decellularized," or removed all the cells, from a mouse heart, a process that takes about 10 hours using a variety of agents. Then, they repopulated the remaining heart framework, or scaffold, with [human] multipotential cardiovascular progenitor (MCP) cells. These replacement cells were produced by reverse engineering fibroblast cells from a small skin biopsy to make induced pluripotent stem cells and then treating the iPS cells with special growth factors to further induce differentiation.

"This process makes MCPs, which are precursor cells that can further differentiate into three kinds of cells the heart uses, including cardiomyocytes, endothelial cells and smooth muscle cell. Nobody has tried using these MCPs for heart regeneration before. It turns out that the heart's extracellular matrix - the material that is the substrate of heart scaffold - can send signals to guide the MCPs into becoming the specialized cells that are needed for proper heart function."

After a few weeks, the mouse heart had not only been rebuilt with human cells, it also began contracting again, at the rate of 40 to 50 beats per minute, the researchers found. More work must be done to make the heart contract strongly enough to be able to pump blood effectively, and to rebuild the heart's electrical conduction system correctly so that the heart rate speeds up and slows down appropriately.

"One of our next goals is to see if it's feasible to make a patch of human heart muscle. We could use patches to replace a region damaged by a heart attack. That might be easier to achieve because it won't require as many cells as a whole human-sized organ would."

Other research teams have prototyped heart patches via decellularization in recent years. It seems to be a popular choice of stepping-stone product for use in medicine, a waypoint on the road to rebuilding hearts completely. There is more competition here from researchers who aim to grow tissues from scratch, however, as they too have demonstrated the ability to create prototype heart patches. So while I don't think that there's any great doubt that decellularization will reach the clinic for whole organs in advance of tissue engineered solutions, it's a different story for smaller and less complex tissue masses.

Measures of health in old age and measures of mortality and longevity should all stem from the same root causes: the state of cellular damage, the integrity of repair systems, decline in function of organs, and so on. So if one of these general measures is shown to be inherited to a given degree, you'd expect the rest to be similarly heritable.

Longevity-associated genes may modulate risk for age-related diseases and survival. The Healthy Aging Index (HAI) may be a subphenotype of longevity, which can be constructed in many studies for genetic analysis. We investigated the HAI's association with survival in the Cardiovascular Health Study and heritability in the Long Life Family Study.

The HAI includes systolic blood pressure, pulmonary vital capacity, creatinine, fasting glucose, and Modified Mini-Mental Status Examination score, each scored 0, 1, or 2 using approximate tertiles and summed from 0 (healthy) to 10 (unhealthy). In Cardiovascular Health Study, the association with mortality and accuracy predicting death were determined with Cox proportional hazards analysis and c-statistics, respectively. In Long Life Family Study, heritability was determined with a variance component-based family analysis using a polygenic model.

Cardiovascular Health Study participants with unhealthier index scores (7-10) had 2.62-fold greater mortality than participants with healthier scores (0-2). The HAI alone predicted death moderately well and slightly worse than age alone. Prediction increased significantly with adjustment for demographics, health behaviors, and clinical comorbidities. In Long Life Family Study, the heritability of the HAI was 0.295 overall, 0.387 in probands, and 0.238 in offspring.

Link: http://www.ncbi.nlm.nih.gov/pubmed/23913930

A little while back a mainstream media entity published a discussion on longevity between Aubrey de Grey of the SENS Research Foundation, an organization working on the foundation for rejuvenation biotechnology, and Walter Bortz, a long-time advocate for a better approach to health and aging, but a skeptic on the development of new and radically more effective ways to intervene in the aging process. This is a later opinion piece in which Bortz comments on the discussion and de Grey replies in the comments:

Bortz:

We had never met each other, but knew ourselves by reputation. Our interface is similar to one that exists between two senior gerontologists Steve Austad and Jay Olshansky. They have bet $1 million that someone will live to be 150 within their lifetimes. Austad bets "yea," Olshansky, "nay." Jay in fact argues that if we don't get a handle soon on our obesity epidemic we will all live less long than our parents.

De Grey actually pushed back from the immortality label, much preferring the more modest "rejuvenation" tag. His, and Austad's, argument simply put is: Given the rapid progress in molecular biology of the past two decades then it is logical to extrapolate to the conclusion that soon several decades may be added to our current estimate of a 120-year max lifespan.

I follow these various suggestions closely, but find their excitement to be curtailed by realism. My take on all of this is based on my devotion to the Second Law of Thermodynamics that roughly states everything in an open system goes inevitably to greater disorder due to heat loss and entropy. No exceptions allowed. Time has only one direction.

An important codicil to this resides in the fitness advocacy that I favor. This asserts that aging may be slowed but not arrested. Fitness confers a 30 year delay in decay. A fit person of 80 is biologically the same as the unfit person of 50. So De Grey and I agreed to disagree. I am secure in my advocacy of 100 healthy years that I insist is currently within our biologic and political realms. De Grey hopes for more.

I like to see myself as an optimist. Norman Cousins said that "no one is smart enough to be a pessimist," but optimism must be tempered always by reality. To me this means that the Second Law of Thermodynamics rules. Even rejuvenation must obey that law. There is no, and won't be, a perpetual motion machine. We, and everything else, wear out. Sci-fi is sci-fi.

de Grey:

It was indeed an enjoyable conversation. It had a few gaps, though, which didn't make it into the printed piece. One was that I never quite learned how the validity of the second law of thermodynamics as a reason why rejuvenation is fantasy can be reconciled with the fact that babies are born young.

As for Walter being an optimist, yes, that's also how Jay Olshansky likes to label himself. The most dangerous pessimists, in my view, are the ones who think of themselves as optimists, because they infer that anyone more optimistic than themselves is a fantasist and their work unworthy of study detailed enough to deliver accurate evaluation. But I'm sure we will meet again!

The second law of thermodynamics is mentioned, but I think that this is often misunderstood - even by scientists - and has little importance in considerations of aging and rejuvenation. It is perfectly possible to take an open system and impose order so as to reduce its level of entropy. This happens all the time, and we are surrounded by examples of it in practice, both in the natural world and in our technology. Repair is only one form of entropy reduction, but we humans manage well enough in any number of system.

Link: http://www.huffingtonpost.com/walter-m-bortz-ii-md/dare-to-be-100-everything_b_3714118.html

I'm not convinced by the idea that mainstream art drives attitudes. To my eyes art is simply another form of conversation, and conversations reflect the current distribution of opinions in the melting pot. Pick one thread at random and it will be unusual in its own ways, pick a hundred and the majority will look roughly the same, sharing many commonalities. The more money involved and the larger the conversation the more it will blend to the average, seeking success through being palatable (or at least unoffensive) to as many people as possible, or successful through having already become broadly palatable.

So we should look at mass art for more of what people are thinking now, or at least what people want you to think they think in order to blend in to what they believe are the majority opinions. The largest cultural currents are full of chameleons trying to blend in, even when that goes against their vested interests: we humans like our hierarchies and social acceptance, perhaps too much for our own good. Consider support for longevity science and extending the healthy human life span, for example. The chameleon who supports healthy life extension today can really only blend in by denying it. This is unfortunate on many levels, not least of which being that support is needed to help make rejuvenation therapies a reality sometime soon, and can only be changed by the slow process of convincing people the old-fashioned way: one by one, with articles, with conversation. Advocacy is a matter of changing the environment to become a new normal, repainting the room one small brushstroke at a time.

What reassurances do the community need regarding life extension? Evidence from studies of community attitudes and an analysis of film portrayals

It is increasingly recognised that community attitudes impact on the research trajectory, entry and reception of new biotechnologies. Yet biogerontologists have generally been dismissive of public concerns about life extension. There is some evidence that biogerontological research agendas have not been communicated effectively, with studies finding that most community members have little or no knowledge of life extension research. In the absence of knowledge, community members' attitudes may well be shaped by issues raised in popular portrayals of life extension (e.g. in movies). In order to investigate how popular portrayals of life extension may influence community attitudes I conducted an analysis of 19 films depicting human life extension across different genres. I focused on how the pursuit of life extension was depicted, how life extension was achieved, the levels of interest in life extension shown by characters in the films, and the experiences of extended life depicted both at an individual and societal level.

Mainstream movies will likely be the last of the great mass media to survive our present explosion of diversity in culture. The economics of the business are so gargantuan that it will take greater tides to wash them away that we'll see in the next few decades. But since the population at large are more or less opposed to living longer - at least in public, where the chameleons have to stay dressed up - you can expect to see that same level of opposition expressed in the movies. So it's usually the case that life extension is punished as hubris, given crippling disadvantages, made a curse, and so forth. When you write the story you can do what you want, regardless of the plausibility: it only has to find a receptive audience who have the same incorrect intuitions about the way the world works.

This isn't propagation of ignorance and mistaken attitudes, it's only a reflection of what already exists. If the average fellow in the street was in favor of longevity science, then the average movie plot would support that view.

Monolithic cultural blocks are disintegrating at an increasing pace given the greater ability for people to communicate and organize through the internet. Walk beyond the mass media and you'll find any number of positive portrayals of radical life extension, assumed and issued as a matter of course. In modern written science fiction great longevity is often a non-event - characters live for centuries or millennia because that is the logical outcome of advanced medical technology. We are biological machines, we can be improved, repaired, and rejuvenated, and this is remarked upon to the same degree as the color of the walls: no big deal, a long-accepted trope, let's move on to talk about the interesting new stuff. For examples, you might look at the works of Greg Egan, the late Iain M. Banks, Alastair Reynolds, Vernor Vinge, and so forth.

The membrane pacemaker hypothesis suggests that longevity is heavily influenced by the composition of mitochondrial membranes, and thus their resistance to oxidative damage. The details of mitochondrial structure and operation correlate strongly with variations in longevity between species, and minor genetic variations between individuals within a species may also correlate with natural variations in longevity, though the evidence for that is less compelling. Damage to mitochondrial DNA is implicated as one of the root causes of degenerative aging, however, and issues with mitochondrial function show up in many of the common age-related diseases.

That mitochondria are so influential in aging means that we should place a high priority on the development of means to repair and replace mitochondria in old tissues, and thus remove whatever contribution to degenerative aging is caused by this damage. Here is a little more evidence that supports the membrane pacemaker hypothesis:

Our studies revealed that lithocholic acid (LCA), a bile acid, is a potent anti-aging natural compound that in yeast cultured under longevity-extending caloric restriction (CR) conditions acts in synergy with CR to enable a significant further increase in chronological lifespan. Here, we investigate a mechanism underlying this robust longevity-extending effect of LCA under CR. We found that exogenously added LCA enters yeast cells, is sorted to mitochondria, resides mainly in the inner mitochondrial membrane, and also associates with the outer mitochondrial membrane.

LCA elicits an age-related remodeling of glycerophospholipid synthesis and movement within both mitochondrial membranes, thereby causing substantial changes in mitochondrial membrane lipidome and triggering major changes in mitochondrial size, number and morphology. In synergy, these changes in the membrane lipidome and morphology of mitochondria alter the age-related chronology of mitochondrial respiration, membrane potential, ATP synthesis and reactive oxygen species homeostasis.

The LCA-driven alterations in the age-related dynamics of these vital mitochondrial processes extend yeast longevity. In sum, our findings suggest a mechanism underlying the ability of LCA to delay chronological aging in yeast by accumulating in both mitochondrial membranes and altering their glycerophospholipid compositions. We concluded that mitochondrial membrane lipidome plays an essential role in defining yeast longevity.

Link: http://www.impactaging.com/papers/v5/n7/full/100578.html

Infusions of massive numbers of immune cells is a promising strategy for treating many conditions, as well as being something that would probably benefit any old person as a periodic compensation for the decline in the aging immune system. The technologies to enable this sort of therapy are falling into place:

Scientists have combined the ability to reprogram stem cells into T cells with a recently developed strategy for genetically modifying patients' own T cells to seek and destroy tumors. The result is the capacity to mass-produce in the laboratory an unlimited quantity of cancer-fighting cells that resemble natural T cells, a type of white blood cell that fights cancer and viruses. In a [recent study] researchers show that the genetically engineered cells can effectively wipe out tumors in a mouse model of lymphoma.

[Researchers] isolated T cells from the peripheral blood of a healthy female donor and reprogrammed them into stem cells. The researchers then used disabled retroviruses to transfer to the stem cells the gene that codes for a chimeric antigen receptor (CAR) for the antigen CD19, a protein expressed by a different type of immune cell - B cells - that can turn malignant in some types of cancer, such as leukemia. The receptor for CD19 allows the T cells to track down and kill the rogue B cells. Finally, the researchers induced the CAR-modified stem cells to re-acquire many of their original T cell properties, and then replicated the cells 1,000-fold.

"By combining the CAR technology with the iPS technology, we can make T cells that recognize X, Y, or Z. There's flexibility here for redirecting their specificity towards anything that you want." Yet questions remain about exactly what kind of cell the researchers created. [The researchers] used gene expression microarrays to compare the mRNA expression profiles of the engineered T cell precursors with several types of natural T cells from the female donor. The analysis revealed that the engineered cells more closely resemble the gd T cell subtype that is involved in an initial broad-spectrum immune response, rather than the αβ subtype, the so-called adaptive subtype, which is slower to respond, but retains a memory of its exposure to various antigens.

Link: http://www.the-scientist.com/?articles.view/articleNo/36994/title/Tumor-Targeting-T-Cells-Engineered/

There are many comparatively simple genetic alterations that enable animals of various different laboratory species to live between 10% to 60% longer. These are changes to the operation of metabolism: perhaps more autophagy, perhaps less fat tissue, perhaps fat tissue that behaves slightly less maliciously, perhaps a more resilient immune system, and so forth. The list is long and getting longer with each passing year as researchers continue to investigate the genetics of aging and longevity.

Here is a question: if all these changes are so simple, just minor genetic alterations, how is it that evolution failed to get there first? Why is it that researchers can alter the mouse genome in many different ways to extend the lives of laboratory mice? Why is the local optimal evolved state of the modern mouse short-lived in comparison to a great many close, easily-reached neighboring states?

The answer to these questions is that additional longevity is only one of many possible advantages to be obtained in evolutionary competition, and probably not a terribly good advantage in the grand scheme of things. In theory, and if individuals successfully evade natural hazards and predators, a longer life span means that a lineage can outbreed its competitors over time. Judging by the fact that very few species are unusually long-lived in comparison to their peers, however, we might conclude that longevity is only rarely more beneficial than other strategies for evolutionary success.

When researchers examine long-lived mutant mice, worms, and other short-lived species, they see signs that these lineages would be outmatched in the wild. Minor genetic changes to enhance longevity, even ones such as improved cellular maintenance that seem wholly beneficial, are not free. They come with attached costs in terms of success in the only game that matters over evolutionary time, which is the competition to propagate copies of your genome.

Hormesis and longevity with tannins: Free of charge or cost-intensive?

Hormetic lifespan extension is, for obvious reasons, beneficial to an individual. But is this effect really cost-neutral? To answer this question, four tannic polyphenols were tested on the nematode Caenorhabditis elegans. All were able to extend the lifespan, but only some in a hormetic fashion.

Additional life trait variables including stress resistance, reproductive behavior, growth, and physical fitness were observed during the exposure to the most life extending concentrations. These traits represent the quality of life and the population fitness, being the most important parameters of a hormetic treatment besides lifespan. Indeed, it emerged that each life-extension is accompanied by a constraining effect in at least one other endpoint, for example growth, mobility, stress resistance, or reproduction. Thus, in this context, longevity could not be considered to be attained for free and therefore it is likely that other hormetic benefits may also incur cost-intensive and unpredictable side-effects.

Laboratory selection for increased longevity in Drosophila melanogaster reduces field performance

Drosophila melanogaster is frequently used in ageing studies to elucidate which mechanisms determine the onset and progress of senescence. Lines selected for increased longevity have often been shown to perform as well as or superior to control lines in life history, stress resistance and behavioural traits when tested in the laboratory. Functional senescence in longevity selected lines has also been shown to occur at a slower rate.

However, it is known that performance in a controlled laboratory setting is not necessarily representative of performance in nature. In this study the effect of ageing, environmental temperature and longevity selection on performance in the field was tested. Flies from longevity selected and control lines of different ages (2, 5, 10 and 15 days) were released in an environment free of natural food sources. Control flies were tested at low, intermediate and high temperatures, while longevity selected flies were tested at the intermediate temperature only. The ability of flies to locate and reach a food source was tested.

Flies of intermediate age were generally better at locating resources than both younger and older flies, where hot and cold environments accelerate the senescent decline in performance. Control lines were better able to locate a resource compared to longevity selected lines of the same age, suggesting longevity comes at a cost in early life field fitness, supporting the antagonistic pleiotropy theory of ageing.

If you are a member of a species with access to advanced medical technology, none of this much matters any more, of course. The future of longevity under those circumstances is determined by progress in technology rather than evolution: natural selection just sets the scene, and ensures that we are all dissatisfied with the hand we have been dealt.

I had somehow missed this event from earlier in the year, a provocative (by mainstream standards) ad campaign mounted by a portion of the insurance industry: "The First Person To Live To 150 Is Alive Today." I take the existence of such a campaign as a sign of progress in ongoing efforts to spread the twofold message that (a) much longer lives are possible in the future, and (b) it is necessary to support the research process in order to make this happen soon enough to matter to you and I. Most of the children born today in wealthier parts of the world will have the opportunity to live for centuries at the very least, but the odds of people presently in mid-life are far more dependent on the pace of medical progress, and whether or not the right research strategies are nurtured.

By the side of an expressway the other afternoon, I saw a billboard paid for by Prudential, the big insurance and financial-services company. The message, in letters large enough that no motorist zipping by could miss them: "The First Person To Live To 150 Is Alive Today."

For centuries, scientists have been debating theories about just how long, with proper health care and judicious personal habits, the human lifespan can extend. In recent years, the 150 number has been up for discussion. Some have scoffed at that prospect, but insurance-company actuaries and retirement-planning accountants are not known for wacky practical jokes - they are as somber-eyed as funeral directors as they calculate just how big a risk they run while writing policies for their customers of various ages - so the sight of that Prudential billboard was a little jarring.

I contacted Prudential's corporate headquarters, and the company forwarded to me a table of federal statistics showing the lengthening average lifespans in the U.S. over the past 80 or so years. In 1930, the average life expectancy (measured at birth) of Americans was 59.7 years. By 1940, it had grown to 62.9. 1950: 68.2. 1960: 69.7. 1970: 70.8. 1980: 73.7 1990: 75.4. 2000: 77. 2010: 78.7.

Whether infants born today are entering a world in which 150th birthdays will eventually become if not common then at least possible, the thought raises separate issues for insurance and financial-planning firms than it does for the rest of us. For those companies, the prospect provides marketing opportunities. But for everyone else, it prompts the vexing question: Would you really want to live that long?

Link: http://www.cnn.com/2013/06/23/opinion/greene-living-to-150

The interaction between genes, metabolism, and natural variations in longevity is an enormously complex space. This complexity is why efforts to slow aging by altering metabolism are doomed to be a very slow, very expensive undertaking, one which is unlikely to produce meaningful results within the next few decades. It will be much easier to instead identify the forms of damage that cause aging and periodically repair them without trying to otherwise change our genes or metabolic processes. We know the metabolism we have when young works just fine, so the focus of longevity science should be on reverting the limited set of changes in and around cells that differentiate old tissues from young tissues.

Here is a good short summary of the current state of knowledge of genetics and longevity, illustrating that researchers are really only just at the outset of a very long process of obtaining a full or at least actionable understanding:

Longevity and healthy aging are among the most complex phenotypes studied to date. The heritability of age at death in adulthood is approximately 25%. Studies of exceptionally long-lived individuals show that heritability is greatest at the oldest ages.

Linkage studies of exceptionally long-lived families now support a longevity locus on chromosome 3; other putative longevity loci differ between studies. Candidate gene studies have identified variants at APOE and FOXO3A associated with longevity; other genes show inconsistent results. Genome-wide association scans (GWAS) of centenarians vs. younger controls reveal only APOE as achieving genome-wide significance (GWS); however, analyses of combinations of SNPs or genes represented among associations that do not reach GWS have identified pathways and signatures that converge upon genes and biological processes related to aging. The impact of these SNPs, which may exert joint effects, may be obscured by gene-environment interactions or inter-ethnic differences.

GWAS and whole genome sequencing data both show that the risk alleles defined by GWAS of common complex diseases are, perhaps surprisingly, found in long-lived individuals, who may tolerate them by means of protective genetic factors. Such protective factors may 'buffer' the effects of specific risk alleles. Rare alleles are also likely to contribute to healthy aging and longevity.

Epigenetics is quickly emerging as a critical aspect of aging and longevity. Centenarians delay age-related methylation changes, and they can pass this methylation preservation ability on to their offspring. Non-genetic factors, particularly lifestyle, clearly affect the development of age-related diseases and affect health and lifespan in the general population. To fully understand the desirable phenotypes of healthy aging and longevity, it will be necessary to examine whole genome data from large numbers of healthy long-lived individuals to look simultaneously at both common and rare alleles, with impeccable control for population stratification and consideration of non-genetic factors such as environment.

Link: http://www.ncbi.nlm.nih.gov/pubmed/23925498

Cryonics is the low-temperature storage of the brain on clinical death, preserving the fine structure of the mind for a future of more advanced technologies. It is a vitally important industry for all that it is overlooked by most of the world and rejected as an alternative to the grave by nearly everyone who has actually heard of it and considered it. Even under the most optimistic plausible course of development for rejuvenation biotechnology, billions of people will die due to degenerative aging before it can be brought under medical control. Yet the technology exists today to preserve those people for a future in which they can be restored to active life through applications of advanced medical nanotechnology.

So there is dead and there is dead and gone. The grave means dead and gone - there is no future technology that can restore you once the pattern of your mind has vanished from the world. But if your brain and the structure encoding the data of your mind is preserved then you are only dead until such time as you can be safely restored. Perhaps that will never happen, but the odds are not zero, as is the case for the traditional options of burial, cremation, and so forth.

In a better world, cryonics would be a vast industry with efficiencies of scale, offering preservation at a far lower cost than it does today. Cryopreservation would be the default traditional option at the end of life, and most people would go into the future with some chance at living again. Alas, we do not live in that world. We live in the world in which people flock to certain oblivion, in which supporting scientific work on human rejuvenation is a hard sell, and in which cryonics after four decades of existence remains a very small niche industry.

The Singularity Weblog author recently visited cryonics provider Alcor for a behind the scenes tour and to interview CEO Max More. He was kind enough to upload some of the resulting video to YouTube.

My Video Tour of Alcor and Interview with CEO Max More

Last month I had the privilege of visiting Max More at the Alcor Life Extension Foundation. Alcor is a non-profit organization founded in 1972 and located in Scottsdale, Arizona. It is the world leader in cryonics, cryonics research, and cryonics technology. [Cryonics is the science of using ultra-cold temperature to preserve human life with the intent of restoring good health when technology becomes available to do so.]

During our visit CEO Dr. More walked us through the Alcor facilities as well as the process starting after clinical death is proclaimed, through the cooling of the body and its vitrification, and ending in long term storage.

After our video tour of Alcor CEO Max More was kind enough to take another 25 minutes and answer some questions. During our conversation with Max we discuss: general affordability and prices for Alcor; long-distance membership and why minimizing cooling delays is critical for optimum body preservation; preserving pets; chemical brain preservation; the importance of preserving the neuron's micro-tubules; the potential for X-prize-type of a competition for minimizing tissue damage and improving preservation; the relationship between cryonics and transhumanism.

My favorite quote that I will take away from this interview with Max More is: "Cryonics is critical care medicine taken to the next step."

There is no technology so beneficial that someone somewhere isn't thinking about how to use it to hurt people. That even holds true for means of rejuvenation, ways to eliminate the vast and terrible cost of degenerative aging, all of the suffering, the tens of millions of deaths each and every year. Some people look at the possibilities for near future human rejuvenation and think "I've figured out a way to use this to more effectively hurt the groups of people that we don't like."

Some argue that retributive punishment (reactionary punishment, such as imprisonment) should be replaced where possible with a forward-looking approach such as restorative justice. I imagine, however, that even opponents of retributive justice would shrink from suggesting that [the worst of offenders] should escape unpunished. I assume - in line with the mainstream view of punishment in the UK legal system and in every other culture I can think of - that retributive punishment is appropriate in [some cases].

Within the transhumanist movement, the belief that science will soon be able to halt the ageing process and enable humans to remain healthy indefinitely is widespread. Dr Aubrey de Grey, co-founder of the anti-ageing SENS Research Foundation, believes that the first person to live to 1,000 years has already been born. The benefits of such radical lifespan enhancement are obvious - but it could also be harnessed to increase the severity of punishments. In cases where a thirty-year life sentence is judged too lenient, convicted criminals could be sentenced to receive a life sentence in conjunction with lifespan enhancement. As a result, life imprisonment could mean several hundred years rather than a few decades. It would, of course, be more expensive for society to support such sentences. However, if lifespan enhancement were widely available, this cost could be offset by the increased contributions of a longer-lived workforce.

When the state enforces a monopoly on criminal dispute resolution, as is the case in most regions of the world these days, the only interests served are those of the state employees and appointees involved. Even in legitimate cases you end up with the worst of all worlds: the system remains based upon serving a desire for vengeance and appeasing the mob, imprisonment (as opposed to banishment or outlawing) removes the ability for an offender to work towards restitution, and those with the greatest interest in obtaining justice and resolution are cut out of the decision-making process. There is worse, however. The methods and traditions created for the worst offenders are soon enough applied to everyone without sufficient power and influence to buy their way clear. Modern systems of state justice are terrible impersonal engines, set upon expansion, and all too quickly used for self-empowerment and suppression of dissent by politicians and bureaucrats.

Link: http://blog.practicalethics.ox.ac.uk/2013/08/enhanced-punishment-can-technology-make-life-sentences-longer/

Many methods of extending life by slowing aging in laboratory animals depend upon increased autophagy, the processes of cellular maintenance that clear out damaged components and proteins. Calorie restriction is one of these methods, for example: some studies have shown that if autophagy is disabled then calorie restriction no longer extends life to a significant degree.

[Scientists] have identified a key factor that regulates the autophagy process, a kind of cleansing mechanism for cells in which waste material and cellular debris is gobbled up to protect cells from damage, and in turn, modulates aging. [The researchers] found a transcription factor - an on/off switch for genes - that induces autophagy in animal models, including the nematode C. elegans. [This] transcription factor, called HLH-30, coordinates the autophagy process by regulating genes with functions in different steps of the process. Two years ago, researchers discovered a similar transcription factor, or orthologue, called TFEB that regulates autophagy in mammalian cells.

"HLH-30 is critical to ensure longevity in all of the long-lived C. elegans strains we tested. These models require active HLH-30 to extend lifespan, possibly by inducing autophagy. We found this activation not only in worm longevity models, but also in dietary-restricted mice, and we propose the mechanism might be conserved in higher organisms as well."

HLH-30 is the first transcription factor reported to function in all known autophagy-dependent longevity paradigms, strengthening the emerging concept that autophagy can contribute to long lifespan. In a previous study, [researchers] discovered that increased autophagy has an anti-aging effect, possibly by promoting the activity of an autophagy-related, fat-digesting enzyme. With these findings, scientists now know a key component of the regulation of autophagy in aging. Autophagy has become the subject of intense scientific scrutiny over the past few years, particularly since the process - or its malfunction - has been implicated in many human diseases, including cancer, Alzheimer's, as well as cardiovascular disease and neurodegenerative disorders. HLH-30 and TFEB may represent attractive targets for the development of new therapeutic agents against such diseases.

Link: http://www.eurekalert.org/pub_releases/2013-08/smri-ssi080513.php

It remains the case that most people think of extended lives in terms of an extended old age, meaning ever more and greater pain, suffering, frailty, and illness. We call this the Tithonus Error, after the mythic figure who obtained the cursed form of immortality, living forever but continuing to suffer the ever worsening consequences of degenerative aging. This is one of any number of cautionary tales that illustrate the merits of carefully removing loopholes from requests made to gods, demons, and sundry other elementals. These days I don't think we're doing ourselves any favors by trying to propagate this idea under the name of the Tithonus Error, however. It's not one of the few immediately recognizable myths, and so doesn't do well as a pithy shorthand that reaches out to grab people.

Whatever you want to call this business of extended degenerative aging, however, it is simply not going to happen in the real world, and no reputable scientist in the aging research community is suggesting that it will happen. All of the various presently ongoing efforts to extend life will (if successful) extend healthy life spans, reducing illness and providing more years of health and youthful vigor. All of the life extension that has occurred as a largely unintentional side effect of broad medical progress in the past century or two has also been of this form: more youth and less age-related suffering. Exactly this - more youth and less age-related suffering - has always been the goal and the most plausible outcome: aging is a matter of accumulated damage within and around cells, and anything that the research community does to reduce the current load of damage will extend the period in which you are comparatively healthy and youthful.

Yet the world at large doesn't seem to listen to the researchers who have explained this, year in and year out, since the late 1990s. In the popular imagination life extension is still locked to the idea of gaining only decades of additional tottering frailty - not an attractive proposition at all. Arguably this misconception is the greatest obstacle to obtaining the necessary public support for truly large-scale research projects of the sort needed to build rejuvenation biotechnology over the next few decades. All it will take to implement working prototype therapies described in the SENS plan for rejuvenation is a few billion dollars, a hundred million a year over that time frame - but this requires a level of awareness and support to equal that presently existing for major named diseases such as Alzheimer's, Parkinson's, and the like.

That I can point to a recent survey by one of the big public opinion organizations on the topic of radical life extension, and to discussion of the survey through the mainstream media, is in and of itself a sign of progress. This certainly wouldn't have happened ten years ago. The ideas have spread far enough, and the science and support within the scientific community grown to the point at which it cannot be completely ignored. However the survey results show that there remains a great deal to do in order to create a world in which the average fellow in the street sees degenerative aging as just another of the big threatening diseases, something that can and should be fought with medical science.

One commentary suggests that the fear of extended decrepitude is exactly the root of ambivalence towards medical research aimed at extending human life:

Americans don't want to extend their declining years. But what if you could stay young?

Would you like to live forever? Probably not. According to a new survey by the Pew Research Center, most Americans don't want to stick around much longer than current life expectancy. Sixty percent don't want to live past 90. Thirty percent don't want to live past 80. People who make lots of money don't want longer lives any more than the rest of us do. Nor do people who think there's no afterlife. What's driving our misgivings? Much of it is uncertainty about what kind of lives we'd be living. Would medical progress keep us feeling young? Or would it only stretch out our declining years?

Why so much resistance? One likely reason is dread about the nature of extended life. Pew's survey explicitly postulated treatments that "slow the aging process." But when you're being asked about living to 120 years or beyond, it's hard not to picture spending much of that time feeling withered, afflicted, and debilitated. Although the survey didn't ask about this assumption directly, several findings are consistent with it.

1. The more you associate medical treatment with higher quality of life, the more you favor life extension.
2. The more you associate longevity with productivity, the more you favor life extension.
3. The more you see extended life as a resource burden, the more you oppose it.
4. The more you see old folks as a problem, the more you oppose life extension.
5. The older you are, the less likely you are to favor life extension.
6. The less you're looking forward to the next decade, the less you favor life extension.
7. People don't want to live past the age at which severe diseases and disabilities are expected.

If resistance to life extension is based on the assumption that the extra years would be frail and painful, look out. That resistance will dissolve in the face of contrary evidence. If modern medicine learns how to slow aging, making the average 90-year-old feel as good as a 70-year-old feels today, people will recalibrate.

As the author points out, however, changes of this nature take time - probably more time than we have to wait before the absolute last minute at which we could successfully kick-start the major research programs needed to fully realize SENS or equivalent means of human rejuvenation, technologies capable of rescuing the elderly from frailty, ill-health, and impending death. This is why advocacy and the grind of fundraising and education are so very important. Success in raising more funding for SENS will mean the difference between life and death for a large fraction of those alive today.

For the species defined by the fact that we create change, humans are surprisingly conservative. Ask anyone what they want and in the vast majority of cases you'll hear a story involving the better end of what exists: they want to be as rich as their well-off neighbors, or live as long as the older folk who do so in good health. Ambition and vision, to see how to make new options that don't yet exist, and to want to put in the work to make it happen, are in desperately short supply.

Yet still there is enormously rapid progress in creating new technologies, new options, new bounds of wealth and choice and, yes, greater longevity. The people who today tell you that they only want to live a little beyond the present median human life span will almost certainly be lining up to take advantage of rejuvenation biotechnologies that enable a person to live for centuries, when such things are available, but they won't do anything to help the development of those technologies. Yet for rejuvenation of the old and the defeat of age-related disease to arrive within our lifetimes, many of these same people must decide to help, to understand the possibilities, to support the research. It's a challenge.

The survey, conducted from March 21 to April 8, 2013, among a nationally representative sample of 2,012 adults, examines public attitudes about aging, health care, personal life satisfaction, possible medical advances (including radical life extension) and other bioethical issues. The telephone survey was carried out on cell phones and landlines, in all 50 states, with an overall margin of error for the full sample of plus or minus 2.9 percentage points.

Asked how long they would like to live, more than two-thirds (69%) cite an age between 79 and 100. The median ideal life span is 90 years - about 11 years longer than the current average U.S. life expectancy, which is 78.7 years. The public also is optimistic that some scientific breakthroughs will occur in the next few decades. For example, about seven-in-ten Americans think that by the year 2050, there will be a cure for most forms of cancer (69%) and that artificial arms and legs will perform better than natural ones (71%). And, on balance, the public tends to view medical advances that prolong life as generally good (63%) rather than as interfering with the natural cycle of life (32%). About half (54%) agree with the statement that "medical treatments these days are worth the costs because they allow people to live longer and better-quality lives," but 41% disagree, saying medical treatments these days "often create as many problems as they solve."

Only 7% of respondents say they have heard or read a lot about the possibility that new medical treatments could in the future allow people to live much longer; 38% say they have heard a little about this possibility, and about half (54%) have heard nothing about radical life extension prior to taking the survey. At this early stage, public reaction to the idea of radical life extension is both ambivalent and skeptical. Asked about the consequences for society if new medical treatments could "slow the aging process and allow the average person to live decades longer, to at least 120 years old," about half of U.S. adults (51%) say the treatments would be a bad thing for society, while 41% say they would be a good thing.

Link: http://www.pewforum.org/2013/08/06/living-to-120-and-beyond-americans-views-on-aging-medical-advances-and-radical-life-extension/

Calorie restriction extends life in most short-lived species where this effect can be measured in a practical amount of time. It is suspected that the effect is smaller in long-lived species such as we humans, but nonetheless calorie restriction produces large benefits to health in human studies, far greater than can be obtained by any presently available medical technology applied to a basically healthy individual. Thus for some years researchers have been working on understanding the exceedingly complex mechanisms of calorie restriction, so as to find out how to recreate the benefits without the reduced calorie intake. It's a challenging task, nowhere near completion: calorie restriction changes just about everything in the operation of metabolism.

This research result, in which researchers shut off part of the life extension of calorie restriction, convincingly adds to the data suggesting that calorie restriction operates through several distinct mechanisms running in parallel:

The roundworm Caenorhabditis elegans lives only about 20 days. This makes it an ideal research subject, as the complete lifecycle of the worm can be studied in a short time. Also, the worm consists of less than a thousand cells, and its genetic make-up has been extensively analysed, and contains many genes similar to humans. [Results] indicate that the receptor NHR-62 must be active for reduced dietary intake to fully prolong the life of worms. If NHR-62 is inactive, Caenorhabditis elegans will live 25% longer under dietary restriction than if this receptor is inactive. "It seems that there is an as yet unknown hormone which regulates lifespan using NHR-62. If we can identify this hormone and administer it to the worm, we may prolong its life without having to change its calorie intake."

A restricted diet also affects the expression of genes dramatically: out of the approximate 20,000 worm genes, 3,000 change their activity, and 600 of these show a dependence on NHR-62. It follows that there are many other candidates for improving life expectancy. Since humans have receptors similar to NHR-62, so-called HNF-4α, the [scientists] suspect that the hormone receptors may not only control the maximum lifespan of roundworms, but might affect human beings as well.

Link: http://www.sciencedaily.com/releases/2013/08/130806145449.htm

Big Religion shares many aspects with Big Business and Big Government, not least of which being that after a certain point the output of functionaries in these three groups, cogs in the middle tiers of the machinery, starts to become indistinguishable. So a white paper is a white paper is a white paper, its origin and intended audience only becoming clear by way of the preface and the summary. Thus the article below on the prospects for radical life extension looks much the same as any one of a number of others from various sources in recent years, and you'd have to read it all to note that it hails from one the more traditionally religious cloisters of the practicing civic religion in the US. It's a complex business when religion goes secular at the edges, or the other way around: in both cases its rather like the snail left the shell, but no-one involved really cares all that much, as dusting the shell is what keeps them busy.

In any case, I think that the article is worth reading, and is a mark of progress. The notion that radical life extension is possible and plausible continues to spread, and over the long term of decades it is that spread of ideas and supporters that is the only reliable way to boost the odds of rejuvenation therapies arriving soon enough to make a large difference to you and I personally as we struggle with old age. In the short term tactics matter, such as the victories of the SENS Research Foundation, the conferences, the noted hierarchs of the research community putting their names to rejuvenation research. But in the long term strategy matters, and strategy is really all about money, and money is really all about the number of people who agree with your goals.

The first step on the road of agreeing with the goal of greatly extending the healthy human life span, and along the way eliminating the disease, frailty, and suffering of aging, is open discussion. The more of that taking place the better, and there remain far too many places and communities in which this topic rarely if ever arises. Growth comes from new supporters, and new supporters result from greater consideration of the science and possibilities of longevity.

To Count Our Days: The Scientific and Ethical Dimensions of Radical Life Extension

The prospect of dying has always fascinated, haunted and, ultimately, defined human beings. From the beginnings of civilization, people have contemplated their own mortality - and considered the possibility of immortality. Indeed, many of humanity's oldest and best-known stories, from the Sumerian tale of "Gilgamesh" to the Old Testament Book of Genesis to Homer's "Odyssey," feature mortality and immortality as prominent themes.

Until recently, however, the possibility of dramatically extending human life has been consigned to the realm of speculation or science fiction. Scientists' understanding of why people age - and how to stop aging - was not sophisticated enough to hold out hope that life could be extended much beyond traditional old age. But that may be changing.

Today, scientists at major universities and research institutions are talking about treatments that could extend average life spans by decades - or even longer. None of these medical prospects is yet a reality, and even the most optimistic researchers acknowledge that major breakthroughs could prove elusive. But for the first time in human history, some experts believe we may be at the threshold of a new aging paradigm, one that replaces the generally accepted limits of human life with more open-ended possibilities.

It's a fairly long piece, by the abbreviated modern standards of online publication, and manages to talk about the Strategies for Engineered Negligible Senescence and medical nanotechnology in addition to the standard quick tour of drug development. That is a hopeful sign, I think, that these are now obligatory topics for any review of this nature.

In the view of the SENS Research Foundation, some of the present large-scale scientific work to reverse the accumulation of beta-amyloid protein (Aβ) associated with Alzheimer's disease (AD) is a form of rejuvenation biotechnology. Amyloids of all sorts are on the list of aging-associated changes that should be repaired in order to revert old tissue to the same state it had when young. The hope here is that many of the technologies developed by the Alzheimer's research community can be repurposed to address other types of unwanted compounds that accumulate between cells:

A key target for rejuvenation biotechnologies to prevent and arrest the course of AD is the removal of aggregated beta-amyloid protein (Aβ) from the brain. Amongst the constellation of factors playing some role in the pathogenesis of AD, there is now a strong case for the thesis that Aβ aggregates are at the root of its aetiology. Moreover, Aβ has also been implicated in the cognitive deficits clinically present in other age-related neurological diseases. For example, brain Aβ deposits and abnormally low levels of Aβ42 in the cerebrospinal fluid (CSF) discriminate people suffering from Parkinson's disease dementia and dementia with Lewy bodies from those suffering from Parkinson's disease but whose cognition remains intact. And even amongst people whose cognition is still within the normal range, the presence of Aβ plaque as detected [on] Positron Emission Tomography (PET) is associated with cognitive deficits and increased rate and extent of gray mattter atrophy.

The need for disease-modifying therapies in AD, and the strength of the case for Aβ as a target, have recently driven substantial regulatory reform and innovations in clinical trial design to accommodate more effective testing of Aβ immunotherapies targeting the removal of Aβ from the brain. The first fruits of these changes are the initiation of a series of large, late-stage clinical trials of Aβ vaccines in the early clinical or even preclinical phases of the disease. These reforms have wider and even more hopeful implications, because they open up the path for faster and more meaningful clinical trials of other rejuvenation biotechnologies as they emerge.

The move by scientists and regulators to begin administering Aβ immunotherapy not only early in clinical dementia, but during the preclinical phase of the disease, is an extremely important development. The new regulatory posture responds to the recognition that the volunteers in these trials are not merely "at high risk of Alzheimer's," but are fated to dementia (and to the many other diseases and disabilities of aging) unless rescued by rejuvenation biotechnology - a fate, it must be emphasized, shared by us all, as part of the degenerative aging process.

Link: http://sens.org/research/research-blog/new-and-better-clinical-trials-rejuvenation-biotechnologies

Humans are long lived in comparison to other primates and similarly sized mammals. In addition some characteristics of human aging are unusual in comparison to those of neighboring species. Aging is near universal but its specific evolved manifestations are highly varied:

Women rarely give birth after ∼45 y of age, and they experience the cessation of reproductive cycles, menopause, at ∼50 y of age after a fertility decline lasting almost two decades. Such reproductive senescence in mid-lifespan is an evolutionary puzzle of enduring interest because it should be inherently disadvantageous. Furthermore, comparative data on reproductive senescence from other primates, or indeed other mammals, remains relatively rare. Here we carried out a unique detailed comparative study of reproductive senescence in seven species of nonhuman primates in natural populations, using long-term, individual-based data, and compared them to a population of humans experiencing natural fertility and mortality.

In four of seven primate species we found that reproductive senescence occurred before death only in a small minority of individuals. In three primate species we found evidence of reproductive senescence that accelerated throughout adulthood; however, its initial rate was much lower than mortality, so that relatively few individuals experienced reproductive senescence before death. In contrast, the human population showed the predicted and well-known pattern in which reproductive senescence occurred before death for many women and its rate accelerated throughout adulthood. These results provide strong support for the hypothesis that reproductive senescence in midlife, although apparent in natural-fertility, natural-mortality populations of humans, is generally absent in other primates living in such populations.

Link: http://dx.doi.org/10.1073/pnas.1311857110

As a sidebar to the recently demonstrated use of transcription activator-like effector nucleases (TALENs) to clear out damaged mitochondrial DNA, something that might be of interest as the basis for therapies to partially treat degenerative aging, I though I'd point out another recent paper on how TALENs can be put to work as tools to create effective gene therapies.

Regular readers will recall that references to work on myostatin-related gene therapies show up here every now and again. Mammalian myostatin loss of function mutants are heavily muscled, have less fat, and seem modestly more resistant to a few of the degenerations of age. It is even the case that a small number of human individuals with this mutation exist. Given the degree to which loss of muscle mass and strength occurs with aging, and the cost of that frailty in terms of mortality and quality of life, some corners of the research community are interested in finding ways to trigger the benefits of myostatin loss. By the time it came anywhere near a clinic, this would probably involve a designed drug to temporarily block myostatin signaling rather than any form of gene therapy, however.

Nonetheless, here we have an example of work taking place on a TALENs based platform for gene therapy to edit the myostatin gene. This is intended to provide the basis for further, more effective research aimed at the production of therapies based on myostatin inhibition:

Targeted Myostatin Gene Editing in Multiple Mammalian Species Directed by a Single Pair of TALE Nucleases

Myostatin (MSTN) is a transforming growth factor-β family member that plays a critical role in negatively regulating skeletal muscle mass. Genetic studies have demonstrated that myostatin gene deficiency leads to muscle hypertrophy due to a combination of increased fiber numbers and increased fiber sizes in multiple species including human, cattle, mouse, sheep, and dog without causing severe adverse consequences. Therefore, extensive efforts have been undertaken to develop effective strategies for blocking the myostatin signaling pathway as therapies for various muscle-wasting diseases such as muscular dystrophy, sarcopenia, and long bedding patients. Indeed, myostatin inhibitors have shown great promise to significantly increase muscle growth in model animals.

Here, we report a new class of reagents based on transcription activator-like effector nucleases (TALENs) to disrupt myostatin expression at the genome level. We designed a pair of MSTN TALENs to target a highly conserved sequence in the coding region of the myostatin gene. We demonstrate that codelivery of these MSTN TALENs induce highly specific and efficient gene disruption in a variety of human, cattle, and mouse cells. Based upon sequence analysis, this pair of TALENs is expected to be functional in many other mammalian species.

In summary, TALEN is an effective genome-editing tool. Application of MSTN TALENs in a variety of cell lines and species would allow further investigation of myostatin functions in mammalian animals that do not have naturally occurring mutant MSTN models yet. Moreover, this TALEN pair would also be a valuable tool for cell engineering in translational research such as myoblast transplantation therapy to replace defective genes in genetic diseases including muscular dystrophy.

Members of the International Longevity Alliance, an advocacy and political action group supportive of modern work on longevity science such as that carried out in the SENS program, are proposing October 1st to be International Longevity Day. This is a way to place the goal of extending healthy human life through medical science into the public eye for one more day each year, and as a methodology for doing so it seems fairly reliable if it can get a little impetus behind it:

Some time ago the idea was raised to celebrate a special day by the longevity movement - the Longevity Day. Now an excellent opportunity to do this is coming -the 1st of October, the official United Nations International Day of Older Persons. Let us make the Longevity Day on that day - the 1st of October this year! Let us hold meetings and other events globally!

The day is especially significant as, on that day, we have an excellent opportunity to link in the public mind the issue of aging with the issue of anti-aging research that is probably the only means to truly address and ameliorate the problem of aging. Nowadays, the issues of aging and anti-aging are often considered separately. We can change this pattern of thought and say on that day: deteriorative aging is a problem, and anti-aging research for healthy longevity can provide the solution!

Organize pro-longevity meetings in your area! There is a precedent. On March 1 this year, meetings in support of longevity and longevity research have been held in over 20 countries. We can organize more meetings in more countries now. The range of the meetings (conferences/ seminars/ study groups/ public demonstrations) can range from large scale, to just meeting with a few friends. Every kind and scope of activity is precious.

Engage mainstream public media! The fact that this is an official international UN day of older persons, and the fact that such pro-longevity events are being organized all across the world - gives you an excellent opportunity to directly approach representatives of public media and offer them to cover the topic. This is an opportunity that should not be missed. In the same way, you can approach politicians, public officials and other decision makers in your area. Point them to that day and the international organization around it, and attempt to raise their interest in the issue of longevity research.

Link: http://www.longevityday.org

Mitochondria are the power plants of the cell, and slowly accumulating damage to the DNA that they contain, distinct from the DNA in the cell nucleus, is thought to be an important contribution to degenerative aging. Further, a range of inherited conditions are caused by genetic errors in mitochondrial DNA, such as Leber's hereditary optic neuropathy.

The SENS Research Foundation is working on ways to eliminate the effects of accumulated mitochondrial DNA (mtDNA) damage in order to build a therapy for aging, and other groups are working on methods of mitochondrial repair aimed at treating inherited mitochondrial disease. Below you'll find recent news of progress from one of those groups. The researchers have a method that should be applicable as a means to reverse the mitochondrial DNA damage that contributes to aging. That damage is centered on thirteen important genes, so can in principle targeted by any one-gene-at-a-time method like the one demonstrated here:

Searching for strategies to repair mitochondrial gene defects, a group of [investigators] explored proteins called transcription activator-like (TAL) effectors. In nature, TAL effectors are found only in certain types of plant-infecting bacteria. They enable the bacteria to use plant DNA to multiply and spread infection.

Scientists recently began using TAL effectors to modify DNA in a variety of organisms. In the lab, TAL effectors can be fused with DNA-breaking proteins called nucleases. These TAL effector nucleases (TALENs) can be used to add or remove specific genes or correct gene mutations - techniques that fall under the broad category of genome editing. During the past few years, scientists have begun adapting TALENs and other genome-editing tools for gene therapy. Until now, scientists had only used TALENs to edit genes in the cell nucleus. Today's report marks the first time TALENs have been used to edit mitochondrial genes.

Using cells in the lab, the investigators designed mitoTALENs to bind and cut mitochondrial DNA that had a specific mutation in the gene Complex I, which causes LHON. The scientists then tested whether the mitoTALENs eliminated the mutant mtDNA. Analysis revealed a temporary drop in cells' total mtDNA, which was due to a reduction in mutant mtDNA. "Once the mitoTALENs bound and cut the DNA at the specified target, the mutant mtDNA was degraded. The drop in total mtDNA stimulated the cells to increase their mtDNA by replicating the unaffected molecules. Two weeks later, mtDNA levels had returned to normal. But since the mutant mtDNA was destroyed, the cells had mostly normal mtDNA. A modest reduction in mutant mtDNA is likely sufficient to effectively treat disease."

Link: http://medicalxpress.com/news/2013-08-mechanism-bacteria-infect-eye-disease.html

Some opponents of increased human healthy longevity argue that if we begin to live for far longer than the present human life span then progress in technology will slow to a crawl. This is often presented as a variation on the stagnation argument: that long-lived people will cling to their ideas and their positions for decades or centuries, resisting all change. It is true that human nature comes with a strong conservative streak, and all change is opposed. But despite that fact change nonetheless happens on a timescale quite short in comparison to human life spans: leaders come and go, like fashions, and revolutions, and changes of opinion, and sweeping redefinitions in culture and society. Rare indeed are those that manage to last for a couple of decades, never mind longer. This pace of change in human affairs is essentially the same as that of the ancient world, despite our much greater adult life expectancy in comparison to the classical Greek period or Roman empire.

If we want to look at raw correlations on the other hand, it seems that the technologies needed to extend healthy life go hand in hand with an increased rate of technological progress. Longevity has made the human world become wealthier and run faster, opening doors of opportunity rather than closing them. The only way to increase the healthy human life span is through the creation of a broad pyramid of enabling technologies that in turn lead to faster progress in all fields, not just medicine. Computing is the present dominant enabler, for example, not just for biotechnology but also for almost all other fields of endeavor. If human nature to date has failed to hold back the tide of progress, I'd say it has little chance at doing so in the future: progress is only speeding up.

As is pointed out in the article excerpted below, people change throughout their lives. This also is the same as in the times of antiquity, despite much longer life spans. Human nature is human nature, and the caricature of inflexible, static old people is just that: a caricature. Minds change, and where the elderly are in fact forced into smaller and smaller circles it is largely through disability and frailty, not choice: the failing body and mind narrow the accessible vista, not the lack of will.

Combatting the "Longer Life Will Slow Progress" Criticism

We are all still children. As far as the Centenarian is concerned, the only people to have ever lived have been children - and we have all died before our coming of age. What if humans only lived to age 20? Consider how much less it would be possible to know, to experience, and to do. Most people would agree that a maximum lifespan of 20 years is extremely circumcising and limiting - a travesty. However, it is only because we ourselves have lived past such an age that we feel intuitively as though a maximum lifespan of 20 years would be a worse state of affairs than a maximum lifespan of 100. And it is only because we ourselves have not lived past the age of 100 that we fail to have similar feelings regarding death at the age of 100. This doesn't seem like such a tragedy to us - but it is a tragedy, and arguably one as extensive as death at age 20.

The current breadth and depth of the world and its past are far too gargantuan to be encompassed by a mere 100 years. If you really think that there are only so many things that can be done in a lifetime, you simply haven't lived long enough or broadly enough. There is more to the wide whorl of the world than the confines and extents of our own particular cultural narrative and native milieu.

Luckily, functional decline as a correlate of age is on the way out. We will live to 100 not in a period of decline upon hitting our mid-twenties, but in a continuing period of youthfulness. There are no longevity therapies on the table that offer to truly prolong life indefinitely without actually reversing aging. Thus, one of the impediments preventing us from seeing death at 100 as a tragedy, as dying before one's time, will be put to rest as well. When we see a 100 year old die in future, they will have the young face of someone who we feel today has died before their time. We won't be intuitively inclined to look back upon the gradual loss of function and physiological-robustness as leading to and foretelling this point, thereby making it seem inevitable or somehow natural. We will see a terribly sad 20 year old, wishing they had more time.

It seems to me a truism that we get smarter, more ethical and more deliberative as we age. To think otherwise is in many cases derivative of the notion that physiology and experience alike are on the decline once we "peak" in our mid-twenties, downhill into old age - which does undoubtedly happen, and which inarguably does cause functional decline. But longevity therapies are nothing more nor less than the maintenance of normative functionality; longevity therapies would thus not only negate the functional decline that comes with old age, [but also] the source of the problem arguably at the heart of the concern that longer life will slow progress.

Increasing longevity will not bring with it prolonged old-age, a frozen decay and decrepit delay, but will instead prolong our youthful lives and make us continually growing beings, getting smarter and more ethical all the time.

Lastly, this thought: so what if increased life spans did slow progress? Even in the hypothetical world in which that did look even remotely plausible, it is still the case that for so long as the pace of longevity is greater than the slowdown, everyone still comes out ahead. Being alive and in good health is the important thing: given that, the only thing that matters with regard to further technological progress is whether it is happening fast enough to keep you alive and in good health. Everything else in life is what you make of it.

It is human nature to be capable of committing acts of great evil or economic self-destruction for years on end, and especially in groups. We are not at all far removed at the moment from large-scale genocides, collapsed kleptocracies, meaningless prohibitions, and more. So it's probably unsafe to assume that no state will outright ban the extension of healthy life via medicine in the future: there are more than enough examples of human collectives acting against the long-term self-interest of all their members for decades, and that becomes ever more likely if those at the top invent the means to profit personally from a widespread destruction of life and wealth.

For all that, I do think it's an unlikely outcome. The more plausible outcome is the one that is taking place right now: great economic harm to the pace and breadth of medical development through heavy, centralized regulation. Enormous, entirely unnecessary costs and very high barriers to entry are imposed on clinical applications of medicine, which ensures that a great deal of possible, plausible research and development never happens. Worse, in a system in which all that is not expressly permitted is forbidden - which is exactly the case for the FDA and similar regulatory bodies elsewhere in the world - radically different new technologies such as the means to treat aging are restricted by default, without any politician or bureaucrat having to raise a finger. The entire system of regulation must be changed to even allow them to be considered: which means more cost, more delay, and more work suppressed because it isn't cost-effective to undertake.

Here the possibility of future restrictions on rejuvenation therapies is considered by someone who is more supportive of the existence of a large state than I am. They see the solution as working within the system, being a petitioner to power to beg for the chance to be free enough to make the world a better place. I'm not sure that this has ever had a good record of success over the long term, certainly not when compared to revolution or the establishment of new colonies far enough distant from the state to be largely free from its bureaucracy:

Most laypeople with an opinion [on] biogerontology assume "[life extension] treatments will be centuries in the future", actual specialists with a medical background tend to be more 'optimistic' and postulate some for of accessibility of these treatments somewhere later this century. I'll abbreviate "Life Extension" as LE and Rejuvenation as RE.

The human that has singlehandedly saved most lives world wide may very well have been Maurice Hilleman. In the late 19th to mid 20th century there was a small number of cynics who insisted that vaccinations (and other treatments intended to make people live longer lives) would contribute to Malthusian overpopulation. It is interesting to realize that many of these objections were based on class-prejudice and racism. People who objected to child vaccinations tended to not like poor people very much, and didn''t want 'their' world overrun by the kind of people they took offense to. These sentiments are by no means dead. A very common objection to the mere realization of RE/LE treatments is that "the world would quickly overpopulate". When quizzed strikingly many people today insist that RE/LE might "have to be declared illegal to avoid an overpopulation disaster". These people seem to be unable to infer comparisons from earlier Life Extension treatments (clean drinking water, sanitation, healthy diets, environmental protection laws, vaccinations) from which they benefited, and regard Biogerontological Life Extension as something different altogether.

The process of development of actual "biological immortality" is likely to be a long trajectory of dead ends and catastrophes. The beta stage of life extension may come with painful episodes and failures. Early adopters may end up forking out large sums of private capital for treatments that may or may not work. If earliest stage regenerative treatments were to emerge in the 2020s it may be decades before these treatments would end up safe, affordable, comfortable and easy to use. What is worse - such treatments don't have a convenient fit in the current medical corporate sector. What does a LE or RE treatment actually do? Does it make people less dependent on other medical treatments? If that is the case many established medical conglomerates may very well vehemently object against these treatments, and declare them "snake oil" or "pseudoscience". It is thus quite likely that on the earliest years of emerging LE/RE many consumers may reject these treatments basing their choices on vicious and deceptive media campaigns.

Link: http://ieet.org/index.php/IEET/more/suntzu20130801

The thymus helps to generate the cell populations of your immune system when young, but it atrophies - a process called involution - quite early in adult life. Many of the frailties of aging have their roots in the age-related decline of the immune system. It fails with age in large part because it is a size-limited population of cells, and ever more of those cells become inappropriately configured and unable to respond to new threats. One of the proposed methods for dealing with this issue is to restore the thymus, and therefore create a stream of new immune cells to take up the slack. Transplanting a thymus from a young mouse into an old mouse improves the immune system and extends life, for example.

For human medicine, the focus is on finding ways to tissue engineer a new thymus from the patient's own cells, or spur regrowth of the existing involuted thymus. Here is an example of progress in the research and development needed for thymic tissue engineering - if you want to build a thymus, you first have to be able to reliably generate large numbers of the right sort of cells. Work on that goal is still in progress:

Thymus transplantation has great clinical potential for treating immunological disorders, but the shortage of transplant donors limits the progress of this therapy. Human embryonic stem cells (hESCs) are promising cell sources for generating thymic epithelial cells. Here, we report a stepwise protocol to direct the differentiation of hESCs into thymic epithelial progenitor-like cells (TEPLCs) by mimicking thymus organogenesis with sequential regulation of Activin, retinoic acid, BMP, and WNT signals.

The hESC-derived TEPLCs expressed the key thymic marker gene FOXN1 and could further develop in vivo into thymic epithelium expressing the functional thymic markers MHC II and AIRE upon transplantation. Moreover, the TEPLC-derived thymic epithelium could support mouse thymopoiesis in T-cell-deficient mice and promote human T cell generation in NOD/SCID mice engrafted with human hematopoietic stem cells (hHSCs). These findings could facilitate hESC-based replacement therapy and provide a valuable in vitro platform for studying human thymus organogenesis and regeneration.

Link: http://dx.doi.org/10.1016/j.stem.2013.06.014

The success of Kickstarter and conceptually similar entities (IndieGoGo, AngelList, and so forth) as fundraising communities has more than adequately demonstrated that crowdfunding works very well in an environment of low-cost, ubiquitous communication and open data. All the old centralized time-proven activities of fundraising in for-profit business can in fact be distributed, turned inside out, and disintermediated. New middle men arise in this process of disruptive change, such as Kickstarter, but the future will see their dominance vanish in favor of open protocols and marketplaces with some sort of an ecosystem of optional gatekeepers and reviewers. This is exactly the same as the transition from early dial-up services and their walled gardens to the open internet, and seems to be something of an inevitability.

Can this be made to work for science and research? Therein lies the question. At the high level, it seems as though the answer is obviously yes: it's all just money, and money is presently invested in research. But at the detail level research is a very different thing from funding a new artwork or widget: it has a much longer time horizon, a far greater degree of uncertainty, and the funders don't walk away at the end with a new widget. A number of companies are presently attempting to find the magic recipe by which crowsourced science funding can be made work in a Kickstarter-like fashion.

Clearly crowdfunding for specific research goals is possible. There are numerous examples of success in the past decade beyond those I'll mention here. The Methuselah Foundation and SENS Research Foundation grew out of crowdfunding initiatives, raising money from hundreds of donors from the transhumanist community and other supporters of longevity science. The advocacy community of Longecity raises modest sums for specific life science research projects connected to longevity and related medical technologies. But these are tailored projects, integrated with specific interest communities: not the same thing at all as building a successful marketplace for diverse forms of project and community.

Crowdfunding intersects with another important trend that arises with ubiquitous, low-cost communication and openly accessible data, which is the distribution of effort in large projects. Complex initiatives can now be undertaken piecemeal by geographically dispersed groups who share a common interest. The open source software development community is far ahead of the rest of the world in this respect: many vital and important software projects have evolved in a worldwide fashion, with self-organizing collaborators who will never meet in person. Science is moving in the same direction: lots of data, lots of complex software, data becoming more open, and more distributed collaboration between researchers in different parts of the world.

What medical science has that the software industry does not is a vast and pervasive edifice of regulation, wherein largely unaccountable regulators insist on centralization and the imposition of enormous costs on research and its application in the form of new therapies and medical technologies. Regulation opposes movement to a more distributed research and development industry in which even exceedingly rare diseases will be worked on by someone, somewhere with a vested interest. Higher costs always mean that marginal work suffers, vanishes entirely, or takes place in black and grey markets with all their attendant issues. It is enormously harmful, and that harm is largely invisible: the technologies not developed, the progress not made, the dead in their millions who might have had a chance at longer lives.

The article quoted below offers some thoughts on all of this in the context of cancer research and proto-crowdfunding efforts that have aimed to spur research and development in therapies for very rare forms of cancers, those that present regulation makes it unprofitable to work on. The points raised are also applicable to the situation for aging and rejuvenation research, however, which is also a collection of related minority fields that are shut out from clinical application by the decisions of regulators.

Can We Build A Kickstarter For Cancer?

Building large analytical databases to mine clinical and molecular data, and scan the scientific literature to identify better treatments for cancer patients is happening today. But what about patients who fall outside what we already know - whose cancer subtypes haven't been discovered yet, and who don't have access to the technologies that could make a difference in unraveling the aberrations driving their cancers? The technology to unravel the molecular drivers of cancer is, for the most part, available today: "-omics" technologies for screening tumor samples from patients and comparing them to healthy tissue samples to pick out cancer-specific mutations; diagnostics that can track patients' response to treatment in real time at a molecular level; and Web-based tools and apps [that] patients and community oncologists can use to guide treatment decisions (and feed those outcomes, good and bad, back into the research process).

Our current research approach - one drug, one clinical trial, one cancer type at a time - won't generate enough of the information we need to unravel cancer's molecular mysteries at the patient level. And it is too slow, too bureaucratic, and too expensive to be sustainable, given the number of compounds we have to test and the limited pool of patients who participate in clinical trials. Only about 3% of all cancer patients participate in cancer clinical trials, and those patients - because of restrictive inclusion/exclusion criteria - are often very different (i.e., healthier) than the average cancer patient, who is likely to be in poorer health and have one or more co-morbidities (obesity, diabetes, etc.). This limits the applicability of even the best drug guidelines based on classical trials for real-world patients. Classical clinical trials lead to a "tyranny of the averages," rather than helping us to - as in the case of cancer - disassemble complex diseases that might share the same clinical symptoms (and which we happen to call cancer or diabetes) but which are really molecularly distinct and thus require different treatment approaches.

In short, we won't develop the drugs or complex treatment regimens we need to for truly personalized cancer treatment regimens for patients if we keep doing business as usual. The patients who have the most to gain from this approach are those who have the most to lose today - patients with rare or hard-to-treat cancers, who fail rapidly on standard or even targeted treatments. And it's exactly these patients who will, in all likelihood, be most eager to embrace the risks and promise of Kickstarting their own cancer research.

It's not just cancer: all of modern medicine would benefit from an overturning of the present centralized regulatory structures in order to allow unfettered diversity in fundraising, research, and clinical application. This is exactly the sort of approach that modern communication technologies enable: let there be far more in the way of researchers connecting to the interested small communities among the broader public - as was the case for the Strategies for Engineered Negligible Senescence - and the best of these initiatives, those that manage to obtain support from both the public and the scientific community, will prosper. This, I think, is a far more promising model for the future of research than the stasis, obstructions, and failures of highly regulated, state-funded scientific and medical monoliths.

This popular science piece outlines some of the evidence for greater height to come with a penalty to longevity. I believe that the most plausible contribution to this effect has to do with growth hormone metabolism, given the degree to which it is linked to longevity in laboratory animals. Broadly speaking less growth hormone means a longer life in species such as mice. Larger individuals with more growth hormone accumulate damage and dysfunction at a faster pace in all areas: they age more rapidly.

One of the goals for future medicine is to make all such correlations in long term health irrelevant. Advanced medical technology, sufficient to repair the causes of aging, will sweep away the effects of differences in genetics and circumstances. This is something to look forward, as with suitable levels of funding and support the first of these new therapies of rejuvenation might be developed and rolled out by the late 2030s.

Physicians and epidemiologists began studying the link between height and longevity more than a century ago. Early researchers believed that tall people lived longer, [but] in fact in the early 20th century height was [a] reflection of better nutrition and hygiene, which increased longevity. Once the studies were limited to otherwise homogeneous populations, a consensus emerged that short people are longer-lived.

Among Sardinian soldiers who reach the age of 70, for example, those below approximately 5-foot-4 live two years longer than their taller brothers-in-arms. A study of more than 2,600 elite Finnish athletes showed that cross-country skiers were 6 inches shorter and lived nearly seven years longer than basketball players. Average height in European countries closely correlates to the rate of death from heart disease. Swedes and Norwegians, who average about 5-foot-10, have more than twice as many cardiac deaths per 100,000 as the Spaniards and Portuguese, who have an average height just north of 5-foot-5. Tall people rarely live exceptionally long lives. Japanese people who reach 100 are 4 inches shorter, on average, than those who are 75. The countries in the taller half of Europe have 48 centenarians per million, compared to 77 per million in the shorter half of the continent.

Setting aside simple mortality, individual diseases are also more common among tall people. American women above 5-foot-6 suffer recurrent blood clots at a higher rate. Among civil servants in London, taller people have been shown to suffer from more respiratory and cardiovascular illness. And then there's cancer. Height is associated with greater risk for most kinds of cancer, except for smoking-induced malignancies.

Unlike intelligence, which has a merely coincidental relationship with height, there are plausible biological explanations for why short people live longer. Researchers have found that the lungs of taller people don't function as efficiently, relative to their bodies' demands, as those of short people. Explanations for the link between height and other disorders are slightly more speculative, but largely credible. Tall people have more cells, which may increase the chances that some of them will mutate and lead to cancer. The hormones involved in rapid growth may also play a role in cancer development. It's even possible that the foods that lead to fast growth during childhood may increase the likelihood that a person will eventually develop cancer. The link between height and clots probably has to do with the length and weight of the columns of blood that travel between the heart and the body's extremities.

Link: http://www.slate.com/articles/health_and_science/science/2013/07/height_and_longevity_the_research_is_clear_being_tall_is_hazardous_to_your.html

Increasing chemotherapy tolerance, so as to allow greater harm to be caused to cancerous tumors while the patient still survives the treatment, is a strategy that will be eclipsed by the next generation of cancer therapies. They will target cancer cells and have few to no side effects, and will certainly not be a case of flooding the body with poisons that are just a little more toxic to cancer than to the rest of the patient's cells. So the discovery made by these researchers will, I think, be something that finds application in regenerative medicine instead: a way to greatly boost stem cell activity in specific tissues should have many uses.

Treating a cancerous tumor is like watering a houseplant with a fire hose - too much water kills the plant, just as too much chemotherapy and radiation kills the patient before it kills the tumor. However, if the patient's gastrointestinal tract remains healthy and functioning, the patient's chances of survival increase exponentially. Recently, [researchers] discovered a biological mechanism that preserves the gastrointestinal tracts in mice who were delivered lethal doses of chemotherapy.

"It's our belief that this could eventually cure later-staged metastasized cancer. People will not die from cancer, if our prediction is true. All tumors from different tissues and organs can be killed by high doses of chemotherapy and radiation, but the current challenge for treating the later-staged metastasized cancer is that you actually kill the patient before you kill the tumor."

[Researchers] found that when certain proteins bind with a specific molecule on intestinal stem cells, it revs intestinal stem cells into overdrive for intestinal regeneration and repair. [Researchers have] worked with these molecules, called R-spondin1 and Slit2, for more than a decade. In the study, 50-to-75 percent of the mice treated with the molecule survived otherwise lethal doses of chemotherapy. All of the mice that did not receive the molecule died. "The next step is to aim for a 100-percent survival rate in mice who are injected with the molecules and receive lethal doses of chemotherapy and radiation."

Stem cells naturally heal damaged organs and tissues, but so-called "normal" amounts of stem cells in the intestine simply cannot keep up with the wreckage left behind by the lethal doses of chemotherapy and radiation required to successfully treat late-stage tumors. However, the phalanx of extra stem cells protect the intestine and gastrointestinal tract, which means the patient can ingest nutrients, the body can perform other critical functions and the bacterial toxins in the intestine are prevented from entering the blood circulation.

Link: http://www.sciencedaily.com/releases/2013/07/130731133155.htm