Fight Aging!

Aubrey de Grey is a tireless advocate for the development of rejuvenation biotechnology, the means to repair and reverse the root causes of aging, and he is the more visible face of the SENS Research Foundation - which is not to diminish the hard work of the many other folk, staff and volunteers, who have helped to make the Foundation the growing success it is today. Without their efforts the path towards human rejuvenation would be far longer. If you've been following along these past years, you'll know that de Grey travels widely to give a great many presentations to the public, and here is one example from a recent TEDx event in Hungary.

Aubrey de Grey is a biomedical gerontologist and the Chief Science Officer of SENS Foundation, a charity dedicated to combating the aging process. He is also Editor-in-Chief of Rejuvenation Research, the world's highest-impact peer-reviewed journal focused on intervention in aging. His research targets the accumulating and eventually pathogenic molecular and cellular side-effects of metabolism that constitute mammalian aging and the design of interventions to repair or obviate them. His comprehensive plan breaks aging down into seven major classes and identifies detailed approaches to addressing each one. Dr. de Grey is a Fellow of both the Gerontological Society of America and the American Aging Association, and sits on the editorial and scientific advisory boards of numerous journals and organisations.

The research proposals and therapies of SENS are one of those obvious-in-hindsight plans that can only emerge because a few people were visionary enough and stubborn enough to keep pushing until it gained acceptance. Without the SENS Research Foundation and the many people who contributed to bringing that organization into existence over the course of the past decade, the aging research community would still be entirely focused on either doing nothing to help treat degenerative aging, or working only on largely ineffective approaches aimed at slightly slowing down aging via the old-style drug discovery pipeline.

The longest lived mice are those that have been altered to remove growth hormone or growth hormone receptors. In humans there is an analogous population of natural mutants, their condition known as Laron syndrome, who, like the mice, seem resistant to cancer and type 2 diabetes. They do not appear to live significantly longer than the rest of us, but that doesn't rule out modest extension of life - the data is lacking to say either way at this time.

Secretion of growth hormone (GH), and consequently that of insulin-like growth factor 1 (IGF-1), declines over time until only low levels can be detected in individuals aged ≥60 years. This phenomenon, which is known as the 'somatopause', has led to recombinant human GH being widely promoted and abused as an antiageing drug, despite lack of evidence of efficacy.

By contrast, several mutations that decrease the tone of the GH/IGF-1 axis are associated with extended longevity in mice. In humans, corresponding or similar mutations have been identified, but whether these mutations alter longevity has yet to be established. The powerful effect of reduced GH activity on lifespan extension in mice has generated the hypothesis that pharmaceutically inhibiting, rather than increasing, GH action might delay ageing. Moreover, mice as well as humans with reduced activity of the GH/IGF-1 axis are protected from cancer and diabetes mellitus, two major ageing-related morbidities.

Here, we review data on mouse strains with alterations in the GH/IGF-1 axis and their effects on lifespan. The outcome of corresponding or similar mutations in humans is described, as well as the potential mechanisms underlying increased longevity and the therapeutic benefits and risks of medical disruption of the GH/IGF-1 axis in humans.

Link: http://dx.doi.org/10.1038/nrendo.2013.67

The mechanisms of insulin signaling are one of the better studied metabolic determinants of longevity, though as for all such things it is a very complex system, not yet fully understood, and there a lot of debate and uncertainty in the resulting science. New data continues to roll in, however, here looking at variations of levels of the receptor for insulin-like growth factor 1 (IGF1R) in various different rodent species:

The insulin/insulin-like growth factor signaling (IIS) pathway is a major conserved regulator of aging. Nematode, fruit fly and mouse mutants with reduced IIS signaling exhibit extended lifespan. These mutants are often dwarfs leading to the idea that small body mass correlates with longevity within species. However, when different species are compared, larger animals are typically longer-lived. Hence, the role of IIS in the evolution of life history traits remains unresolved.

Here we used comparative approach to test whether IGF1R signaling changes in response to selection on lifespan or body mass and whether specific tissues are involved. The IGF1R levels in the heart, lungs, kidneys, and brains of sixteen rodent species with highly diverse lifespans and body masses were measured. [We] report that IGF1R levels display strong negative correlation with maximum lifespan only in brain tissue and no significant correlations with body mass for any organ. The brain-IGF1R and lifespan correlation holds when phylogenetic non-independence of data-points is taken into account. These results suggest that modulation of IGF1R signaling in nervous tissue, but not in the peripheral tissues, is an important factor in the evolution of longevity in mammals.

Link: http://impactaging.com/papers/v5/n4/full/100552.html

The SENS Research Foundation is one of the few organizations presently focused on developing medical technologies that will produce rejuvenation in the old. The Foundation researchers and staff undertake targeted research programs in areas that are not getting enough attention from the mainstream life science community, and engage in advocacy to convince more of the research community to work on the goal of reversing degenerative aging, thus preventing age-related disease, frailty, and disability, and extending healthy life.

A newsletter from the Foundation arrived today, with a link to the Foundation's 2012 annual report (PDF). Good news on the budgetary side of things is the order of the day, and the Foundation is continuing to grow its research efforts. The total budget in 2012 was $3 million, in comparison to the $1 million only a couple of years earlier:

We are pleased to report that, in 2012, SENS Research Foundation was able to support expenses that were double those from the previous year. This was made possible through not only the continued support of our generous donors, but the first in a series of annual disbursements from the de Grey family trust, which together caused SRF's income to increase by about $2 million.

As a research-based outreach organization, the scientific work that we fund plays a critical role in our mission. For this reason, we have focused our growth on our extramural research program, tripling its size by adding more than $750,000 of funding. This aggressive expansion has led to the addition of nine new projects, including two at the Wake Forest Institute for Regenerative Medicine, bringing our total funded to seventeen. Meanwhile, we were able to add $300,000 to our intramural research budget, bringing a third major project, more staff, and new equipment to our Research Center in Mountain View, California.

Simultaneously, we built SRF Education into a larger and more robust educational program, creating our first online course and a successful summer internship program that involved both our Research Center and the Buck Institute for Research on Aging. This has set the stage for further growth in 2013, which will include the development of more coursework and the addition of new internship campuses.

Overall, our expenses in 2013 should increase by an amount equal to 2012's increase. Given our secure base of funding sources, we expect to sustain this higher level of operation indefinitely. We are deeply appreciative of the individuals and foundations that enable us to pursue our mission through their support. We would like to thank Peter Thiel, Jason Hope, the de Grey family trust, the Methuselah Foundation, and the many other donors who make all of our efforts possible.

If you read through the report, you'll find good overviews of the present research programs supported by the Foundation, as well as news of recent progress.

Lysosomal Aggregates

Researchers funded by the Foundation are searching for bacterial enzymes that can be safely introduced into the body to break down harmful metabolic byproducts that build up in the lysosomes within cells, degrading their ability to keep up with cellular housekeeping, and contributing to a range of age-related conditions. There are many different types of chemical gunk that building up in the lysosome, so researchers have so far focused on those best known to the research community.

At the SENS Research Foundation Research Center (SRFRC), our Lysosomal Aggregates team is working to efficiently deliver promising A2E-degrading enzymes identified in our earlier research into the lysosome of cells. One in particular (SENS20) has demonstrated tremendous efficacy in degrading A2E not only in vitro but in A2E-loaded retinal pigment epithelium cells.

In 2013, the team will put a recombinant form of SENS20 to the test, assessing its ability to degrade A2E in vitro and in retinal pigment epithelium cells, and verifying that it is not toxic to the cell

It has to be said that it is very pleasing to see the Foundation at the stage of giving the characteristic drug/therapy candidate names (SENS20 in this case) to the results of their work.

Mitochondrial Mutations

Our mitochondria become damaged with age, causing a range of catastrophic consequences to our cells and tissues. The SENS approach to fixing this is to put backup copies of vulnerable mitochondrial genetic material into the cell nucleus. The challenge here was never getting the genes into the nucleus, as that's just straightforward gene therapy, but rather getting the proteins from those genetic blueprints back into the mitochondria where they are needed. This was slow going until fairly recently, when a potential game-changing advance emerged from the broader research community.

It sounds like the SENS Research Foundation folk are working to integrate this new approach into their efforts, as it could in theory allow all the necessary genes to be moved into the nucleus via the same basic method - so get it working once and you're done.

SRF-RC scientists are now working to master and refine a superior method for accomplishing this goal. Our team has taken four cell lines from patients suffering from severe diseases caused by inherited mitochondrial mutations, and made stable lines that express their improved mitochondrial gene constructs. They have begun collecting data confirming the targeting of gene transcripts and proteins to their mitochondrial locations, and the functional activity of the mitochondrial energy system, in such re-engineered cells.

I am very impatient to see a demonstration of mitochondrial repair or DNA replacement running in a mouse life span trial - it is my belief, based on the range of research I've seen over the years, that mitochondrial damage is the dominant cause of degenerative aging, and I'm looking forward to seeing just how right or wrong that hypothesis might be. It's not unrealistic at this point to think that ten years from now we'll have that data in hand.

Extracellular Matrix Stiffening

Crosslinks such as advanced glycation end-products form relentlessly in our tissues, gumming up protein machinery and causing a fair portion of the visible symptoms of skin aging - and worse, the loss of flexibility in blood vessels and other important tissue structures. Old skin I could live with, but you can't live with old blood vessels; they'll kill you in the course of time. The short history of attempts to develop therapies to break down AGEs has been a short history of frustration, with only very limited success to date. Fortunately, we are now past a critical point of discovery regarding AGEs, which is that in human tissue they overwhelmingly consist of a single compound called glucosepane. Unfortunately, beyond the SENS Research Foundation next to nobody cares to do anything about this aspect of aging.

Late in 2012, we announced the establishment of our new SENS Research Foundation Laboratory in partnership with the University of Cambridge Institute of Biotechnology. In collaboration with Dr. Spiegel's lab, the SRF Cambridge center will initiate work on new agents to cleave apart crosslinked proteins, restoring youthful elasticity and buffering capacity to arteries. The specific molecular target will be glucosepane, the main crosslink that accumulates in aging human arteries and other tissues.

Dr. Spiegel has already developed a way to synthesize glucosepane in the lab; this artificially-produced glucosepane can now be used to develop reagents that can rapidly and specifically detect proteins that have been crosslinked by it.

The Cambridge group has been working on methods of extracting crosslinked proteins intact from the tissues of dogs and marmoset monkeys, and to measure glucosepane cleavage in the test tube and in animal and human tissues. It is clear from this research that none of the commercially available monoclonal antibodies against related crosslink molecules are able to cleave glucosepane to any significant degree, and many are useless. All of these findings further emphasize the importance of this project in developing novel crosslink-breaking therapies.

Other Research Programs

A range of other current research programs are given just as much attention in the annual report. I hope that the notes above encourage you to look them over. This is what the future of longevity science looks like: deliberately and carefully working to reverse specific forms of damage that occur in old tissue but not in young tissue. It is a world away from the old school drug discovery process in the Big Pharma mainstream that aims only at modestly slowing down aging - the sirtuins, and resveratrol, and rapamycin, and all the other potential and so far largely disappointing age-retarding drugs. SENS is the only path forward that is likely to produce significant rejuvenation in the old when its therapies are ready for clinical use.

For you and I to have a good shot at living far longer than our ancestors, the SENS approach must come to dominate the mainstream of aging research, displacing less effective and more expensive approaches. Fast progress requires large budgets and hundreds of researchers. The sooner that this happens, the more likely it is that we will still be alive and in good health when rejuvenation therapies arrive.

Today I noticed this very readable open access paper that reviews calorie restriction research and ongoing efforts to produce drugs that can mimic some of the beneficial effects of calorie restriction on health and longevity. It can be downloaded in PDF format from the journal website:

Everyone desires a long and healthy life, and many researchers have investigated methods to overcome and to retard the aging process. The most well defined intervention of retarding aging is caloric restriction. Caloric restriction, also known as dietary restriction, is the reduction of food intake without malnutrition. Experimentally, caloric restriction means a reduction in calorie intake by 10-30% when compared to an ad libitum diet. Lifespan extension in response to caloric restriction is thought to be caused by a decreased rate of increase in age-specific mortality. It is widely believed that caloric restriction delays the onset of age-related decline in many species, as well as the incidence of age-related diseases such as cancer, diabetes, atherosclerosis, cardiovascular disease, and neurodegenerative diseases. Caloric restriction affects the behavior, animal physiology, and metabolic activities such as modulation of hyperglycemia and hyperinsulinemia, as well as increases insulin sensitivity.

Reductions of protein source in the diet without any changes in calorie level have been shown to have similar effects as caloric restriction. Furthermore, restriction of individual amino acids has been shown to induce lifespan extension in some species, especially methionine restriction. Moreover, the restriction of tryptophan is believed to have a positive effect on longevity. Thus, several researchers have stated that this phenomenon occurs as a result of dietary restriction, not caloric restriction. However, other studies have indicated that protein and/or methionine restriction is not involved in the caloric restriction-induced lifespan extension.

Link: http://www.bmbreports.org/fulltext/bmbreports/view.php?vol=46&page=181

Here is a pointer to the website for a forthcoming conference to be held at the Buck Institute for Research on Aging in California. It is one of the many signs indicating that large, conservative financial entities like Burrill & Company are becoming more interested in longevity science:

Around the world, lifespans are increasing and populations are aging. This demographic shift presents opportunities for drug and device developers, as well as significant challenges for healthcare systems and payers. Diseases of aging are among the costliest and most intractable diseases we face. These include heart disease, stroke, cancer, neurological disease, pulmonary disease, and diabetes. While policy makers across the globe have taken steps to look for ways to restrict spending, others are turning to innovative approaches that can keep people healthy and allow them to live independently longer. Please join us at this inaugural Burrill & Buck Aging Meeting as we explore the consequences of aging, how therapeutics in development seek to address chronic diseases related to aging, and how innovative approaches from regenerative medicine to digital health stand to change our notion of what it means to grow old.

Link: http://www.burrillbuckaging.com

Human calorie restriction studies continue onward at the normal sedate pace of all human research, as noted in a recent post on the CALERIE program. It remains the case that the vast majority of work on calorie restriction and its beneficial effects involves mice, flies, worms, and other laboratory animals. Most such species exhibit increased longevity and improved measures of long term health when on a calorie restricted diet, provided that they still receive suitable levels of nutrition. That this is so universal is one of the reasons to suggest calorie restriction with optimal nutrition as a lifestyle choice in humans.

Other reasons include the results from human studies to date; if there was a pill you could take that provided half the benefits that calorie restriction has been shown to produce in humans, then everyone would be falling over themselves to take it. It's somewhat harder to convince people to eat less in this day and age, however, no matter how beneficial the results might be. The paper quoted below is illustrative of results from human studies, in that the measures taken tend to line up with what is seen in short-lived animals like mice and rats:

Calorie restriction in humans inhibits the PI3K/AKT pathway and induces a younger transcription profile

Caloric restriction (CR) and down-regulation of the insulin/IGF pathway are the most robust interventions known to increase longevity in lower organisms. However, little is known about the molecular adaptations induced by CR in humans. Here we report that long-term CR in humans inhibits the IGF-1/insulin pathway in skeletal muscle, a key metabolic tissue. We also demonstrate that CR-induced dramatic changes of the skeletal muscle transcriptional profile that resemble those of younger individuals. Finally, in both rats and humans CR evoked similar responses in the transcriptional profiles of skeletal muscle. This common signature consisted of three key pathways typically associated with longevity: IGF-1/insulin signaling, mitochondrial biogenesis and inflammation.

If you wander over to Extreme Longevity you can find a PDF copy of the full paper.

The fact that more easily gathered measures of metabolism like those noted above are similar for rat and human calorie restriction makes CR look like a good option - where these measures match up, the hope is that the long term rewards do so as well. Studies in rats can achieve what studies in humans cannot, which is to follow large numbers of rats for their entire lives and catalog the impressive long term health benefits, as well as the characteristic increase in life expectancy, that accompanies CR in rodent species. This is one of many examples, in which the researchers focus as much on exercise as CR:

Effects of dietary restriction and exercise on the age-related pathology of the rat

The most efficacious and commonly used intervention used to retard the aging processes is dietary restriction (DR). It increases mean and maximum life spans, delays the appearance, frequency, and severity of many age-related diseases, and more importantly, attenuates much of the physiological decline associated with age. Although the subject of intense research, the mechanism by which DR alters the aging processes is still unknown.

Physical exercise is another effective intervention shown to affect aging phenomena, especially when applied in combination with DR. Mild exercise in concert with DR is beneficial, but vigorous exercise coupled with DR could be deleterious. With regard to pathology, exercise generally exerts a salutary influence on age-related diseases, both neoplastic and non-neoplastic, and this effect may contribute to the increase in median life span seen with exercised rats.

Exercise coupled with 40% DR was found to suppress the incidence of fatal neoplastic disease compared to the sedentary DR group. Exercise with mild DR suppressed the incidence of multiple fatal disease and chronic nephropathy, and also delayed the occurrence of many age-related lesions compared to the ad libitum (AL) control group. However, these effects may have little bearing on the aging process per se, as maximum life span is only minimally affected. Although not as intensively studied as DR, results from studies that utilize exercise as a research probe, either alone or in combination with DR, have helped to assess the validity of proposed mechanisms for DR and aging itself.

Neither the retardation of growth rate nor the increase in physical activity, observed with either exercise or DR, appear to contribute to the anti-aging action of DR. Moreover, results from lifelong exercise studies indicate that the effects of DR do not depend upon changes in energy availability or metabolic rate. The mechanisms involving effects on adiposity or immune function are also inadequate explanations for the action of DR on aging. Of the proposed mechanisms, only one, as postulated by the Oxidative Stress Hypothesis of Aging, tenably accounts for the known effects of DR and exercise on aging.

Some people are more predisposed to suffer Parkinson's disease than others, a fraction of those due to mutations in genes involved in mitochondrial quality control. The state of mitochondrial function shows up as an important component of many different conditions and indeed in aging itself. In Parkinson's disease it is thought that mitochondrial dysfunction contributes to the conditions in which the population of dopamine-producing neurons in the brain die off, producing the characteristic symptoms of the disease.

It may be that more of Parkinson's disease is genetic than was previously thought, and the odds of that being the case increase as the chain of molecular machinery involved in mitochondrial quality control is followed and new components identified. This sort of work also helps clarify the mechanisms associated with mitochondrial dysfunction in aging:

Mitofusin 2 (Mfn2) is known for its role in fusing mitochondria together, so they might exchange mitochondrial DNA in a primitive form of sexual reproduction. "Mitofusins look like little Velcro loops. They help fuse together the outer membranes of mitochondria. Mitofusins 1 and 2 do pretty much the same thing in terms of mitochondrial fusion. What we have done is describe an entirely new function for Mfn2."

Mitochondria work to import a molecule called PINK. Then they work to destroy it. When mitochondria get sick, they can't destroy PINK and its levels begin to rise. Once PINK levels get high enough, they make a chemical change to Mfn2, which sits on the surface of mitochondria. This chemical change is called phosphorylation. Phosphorylated Mfn2 on the surface of the mitochondria can then bind with a molecule called Parkin that floats around in the surrounding cell.

Once Parkin binds to Mfn2 on sick mitochondria, Parkin labels the mitochondria for destruction. The labels then attract special compartments in the cell that "eat" and destroy the sick mitochondria. As long as all links in the quality-control system work properly, the cells' damaged power plants are removed, clearing the way for healthy ones. "But if you have a mutation in PINK, you get Parkinson's disease. And if you have a mutation in Parkin, you get Parkinson's disease. About 10 percent of Parkinson's disease is attributed to these or other mutations that have been identified." The discovery of Mfn2's relationship to PINK and Parkin opens the doors to a new genetic form of Parkinson's disease.

Link: http://www.sciencedaily.com/releases/2013/04/130425142357.htm

The electron transport chain is the core piece of biological machinery inside mitochondria, the cell's power plants. It occupies a central place in the various free radical theories of aging as well. A good number of longevity-related mutations in laboratory animals appear to alter electron transport chain function as their primary mode of operation, and a good case is made for a large portion of degenerative aging to rest atop damage to the mitochondrial genes that encode proteins essential to proper electron transport chain function.

Most biogerontologists agree that oxygen (and nitrogen) free radicals play a major role in the process of aging. The evidence strongly suggests that the electron transport chain, located in the inner mitochondrial membrane, is the major source of reactive oxygen species in animal cells.

It has been reported that there exists an inverse correlation between the rate of superoxide/hydrogen peroxide production by mitochondria and the maximum longevity of mammalian species. However, no correlation or most frequently an inverse correlation exists between the amount of antioxidant enzymes and maximum longevity. Although overexpression of the antioxidant enzymes SOD1 and CAT (as well as SOD1 alone) have been successful at extending maximum lifespan in Drosophila, this has not been the case in mice. Several labs have overexpressed SOD1 and failed to see a positive effect on longevity. [Although overexpression of CAT has been shown to extend life in mice by some groups].

An explanation for this failure is that there is some level of superoxide damage that is not preventable by SOD, such as that initiated by the hydroperoxyl radical inside the lipid bilayer, and that accumulation of this damage is responsible for aging. I therefore suggest an alternative approach to testing the free radical theory of aging in mammals. Instead of trying to increase the amount of antioxidant enzymes, I suggest using molecular biology/transgenics to decrease the rate of superoxide production, which in the context of the free radical theory of aging would be expected to increase longevity.

Personally I think the better approach to testing theory here is to implement mitochondrial repair or replacement, both of which are very feasible, and see what effect that has on older animals. It will both extend life and produce some degree of rejuvenation if the mitochondrial free radical theory of aging is correct.

Link: http://www.ncbi.nlm.nih.gov/pubmed/23604868

I mentioned GIFT/LIFT, the immune cell transplant approach to cancer therapy in a short list of research that might lead to cancer cures yesterday. This line of research derives from the fortuitous discovery of a cancer-immune lineage of laboratory mice, followed by the finding that this immunity is transferable via transplant of granulocyte or other forms of leukocyte immune cells.

This discovery raises the possibility that effective cancer treatments can be established by finding donors with appropriately equipped immune cells and then transplanting those cells into patients, even in advance of a complete understanding of how this all works. That complete understanding might enable an effective cure for cancer therapy based on altering a patient's own immune cells, or a much more reliable way to determine useful donors, but it'll take much longer to get to that point, possibly decades. Thus there is considerable incentive to take the shortcut if there's one to be had, in the same way as first generation stem cell transplant therapies continue to be established usefully far in advance of the complete understanding of how they work.

You can look back in the archives for posts that cover this topic, though I should mention that the younger organizations mentioned as being involved in work on this are mostly defunct or going nowhere, it seems. Finding funding is an issue, though the Florida clinical trial partially funded by the Life Extension Foundation is apparently still ongoing. Good for them.

• The State of Leukocyte or Granulocyte Transplants to Kill Cancer
• LEF Funds Granulocyte Cancer Therapy
• Seeking Funding to Explain Granulocyte Cancer Therapy

Today a reader pointed me to recently published research on the cancer-immune mice, which is much appreciated. Follow-on research often drifts by me, as it's harder to pick out papers from the flow once they start to focus on specific concerns and subtopics. This open access paper reinforces the previous work by Zheng Cui and others, demonstrating once more a transfer of cancer immunity between mice, but the authors note that the approach isn't as general as hoped - meaning that there are other factors at work that will make it much more of a hard slog to either (a) find a donor with immune cells that will work on your cancer, or (b) figure out how what's going on under the hood here. Why does it work for some cancers and not for others? So it's the same old story: biology is always considerable more complicated than we'd like it to be.

Immune Cells from SR/CR Mice Induce the Regression of Established Tumors in BALB/c and C57BL/6 Mice

Mouse strains that survive injection of large numbers of cancer cells are rare. Such mice constitute important experimental models for cancer resistance at the cellular and molecular levels. The spontaneous regression/complete resistance (SR/CR) mice were derived from BALB/c mice and described by Cui and colleagues in 1999. The phenotype was characterized by the ability to resist challenges from a number of cancer cell lines. This resistance involved innate immune cells, including polymorphonuclear granulocytes (PMNs), macrophages, and NK cells.

Interestingly, adoptive transfer (AT) of SR/CR leukocytes rendered recipients resistant to the intraperitoneal injection of S180 [sarcoma cancer] cells and also induced the regression of solid tumors. [In] this study we tested whether the cancer resistance of the SR/CR mice could be transferred to cancer susceptible mice by AT of selected immune cells.

In contrast to previous observations, the cancer resistance was limited to S180 sarcoma cancer cells. We were unable to confirm previous observations of resistance to EL-4 lymphoma cells and J774A.1 monocyte-macrophage cancer cells. The cancer resistance against S180 sarcoma cells could be transferred to susceptible non-resistant [mice. In] the responding recipient mice, the cancer disappeared gradually following infiltration of a large number of polymorphonuclear granulocytes and remarkably few lymphocytes in the remaining tumor tissues. This study confirmed that the in vivo growth and spread of cancer cells depend on a complex interplay between the cancer cells and the host organism.

Here, hereditary components of the immune system, most likely the innate part, played a crucial role in this interplay and lead to resistance to a single experimental cancer type. The fact that leukocytes [could] be transferred to inhibit S180 cancer cell growth in susceptible recipient mice support the vision of an efficient and adverse event free immunotherapy in future selected cancer types.

The failure to replicate early work for more than one form of cancer suggests that the underlying mechanisms here are, as mentioned above, not as general or as simple as we'd like them to be. It is very effective when it does work, however, not just causing remission of cancer, but also granting immunity. This means that research will continue, though as usual never as rapidly nor with as much funding as we'd like.

Damage to mitochondrial DNA accumulates as a side-effect of the operation of mitochondria in your cells, and per the mitochondrial free radical theory of aging proceeds to cause some fraction of degenerative aging though a long chain of ever worsening consequences.

Below you'll find recently published research that shows long-lived mice to have less mitochondrial DNA damage, which is what you'd expect to see under this model. This reinforces the need for ways to repair or replace mitochondrial DNA throughout the body in order to remove this contribution to degenerative aging. A wide range of possible approaches exist, but currently little funding is devoted towards realizing them and there is no path to getting treatments to reverse aging through the regulatory process - the standard lament when it comes to rejuvenation biotechnology.

The single gene mutation of Ames dwarf mice increases their maximum longevity by around 40% but the mechanism(s) responsible for this effect remain to be identified. This animal model thus offers a unique possibility of testing the mitochondrial theory of aging.

In this investigation, oxidative damage to mitochondrial DNA (mtDNA) was measured for the first time in dwarf and wild type mice of both sexes. In the brain, 8-oxo,7,8-dihydro-2'-deoxyguanosine (8-oxodG) in mtDNA [a measure of oxidative stress] was significantly lower in dwarfs than in their controls both in males (by 32%) and in females (by 36%). The heart of male dwarfs also showed significantly lower mtDNA 8-oxodG levels (30% decrease) than the heart of male wild type mice, whereas no differences were found in the heart of females.

The results, taken together, indicate that the single gene mutation of Ames dwarfs lowers oxidative damage to mtDNA especially in the brain, an organ of utmost relevance for aging. Together with the previous evidence for relatively lower level of oxidative damage to mtDNA in both long-lived and caloric restricted animals, these findings suggest that lowering of oxidative damage to mtDNA is a common mechanism of life extension in these three different mammalian models.

Link: http://www.ncbi.nlm.nih.gov/pubmed/23604907

Organovo has demonstrated the 3-D printing of small amounts of functional liver tissue, suitable for use in research. The limiting factor for printing larger masses is at this time largely the challenge of creating a suitable blood vessel network - something that researchers are still working on.

For the first time, human liver tissues have been generated that are truly three-dimensional, being up to 500 microns in thickness in the smallest dimension, and consisting of multiple cell types arranged in defined spatial patterns that reproduce key elements of native tissue architecture. The tissues, fabricated using Organovo's [bioprinting] platform, are highly reproducible and exhibit superior performance compared to standard 2D controls.

"We have achieved excellent function in a fully cellular 3D human liver tissue. We've combined three key features that set our 3D tissues apart from 2D cell-culture models. First, the tissues are not a monolayer of cells; our tissues are approximately 20 cell layers thick. Second, the multi-cellular tissues closely reproduce the distinct cellular patterns found in native tissue. Finally, our tissues are highly cellular, comprised of cells and the proteins those cells produce, without dependence on biomaterials or scaffold for three-dimensionality. They actually look and feel like living tissues. Not only can these tissues be a first step towards larger 3D liver, laboratory tests with these samples have the potential to be game changing for medical research. We believe these models will prove superior in their ability to provide predictive data for drug discovery and development, better than animal models or current cell models."

Link: http://ir.organovo.com/news/press-releases/press-releases-details/2013/Organovo-Describes-First-Fully-Cellular-3D-Bioprinted-Liver-Tissue

Today's topic is the cure for cancer, something a grail in medicine. It will be challenging to produce, but I think that the difficulty is presently overestimated by much of the public and those in the mainstream of the research community. The reasons for this are understandable: the past half century of cancer research is a story of continually discovered ever greater complexity in cancer biology. It is the sheer exuberant variation in cancer - between types, between tissues, between individuals, and even between tumors in an individual - that makes it such a daunting foe. Every cancer is an evolving mess of broken cells with its own character and biochemical quirks.

We stand now in the early stages of a revolution in biotechnology, however, and the rapidly expanding capabilities that brings to the research community are beginning to reveal that, for all their variety, cancers do have at least some shared characteristics and shared vulnerabilities. It is the commonalities in cancer, things that are emerging now and would have been exceedingly expensive to discover and exploit even a mere twenty years past, that will act as a foundation for the coming generation of effective cancer therapies. In that spirit, I offer you three and a half ways to cure cancer, outlined very briefly below:

1) WILT, whole-body interdiction of lengthening of telomeres

WILT is my least favorite cure for cancer, but it is nonetheless hard to argue that it isn't in fact the ultimate cure for cancer. Cancers absolutely depend upon ways to lengthen telomeres, the protective caps at the end of chromosomes that shorten with each cell division, putting a limit on the life span of ordinary cells. A cell with little left of its telomeres stops dividing, destroys itself, or becomes senescent - and thus not much use as a cancer cell. Telomeres are lengthened by the activities of the telomerase enzyme and the mechanisms imaginatively known as alternative lengthening of telomeres (ALT), both of which are abused by all cancers in order to create unfettered growth.

Disable telomerase and the genes for ALT in a human, and the result will most likely be a human who cannot suffer cancer. There is a reason this is my least favorite approach however, and that is that your stem cell populations require the ability to lengthen telomeres in order to continue to maintain your tissues over the long term. A person who underwent a hypothetical WILT treatment would need stem cell transplants or a similar way to refresh all of the different stem cell populations of the body - and there are many - every decade at least. WILT means exchanging the threat of cancer for an arguably greater dependency on medical technology.

Research into WILT is currently funded to a modest degree by the SENS Research Foundation under the OncoSENS program, with a focus on establishing a a sufficient understanding of ALT to determine the best and most comprehensive way to disrupt its mechanisms.

2) LIFT/GIFT, leukocyte/granulocyte transfusions

Somewhere out there, someone possesses immune cells (the white blood cells called leukocytes or granulocytes) that can kill your cancer. You might consider this approach to immune therapy as being analogous to first generation stem cell therapies that are presently available in many parts of the world: take someone else's immune cells, grow them in culture, and then transplant large numbers of them into your body, where they work to destroy cancer. This methodology has been shown to produce exceedingly impressive results in mice, such as entire lineages of cancer-resistance mice, but it isn't known why exactly it works so well - which makes it hard to proceed to clinical applications in the US, where a full scientific understanding of the mechanisms involved is generally required.

A couple of startups are presently working in this area, such as ImmunePath (probably) and Munogenics, with little funding and slow progress, so far as I'm aware. There is also a small ongoing clinical trial in Florida that looks like it'll wrap up later this year.

This is exactly the sort of application of cell therapies that should do well in the medical tourism arena, and indeed is appearing as an option in some overseas clinics. It is easy enough to implement that any group that can presently carry out stem cell transplants should also be able to manage immune cell transplants. More publicity, signs of progress in obtaining human results, and greater funding for trials would go a long way towards speeding the spread of this therapy and this determining whether the results in mice continue to translate well into humans.

3) Targeted cell killing technology, plus the search for commonalities in cancer

Modular targeted cell killing technology platforms with a slot for a sensing system are well in hand in the lab, and are a big part of why the next generation of cancer therapies will be far more effective and far less traumatic than chemotherapy. A great variety of such systems are presently under development: nanoparticles such as gold rods that can be heated by radiation; nanoparticles such as dendrimers that carry motes of chemotherapy drugs; nanoparticles that carry an RNA interference payload; engineered viruses; engineered bacteria; trained immune cells; and so forth.

The commonality here is that all of these systems are designed to destroy specific cells with minimal damage to surrounding cells - all that is needed are mechanisms to ensure that these cell-killers only target cancer cells. This largely means discovering suitable markers on a cell surface: specific proteins that differentiate cancer cells by the degree to which they are present, and which are sufficiently general to appear in a sizable population of patients or many types of cancer.

The big uncertainty here is whether or not researchers will find targets shared by many cancers that are sufficiently discriminating to allow enough preferential targeting of cancer cells. It's possible to layer multiple poorly discriminating targets to get a highly discriminating system, however, and there are promising signs of late on this front. You might look at trials involving therapies targeting CD47, for example, which appears on most cancers per the latest research.

If there are enough markers like CD47 out there, then it should be possible to build a comparatively small suite of general cancer therapies that will kill 80% of cancers at any stage, metastatic or not, with minimal side effects. At this point in the development of medicine even twenty different loads for the same basic system to effectively tackle 80% of all cancers looks like a very good thing - and very plausible too, if the process of discovering cancer commonalities keeps going the way it is. All that is needed is one kill mechanism and a delivery platform modular enough to accept the different sensor mechanisms while still being manufacturable at low cost, such as through the use of dendrimers or viruses.

3.5) The mechanisms used by naked or blind mole rats

Naked mole rats don't get cancer, and it appears the same is true of blind mole rats, but for different reasons. Present understanding of the evolved mechanisms by which these animals manage to stay cancer-free for the several decades of their life spans, even while living in an environment that produces a tremendous amount of cellular damage, is advanced enough to have a sensible discussion on how to recreate it in humans.

This really only counts as half a potential cancer cure, however. It does seem to grant cancer immunity, or as near to it as counts, but it is a big question mark as to how hard it will be to safely have our cells start to behave in the same way as those of a mole-rat - even only temporarily. In the case of naked mole rats, the mechanism in question involves the genes p16 and p27, which suggests that it's something that could be accomplished via gene therapy, but much remains to be done in order to find out how much work there is here.

So this is certainly as intrusive a proposal as WILT, i.e. we're talking about altering human metabolism and genetic programming, but far less is known regarding how best to move forward with this strategy. Still, it is probably the case that more researchers are working on it than are in the case of WILT - the cancer community is large and well funded, and the study of mole rats is well recognized these days.

Cartilage is one of the more challenging tissues to regenerate - it's comparatively easy to grow something that's more or less like cartilage, but it's proven hard to reproduce the necessary small-scale structure and mechanical properties of the real thing. So work continues in laboratory animals:

[Researchers] have suggested that articular cartilage defects can be repaired by a novel thermo-sensitive injectable hydrogel engineered with gene modified bone marrow mesenchymal stromal cells (BMSCs). The chitosan and polyvinyl alcohol composite hydrogel containing hTGFβ-1 gene modified BMSCs was injected into rabbits with defective articular cartilage. Sixteen weeks later the defected cartilage regenerated.

No reliable approach is currently available for complete restoration of damaged articular cartilage. Tissue engineering combined with gene therapy technology has the potential to manage the repair of defective articular cartilage. CS/PVA gel can be applied to the repair of articular cartilage defects as an injectable material in tissue engineering, and the regenerated cartilage can secrete cartilage matrix and perform the functions of hyaline cartilage. Use of this gel for cartilage repair has advantages such as the minor surgical procedure required, tight bonding with the damaged tissue and lack of rejection.

Link: http://www.eurekalert.org/pub_releases/2013-04/sfeb-rac042313.php

Here is one of many examples of different forms of targeted cancer therapies under development. Most use nanoparticles, immune cells, or viruses as the agent that selectively transports a cell-killing mechanism to the cancer cells, but bacteria are also a viable possibility:

[Researchers] have developed a therapy for pancreatic cancer that uses Listeria bacteria to selectively infect tumor cells and deliver radioisotopes into them. The experimental treatment dramatically decreased the number of metastases (cancers that have spread to other parts of the body) in a mouse model of highly aggressive pancreatic cancer without harming healthy tissue.

Several years ago, scientists observed that an attenuated (weakened) form of Listeria monocytogenes can infect cancer cells, but not normal cells. [The] tumor microenvironment suppresses the body's immune response, allowing Listeria to survive inside the tumors. By contrast, the weakened bacteria are rapidly eliminated in normal tissues. Scientists later showed that Listeria could be harnessed to carry an anti-cancer drug to tumor cells in laboratory cultures, but this concept was never tested in an animal model. These findings prompted [researchers to couple] a radioactive isotope called rhenium to the weakened Listeria bacteria. "We chose rhenium because it emits beta particles, which are very effective in treating cancer. Also, rhenium has a half-life of 17 hours, so it is cleared from the body relatively quickly, minimizing damage to healthy tissue."

Mice with metastatic pancreatic cancer were given intra-abdominal injections of the radioactive Listeria once a day for seven days, followed by a seven-day "rest" period and four additional daily injections of the radioactive bacteria. After 21 days, the scientists counted the number of metastases in the mice. The treatment had reduced the metastases by 90 percent compared with untreated controls. In addition, the radioactive Listeria had concentrated in metastases and to a lesser extent in primary tumors but not in healthy tissues, and the treated mice did not appear to suffer any ill effects.

Link: http://www.eurekalert.org/pub_releases/2013-04/aeco-rbt041713.php

When I discuss the corrosive effects of regulation on progress in medicine, such as the enormous and entirely unnecessary costs and barriers put in place by the US Food and Drug Administration (FDA), I usually focus on the research and development side of the coin: the process of creating new therapies. That is greatly impacted, not least because as the system presently stands it is actually impossible to gain approval for any treatment for degenerative aging - no medicine is permitted into the clinical trial system if its purpose is to treat old people to reverse some of their symptoms. The FDA doesn't recognize aging as a named medical condition that can be be treated, and there is no path short of complete revolution in the regulatory system in the US to make this any different.

The costs and prohibited actions due to the FDA propagate back down the fundraising chain. You can't raise venture capital if there's prospect for selling the resulting therapy. It's harder to raise funds for basic research when there's no connection to later commercial activity. There are thus far fewer research groups working on potentially important ways to address aging than there might be, and less press and public understand of what might happen if the FDA were not standing in the way, a hideous roadblock, a ball and chain that stops the research community from improving the human condition. The invisible costs, the therapies that might have existed but do not because of regulation, are always the hardest to make people understand.

But that's just one side of the coin. The other side is the provision of medical services: once therapies exist, how are they delivered, priced, and bought and sold? Here the institutions of regulation have just as horrific and corrosive an effect, raising costs and reducing availability to no good end - a system has come into being that benefits no-one, as every individual would be better off under a free market for medical services, and yet this system seems destined to become even worse in the future. Perverse short term incentives steer us all in the wrong direction. Allow me to point out an article that provides an unusually clear vision of how one facet of this process is proceeding:

How Government Killed the Medical Profession

At first, the decay was subtle. In the 1980s, Medicare imposed price controls upon physicians who treated anyone over 65. Any provider wishing to get compensated was required to use International Statistical Classification of Diseases (ICD) and Current Procedural Terminology (CPT) codes to describe the service when submitting a bill. The designers of these systems believed that standardized classifications would lead to more accurate adjudication of Medicare claims.

What it actually did was force doctors to wedge their patients and their services into predetermined, ill-fitting categories. This approach resembled the command-and-control models used in the Soviet bloc and the People's Republic of China, models that were already failing spectacularly by the end of the 1980s.

Before long, these codes were attached to a fee schedule based upon the amount of time a medical professional had to devote to each patient, a concept perilously close to another Marxist relic: the labor theory of value. Named the Resource-Based Relative Value System (RBRVS), each procedure code was assigned a specific value, by a panel of experts, based supposedly upon the amount of time and labor it required. It didn't matter if an operation was being performed by a renowned surgical expert--perhaps the inventor of the procedure--or by a doctor just out of residency doing the operation for the first time. They both got paid the same.

Hospitals' reimbursements for their Medicare-patient treatments were based on another coding system: the Diagnosis Related Group (DRG). Each diagnostic code is assigned a specific monetary value, and the hospital is paid based on one or a combination of diagnostic codes used to describe the reason for a patient's hospitalization. If, say, the diagnosis is pneumonia, then the hospital is given a flat amount for that diagnosis, regardless of the amount of equipment, staffing, and days used to treat a particular patient. As a result, the hospital is incentivized to attach as many adjunct diagnostic codes as possible to try to increase the Medicare payday. It is common for hospital coders to contact the attending physicians and try to coax them into adding a few more diagnoses into the hospital record.

Coding was one of the earliest manifestations of the cancer consuming the medical profession, but the disease is much more broad-based and systemic. The root of the problem is that patients are not payers. Through myriad tax and regulatory policies adopted on the federal and state level, the system rarely sees a direct interaction between a consumer and a provider of a health care good or service. Instead, a third party - either a private insurance company or a government payer, such as Medicare or Medicaid - covers almost all the costs. According to the National Center for Policy Analysis, on average, the consumer pays only 12 percent of the total health care bill directly out of pocket. There is no incentive, through a market system with transparent prices, for either the provider or the consumer to be cost-effective.

Once free to be creative and innovative in their own practices, doctors are becoming more like assembly-line workers, constrained by rules and regulations aimed to systemize their craft. It's no surprise that retirement is starting to look more attractive. A June 2012 survey of 36,000 doctors in active clinical practice by the Doctors and Patients Medical Association found 90 percent of doctors believe the medical system is "on the wrong track" and 83 percent are thinking about quitting. Another 85 percent said "the medical profession is in a tailspin." 65 percent say that "government involvement is most to blame for current problems."

If provision of medicine stultifies, then so does much of the impetus for research. In the field of aging and human longevity that matters greatly - we're on a timer, all aging to death one day at a time, and cannot afford to suffer through decades of collapse and slow progress in research, development, and provision of medical services. To my eyes the present system is doomed; the only way through is for it to fail utterly in one way or another. The most plausible collapse is the one the US regulatory monolith continues to exist, a drain on the declining US, but where near everyone travels to Asia-Pacific countries or other less regulated destinations for any meaningful medical services - in other words much like the UK, or other European countries. The only hope for the future is competition through medical tourism, which requires that other advanced regions of the world maintain far less onerous regulations for medicine.

You might look back in the Fight Aging! articles for links to a few other articles on the same theme, which variously blame the guild system of the medical profession and the command and control socialism of the hospitals for the present decline in medicine:

• The Doom that Fell Upon Medical Progress in the US
• The Cost of Medical Socialism
• The Costs and Consequences of Medical Socialism

CALERIE is an ongoing series of studies on calorie restriction in humans and its effects on measures of health and metabolism. In this blog post you'll find some notes on results from the latest phase, yet to be published formally, but presented at conferences:

Three speakers described how a select group of 220 healthy volunteers [chose] to shun a quarter of their dietary calories in the hope of improving their long-term health and, potentially, extending lifespan. These participants of the CALERIE phase 2 trial were randomized to 25 percent CR or ad libitum eating. The large NIH-funded, mulitcenter, parallel group, randomized controlled trial was designed to evaluate how a calorie restricted diet affected biomarkers of aging and age-related disease over the long-term.

The primary aim of the trial [was] to evaluate whether 25 percent CR resulted in a sustained metabolic adaptation. One of the underlying theories of how CR worked is that attenuates the biological aging process by reducing resting metabolic rate (RMR) leading to reduced cumulative oxidative damage from aerobic respiration. [However] the calorie restriction did not cause a change in body temperature that would be indicative of reduced resting metabolic rate that would show adaptation. These data (which are not published yet) are currently being evaluated for proper interpretation. [The] findings are interesting because they are inconsistent with previous studies in animals and a recently in humans showing a metabolic adaptation through RMR and core body temperature in response to CR.

"Basically, these are the primary mechanisms in humans - reduction of metabolic rate and core body temperature - we did not find an adaptation in the resting component, but we did find an adaptation in the non-resting component. If there was a reduction, that is supposed to lend support to the oxidative theory. What exactly this means is still being worked out."

The long-term CR had a significant effect on a variety of [cardiovascular disease risk factor] measurements including a reduced metabolic syndrome score, reduced systolic blood pressure, reduced LDL, reduced triglycerides, and increased HDL that were maintained over the study. There were no significant differences on glucose measures or inflammatory markers IL-6 and TNF-a. These results are consistent with previous studies related to reductions in body weight.

Link: http://evolvinghealth.wordpress.com/2013/04/21/is-long-term-calorie-restriction-in-humans-worth-it/

The CR Society is a long-standing organization that promotes and provides information about the practice of calorie restriction with optimal nutrition, something shown to extend life and greatly improve measures of health in many species. There are some thousands of members, and the Society mailing lists are quite busy. The Society has done well over the years in encouraging research into the long-term health and potential longevity benefits of calorie restriction in humans, and is an excellent example of what can be achieved by building strong ties between health advocates and the scientific community.

The next CR Society conference is coming up in June, so there's still time to register:

The next CR Society conference will be held at the Buck Institute for Research on Aging in Novato California June 5 - 8, 2013. This conference will mark the 10-year anniversary of the founding of the CR Society as a non profit organization.

The topics will include CR and Cancer, CR Primate Studies, Biological Clocks and Physical Activity, Stem cell/senescence/rejuvenation. This will be a very special opportunity to interact with CR comrades, and researchers at the Buck Institute, see and tour the Buck Institute - not to be missed!

Link: http://www.crsociety.org/science/conference/CR_008a

The field of stem cell research is very broad, very large, and very well funded nowadays - which we should all be appropriately thankful for, given its necessary part in producing the means to reverse the causes and consequences of aging. Regenerative medicine based on the transplant and manipulation of stem cells will be used for critical repairs in age-damaged tissues, and ultimately to replace or repair the stem cells and stem cell niches that have become too damaged to properly maintain the body. Progress towards stem cell therapies is much faster now than even ten years ago, and what would have been major advances back then, heralded in the popular press, are now routinely occurring on a weekly basis.

Stem cell research is also branching into many subfields and distinct, separate lines of research. There are efforts to make stem cell transplants more effective; work on finding signals that will override the programming of aged stem cells in the body; continuing efforts to find and classify populations of stem cells that are good sources for transplants or studies; initiatives seeking better ways to reprogram cells, such that ordinary cells can be transformed into stem cells, or stem cells guided to form specific cell types; and so on. Many distinct infrastructures are being built beneath the umbrella goal of regeneration from injury and aging, much of which involves finding ways to make cells to do as they are told, more effectively and at less expense.

Here are examples of recent advances in this sort of infrastructural work, efforts to make a branch of stem cell therapy or one of the underlying technologies more effective.

Antibody Transforms Stem Cells Directly Into Brain Cells

[Researchers screened] for antibodies that could activate the GCSF receptor, a growth-factor receptor found on bone marrow cells and other cell types. GCSF-mimicking drugs were among the first biotech bestsellers because of their ability to stimulate white blood cell growth - which counteracts the marrow-suppressing side effect of cancer chemotherapy. The team soon isolated one antibody type or "clone" that could activate the GCSF receptor and stimulate growth in test cells. The researchers then tested an unanchored, soluble version of this antibody on cultures of bone marrow stem cells from human volunteers.

Whereas the GCSF protein, as expected, stimulated such stem cells to proliferate and start maturing towards adult white blood cells, the GCSF-mimicking antibody had a markedly different effect. The cells proliferated, but also started becoming long and thin and attaching to the bottom of the dish. The cells were reminiscent of neural progenitor cells -- which further tests for neural cell markers confirmed they were.

Changing cells of marrow lineage into cells of neural lineage -- a direct identity switch termed "transdifferentiation" -- just by activating a single receptor is a noteworthy achievement. Scientists do have methods for turning marrow stem cells into other adult cell types, but these methods typically require a radical and risky deprogramming of marrow cells to an embryonic-like stem-cell state, followed by a complex series of molecular nudges toward a given adult cell fate. Relatively few laboratories have reported direct transdifferentiation techniques. "As far as I know, no one has ever achieved transdifferentiation by using a single protein -- a protein that potentially could be used as a therapeutic."

Stem Cell Transplant Restores Memory, Learning in Mice

Human embryonic stem cells have been transformed into nerve cells that helped mice regain the ability to learn and remember. Once inside the mouse brain, the implanted stem cells formed two common, vital types of neurons, which communicate with the chemicals GABA or acetylcholine.

[Researchers] chemically directed the human embryonic stem cells to begin differentiation into neural cells, and then injected those intermediate cells. Ushering the cells through partial specialization prevented the formation of unwanted cell types in the mice. Ensuring that nearly all of the transplanted cells became neural cells was critical. "That means you are able to predict what the progeny will be, and for any future use in therapy, you reduce the chance of injecting stem cells that could form tumors. In many other transplant experiments, injecting early progenitor cells resulted in masses of cells - tumors. This didn't happen in our case because the transplanted cells are pure and committed to a particular fate so that they do not generate anything else. We need to be sure we do not inject the seeds of cancer."

The mice were a special strain that do not reject transplants from other species. After the transplant, the mice scored significantly better on common tests of learning and memory in mice. For example, they were more adept in the water maze test, which challenged them to remember the location of a hidden platform in a pool.

Within a given species, larger individuals tend to age faster and die younger. Between species, larger species tend to live longer - though there are many exceptions to this rule. Here is an open access article on this phenomenon from a programmed aging perspective, i.e. the author is building on his hyperfunction theory to say that aging is a genetic program of growth that runs awry to cause damage in old age, past the point at which evolutionary selection guides its operation. This is as opposed to aging as straightforward "wear and tear" type damage that accumulates as a result of the normal operation of metabolism over time, becoming meaningfully harmful only past the age at which evolutionary selection favors further adaptations to reduce, avoid, or repair this damage.

It has been known for millennia that large animals live longer, inspiring numerous theories of aging. For example, elephants and humans live longer than mice, which in turn live longer than worms and flies. The correlation is not perfect, with many explainable exceptions, but it is still obvious. In contrast, within each species (e.g., mice and some other mammals) small body size is associated with longevity and slow aging. The concept that aging (and age-related diseases) is an aimless continuation of developmental growth, a hyperfunction driven by the same nutrient-sensing and growth-promoting pathways such as MTOR, may explain this longstanding paradox.

Fast versus slow aging may depend on whether the organism "grows fast" or "develops longer": first case should be associated with high MTOR. Exceptions may be numerous. Small size is not always related to the GH/IGF/MTOR pathway but instead may be caused by defects that shorten life span. But understanding of each exception will further illuminate the rules. On a wider scale (from worm to whale), large animals live longer because aging is quasi-programmed. In contrast, "big" mice live shorter because they grow faster than dwarf mice and growth is driven by the same pathways that drive aging. Fast-growing mice are expected to have over-activation of growth-promoting pathways (either by excessive calorie consumption or due to genetic mutations), which drive aging and age-related diseases later. Cellular hyperfunction is the key feature of aging cell, leading to organismal death. Yet, there are also two other crucial aspects of hyperfunction theory: (a) aging as a quasi-program of developmental growth and (b) both processes are driven by the same growth-promoting-signaling pathways including MTOR.

Link: http://impactaging.com/papers/v5/n4/full/100551.html

This study result is contrary to the mainstream view, which is that absent advances in medicine the risk of suffering dementia will continue to rise along with life span. However, it makes sense from a reliability theory point of view; if aging and dysfunction and life span are all consequences of the level of damage suffered in cells and molecular machinery, then reducing that damage should extend life by slowing aging and also reducing dysfunction.

The risk of developing dementia may have declined over the past 20 years, in direct contrast to what many previously assumed. The result is based on data from SNAC-K, an ongoing study on aging and health that started in 1987.

"We know that cardiovascular disease is an important risk factor for dementia. The suggested decrease in dementia risk coincides with the general reduction in cardiovascular disease over recent decades. Health check-ups and cardiovascular disease prevention have improved significantly in Sweden, and we now see results of this improvement reflected in the risk of developing dementia."

The result shows the prevalence of dementia was stable in both men and women across all age groups after age 75 during the entire study period (1987-1989 and 2001-2004), despite the fact that the survival of persons with dementia increased since the end of the 1980s. This means that the overall risk of developing dementia must have declined during the period, possibly thanks to prevention and better treatment of cardiovascular disease.

"The reduction of dementia risk is a positive phenomenon, but it is important to remember that the number of people with dementia will continue to rise along with the increase in life expectancy and absolute numbers of people over age 75."

Link: http://ki.se/ki/jsp/polopoly.jsp?l=en&d=130&a=162905&newsdep=130

Philanthropy by high net worth individuals has the potential to move the needle on any major biotechnology project these days. The cost of research in the field is falling rapidly, thanks to spectacular ongoing gains in computational power and materials science. There are now thousands of individuals in the world with a net worth sufficient to completely fund a cure for a disease, from a starting point of nothing but ideas through to first human trials. But of course to exchange your entire net worth for a cure, to give up on the whole of the vast process that has been your business life to date, you'd have to be something of a visionary zealot - and people tend not to be both very wealthy and visionary zealots of this nature; the two paths are mutually exclusive.

The cost to develop the various biotechnologies of rejuvenation enumerated in the SENS vision - a digest of discoveries from the past twenty years in many fields of the life sciences, coupled with innovative, detailed plans to develop therapies - might be in the vicinity of a billion dollars over ten to twenty years. That would give you a good chance at demonstrating rejuvenation in old mice, such as by doubling their remaining life span, with commensurate improvements in their health and reductions in risk of age-related disease. There are perhaps a hundred people in the world who could fund that project end to end on 10% of their net worth or less, though as I've noted in the past a billionaire is possibly best viewed more as the head of a city-state than a person with complete agency over their own fortune.

One portion of the advocacy and fundraising for new approaches to longevity science like SENS involves gathering a strong grassroots community and leaning on their modest financial support. This sort of activity typically takes place during the bootstrapping phase of development, and in the process validates your cause in the eyes of established funding sources, high net worth philanthropists, and so forth. These institutions and individuals tend to be very conservative in how they devote their resources to scientific projects, which means that you must have some backing and widespread validation in order to become an attractive recipient. So it has traditionally been the case that you can't really make too much of a mark without both a broad base of support among the public and interested followers, and then atop that some circle of people and institutions capable of devoting large-scale funding to solving specific problems. The rise of crowdfunding is changing that balance, but it still generally holds - it's the rare organization that manages to skip past the need for wealthy donors due to the size and strength of its community.

Given all of this you might look at the advocacy and outreach for SENS or other disruptive, next-generation, high-yield approaches to extending healthy human life as something that has three components:

• Convince the scientific community.
• Convince the general public.
• Convince high net worth donors and funding institutions.

In the third category, there is the constant process of networking - connections, discussions, and introductions that we don't see all that much of from the outside - but there is also the matter of messaging via channels aimed at the wealthier and more influential portions of society. One example of that is a recent article by researcher and advocate Aubrey de Grey in the Private Journey, a magazine aimed at luxury consumers. Via the Reddit SENS community, I note that a PDF copy can be downloaded from the SENS Research Foundation site archives:

The Undoing of Aging

The desire to defeat aging is surely even more long-standing than the quest to reach the stars. Unfortunately, the idea that we will crumble and die is so crippling that most people evidently need to convince themselves, by whatever means, that it is not such a bad thing after all. Whether it's the existence of a joyous afterlife, or the presumption that a post-aging world would be unsustainably overpopulated, or the fear of immortal dictators, a conversation with nearly anyone about the idea of developing medicine to prevent age-related ill-health is almost certain to be derailed into arguments about whether such medicine would be a good thing at all.

A key pillar of many people's thinking about this topic is the misconception that "aging itself" is somehow a different sort of thing than the diseases of old age. There is actually no such distinction. Age-related diseases spare young adults simply because they take a long time to develop, and they affect everyone who lives long enough because they are side-effects of the body's normal operation rather than being caused by external factors such as infections. In other words, aging is simply the collection of early stages of the diseases and disabilities of old age, and treatment of aging is simply preventative medicine for those conditions - preventative geriatrics. It is thus logically incoherent to support medicine for the elderly but not medicine for aging.

I claim no originality for the above: it has long been the virtually universal view of those who study the biology of aging. I believe it is resisted by the wider world, despite those experts' energetic efforts, overwhelmingly because people don't believe there is much chance of significant progress in their or even their children's lifetimes and they don't want to get their hopes up. But in recent years, the justification for such pessimism has evaporated.

It has done so above all because of progress in regenerative medicine, which colloquially (but see below) consists of stem cells and tissue engineering. Regenerative medicine can be defined as the restoration of bodily function by restoration of structure. We may replace entire organs (tissue engineering), or we may repair organs by replacing their constituent cells (stem cell therapy). In a sense, regenerative medicine is maintenance for the human body. as such, it should in principle be capable of constituting preventative maintenance for the chronic, slowly progressive, initially harmless but eventually fatal processes that jointly make up aging and the diseases of old age. Regenerative medicine has only recently, however, become recognized as a promising avenue for postponing age-related ill-health. This is for two reasons. firstly, it was originally conceived and pursued for its potential to treat acute injury, such as spinal cord trauma, rather than chronic damage: thus, regenerative medicine pioneers and biologists of aging simply didn't talk to each other very much, with the result that those studying aging were insufficiently informed about progress in regenerative medicine to appreciate its potential. The second reason was equally important: in order to be plausibly applicable to aging, regenerative medicine must be broadened into a host of other areas, over and above stem cells and tissue engineering, and those areas are mostly at considerably earlier stages of development.

But not fancifully early. In the decade since I first laid out a putatively comprehensive classification of the various types of molecular and cellular "damage" that must be periodically repaired in order to stave off the decline of old age, and the specifics of how we might do it, progress has been gratifyingly rapid (though I estimate it could be at least three times faster if the potential of this approach were more widely understood and funding for it correspondingly elevated). Furthermore, that plan has abundantly stood the test of time, undergoing only minor adjustments.

In this short, general-audience piece I can only hint at the advances over the past year or two achieved by researchers worldwide in this space. SENS Research Foundation was created for this purpose, and alongside numerous other institutes and organizations, both commercial and nonprofit, we have achieved not only the retardation of aging but its actual repair, restoring youthful health to animals that were suffering widespread age-related decline. Much remains to be done to extend these results, before they can realistically be applied in the clinic. However, the removal of toxic metabolic by-products shows clear promise of completely eliminating cardiovascular disease, the Western world's foremost killer, and also macular degeneration, the leading cause of blindness in the elderly. Similarly, removing cells that have become dysregulated and toxic to the body was recently shown, in multiple models, to restore function to sick animals. Advances like these, in combination with traditional regenerative medicine, may in the next few decades deliver a truly comprehensive and dramatic postponement of age-related ill-health.

Many longevity mutations discovered in lower animals such as nematodes involve alterations to mitochondrial function - which only reinforces the apparent importance of mitochondria in determining life span. Mitochondria swarm within cells, working to produce the chemical energy stores used to power cellular operations. In doing so they emit reactive oxygen species, however, that can cause all sorts of harm to the molecular machinery of a cell if not neutralized by a cell's native antioxidants. It is damage to mitochondrial DNA, however, that seems to be one of the root causes of degenerative aging, via a Rube Goldberg sequence of consequences that causes cells to become dysfunctional mass exporters of reactive, harmful molecules.

From a practical therapy standpoint, the research community should be working on ways to repair, replace, or back up mitochondrial DNA in our cells if we want this contribution to aging to go away. That work is very poorly funded, however, in comparison to the benefits it might deliver. Meanwhile, examination of longevity mutations in lower animals continues to reinforce the fact that this is an important direction for therapies to treat and reverse aging.

Some mitochondrial longevity mutations work via hormesis; they cause a slight increase in the level of emitted reactive oxygen species, which in turn causes the cell to react with increased housekeeping and repair activities, resulting in a net gain - less damage over the long term translates into slower aging. Other mutations lower the level of emitted reactive oxygen species, which again means less damage over the long term. Yet more mitochondrial mutations extend life in less obvious ways, or cause mitochondrial dysfunction that appears at the high level to be broadly similar to that of longevity mutants, yet reduces life span. Once you start digging in to the mechanisms of the mitochondrial interior - the electron transport chain with it's multiple complexes - it's all far from simple

Here is an example of research into the mechanisms of mitochondrial longevity mutations in nematode worms:

Many Caenorhabditis elegans mutants with dysfunctional mitochondrial electron transport chain are surprisingly long lived. Both short-lived (gas-1(fc21)) and long-lived (nuo-6(qm200)) mutants of mitochondrial complex I have been identified. However, it is not clear what are the pathways determining the difference in longevity.

We show that even in a short-lived gas-1(fc21) mutant, many longevity assurance pathways, shown to be important for lifespan prolongation in long-lived mutants, are active. Beside similar dependence on alternative metabolic pathways, short-lived gas-1(fc21) mutants and long-lived nuo-6(qm200) mutants also activate hypoxia-inducible factor-1α (HIF-1α) stress pathway and mitochondrial unfolded protein response (UPRmt).

The major difference that we detected between mutants of different longevity is in the massive loss of complex I accompanied by upregulation of complex II levels, only in short-lived, gas-1(fc21) mutant. We show that high levels of complex II negatively regulate longevity in gas-1(fc21) mutant by decreasing the stability of complex I. Furthermore, our results demonstrate that increase in complex I stability, improves mitochondrial function and decreases mitochondrial stress, putting it inside a "window" of mitochondrial dysfunction that allows lifespan prolongation.

Link: http://dx.doi.org/10.1371/journal.pone.0059493

The indy gene - named for "I'm not dead yet" - was one of the earliest longevity mutations to be uncovered in flies, and consequently is somewhat better studied than the many that have followed since then. Here is an open access paper on the subject:

Decreased expression of the fly and worm Indy genes extends longevity. The fly Indy gene and its mammalian homolog are transporters of Krebs cycle intermediates, with the highest rate of uptake for citrate. Cytosolic citrate has a role in energy regulation by affecting fatty acid synthesis and glycolysis. Fly, worm, and mice Indy gene homologs are predominantly expressed in places important for intermediary metabolism. Consequently, decreased expression of Indy in fly and worm, and the removal of mIndy in mice exhibit changes associated with calorie restriction, such as decreased levels of lipids, changes in carbohydrate metabolism and increased mitochondrial biogenesis. Here we report that several Indy alleles in a diverse array of genetic backgrounds confer increased longevity.

The paper is a good example of the way in which calorie restriction muddies the water of longevity studies; the effects of calorie restriction on life span are very strong in lower animals like flies and worms, and many past studies failed to fully account for differing dietary calorie intakes between populations of these animals. The authors of this paper point out a number of past papers with results that may tainted due to differing calorie intake, and note that their own work tries to control for this.

Link: http://www.frontiersin.org/Genetics_of_Aging/10.3389/fgene.2013.00047/full

The gene BubR1 is of interest to cancer researchers involved in the study of various forms of nuclear DNA damage, the intricate but usually very reliable DNA repair mechanisms that strive to revert that damage, dysfunction in those repair mechanisms, and how these items relate to cancer and aging. Cancer is quite clearly a condition spawned by damage to the DNA in the cell nucleus; the more of that damage you suffer, the more likely it is that one of your cells will undergo the right combination of mutations to turn it into an unfettered, self-replicating cancer seed - something that looks and acts a lot like a stem cell, spawning copies of itself and a legion of descendants prone to further mutation and causing havoc.

For those of us who follow longevity science, the gene BubR1 is of interest because altering its gene expression level is one of the few simple mechanisms than can both shorten and extend life in mice. Less BubR1 produces an accelerated aging condition, while more of it appears to slow aging, reducing the incidence of various common age-related conditions in the mice that have this gene therapy applied to them.

It is important to note that accelerated aging conditions are generally classed as DNA repair dysfunctions. The worse the dysfunction, the faster that the individual suffers what looks a lot like accelerated aging - but there is some debate in the research community as to whether what is happened should be described as accelerated aging. From the perspective of those of us interested in ways to extend healthy life, research results involving laboratory animals suffering from artificially induced forms of accelerated aging have to be viewed carefully, because they are rarely straightforwardly applicable to normal aging. When you alter genes in a way that causes accelerating aging, such as by reducing the efficiency of some crucial part of DNA repair, this is analogous to breaking a part of a machine - you shouldn't be surprised to find that it fails sooner and more readily than its unbroken peers. That doesn't necessarily say anything about how you might extend the working life of that type of machinery, however.

So you really have to look at each research result on a case by case basis; the ones that are interesting and do have something to say about normal aging are almost always those in which the mechanism causing accelerating aging can be turned around to extend life, as is the case for BubR1 levels.

As it so happens, this all ties in to cellular senescence, another topic of interest to those of us who follow developments in longevity science. Senescent cells are those that have left the cell cycle due to age or damage - such as damage to their nuclear DNA - and really should be destroyed, either by their own programmed cell death processes or by the immune system. Cellular senescence might be thought of as a part of the evolved balance between cancer risk and the need for cells to work and maintain tissues; the more damage there is in the cellular environment, the more cells become senescent, an adaptation that lowers the risk of cancer by preventing damaged cells from undertaking their normal range of activities.

Unfortunately senescent cells are still harmful in and of themselves, as they secrete all sorts of unwanted signals and remodel their local environment. The more of them there are, the more their presence damages the surrounding tissue. The growth in senescent cells with age is one of the root causes of degenerative aging, and getting rid of them on a regular basis is one of the proposed rejuvenation therapies in the SENS vision for reversing the course of aging.

A demonstration of improved health measures in mice through destruction of senescent cells was carried out two years ago. The study used BubR1 mutants suffering from accelerated aging - and thus a faster accumulation of DNA damage and senescent cells. Researchers often use accelerated aging as a way to enable studies to conclude more rapidly, and thus be conducted at an affordable cost; there is an enormous difference in cost between a study that runs a few months and one that runs a few years. Here, however, it is the case that the researchers involved are as much interested in cancer and DNA damage as they are in aging, and the BubR1 mice are their main object of study for many reasons. That they are producing results of interest to longevity science on the matter of cellular senescence is a side-effect of the main thrust of their research, and a consequence of the overlapping mechanisms involved: DNA damage, DNA repair, cancer, aging, accelerated aging, and cellular senescence.

So that all said, let me point you to the latest research publication from this group, which pleasantly enough is open access. You might want to try the summary first, which explains their conjecture that cellular senescence resulting from DNA damage falls most heavily on the stem-like cells responsible for tissue maintenance:

Mayo Clinic researchers discover that stem cell senescence drives aging

BubR1 is an essential part of the mitotic checkpoint, the mechanism controlling proper cell division or mitosis. Without sufficient levels of BubR1, chromosomal imbalance will occur, leading to premature aging and cancer. Using mutant mice that expressed low levels of BubR1, the researchers found development of dysfunctional tissue with impaired cell regeneration. In analyzing the progenitor populations in skeletal muscle and fat, they found that a subset of progenitors was senescent.

"Earlier we discovered that senescent cells accumulate in tissues with aging and that removal of these cells delays age-related functional decline in these tissues. The key advance of the current study is that the progenitor cell populations are most sensitive for senescence, thereby interfering with the innate capacity of the tissue to counteract degeneration."

As to the open access paper itself, I should mention it is largely concerned with one specific fairly drastic form of DNA damage, the class of chromosome abnormalities known as aneuploidy, and the relationships between aneuploidy, cancer and aging, but touches on much of what was discussed above.

Aneuploidy in health, disease, and aging

The link between BubR1 and early aging raises the question as to whether BubR1 is implicated in natural aging. One observation consistent with such a role is that BubR1 levels decline in various tissues with chronological aging, at least in mice. The underlying mechanisms are poorly understood: [BubR1] expression could simply decline as a result of reduced cell proliferation with aging, but a study on transgenic mice that constitutively overexpress BubR1 and are not subject to an age-related drop in BubR1 seem to argue against this. BubR1 transgenic mice live longer than normal mice and have an increased healthspan (the period during which an organism is free from serious or chronic disease, including cancer) characterized by attenuated muscle and renal atrophy, glomerulosclerosis, and increased cardiac function.

These studies further uncovered that aneuploidization is a hallmark of aging, raising the possibility that age-related aneuploidy contributes to tissue dysfunction. Consistent with this idea, reduced senescence and tissue deterioration in BubR1 transgenic mice tightly correlated with attenuated age-related aneuploidy. How BubR1 overexpression counteracts chromosome missegregation remains under investigation, with early evidence suggesting that defects in mitotic checkpoint control and microtubule-kinetochore attachment are ameliorated. This would imply that both these mitotic processes are subject to age-related decline and at least partially responsible for age-related aneuploidy.

As you can see, this also relates to the debate regarding the degree to which nuclear DNA damage is a cause of degenerative aging versus merely a marker of advancing age and a determinant of cancer risk. There are of course many different forms of DNA damage, and some arguments revolve around one type or another (such as double-strand breaks) being important in aging.

A range of research in laboratory animals associates alterations to the reproductive system with alterations in longevity. Nematode worms live longer if you remove their germ cells, for example. Transplanting younger ovaries into older mice extends life as well. There is some thought that these varied approaches work through common longevity mechanisms such as insulin-like signaling pathways, but that's by no means certain.

Here is another set of data to add to the existing research on this topic:

Reproduction is a risky affair; a lifespan cost of maintaining reproductive capability, and of reproduction itself, has been demonstrated in a wide range of animal species. However, little is understood about the mechanisms underlying this relationship. Most cost-of-reproduction studies simply ask how reproduction influences age at death, but are blind to the subjects' actual causes of death. Lifespan is a composite variable of myriad causes of death and it has not been clear whether the consequences of reproduction or of reproductive capability influence all causes of death equally.

To address this gap in understanding, we compared causes of death among over 40,000 sterilized and reproductively intact domestic dogs, Canis lupus familiaris. We found that sterilization was strongly associated with an increase in lifespan, and while it decreased risk of death from some causes, such as infectious disease, it actually increased risk of death from others, such as cancer.

Although a retrospective, epidemiological study such as this cannot prove causality, our results suggest that close scrutiny of specific causes of death, rather than lifespan alone, will greatly improve our understanding of the cumulative impact of reproductive capability on mortality. Our results strongly demonstrate the need to determine the physiologic consequences of sterilization that influence causes of death and lifespan. Shifting the focus from when death occurs to why death occurs could also help to explain contradictory findings from human studies.

Link: http://dx.doi.org/10.1371/journal.pone.0061082

Will it be possible in years ahead to temporarily adjust the programming of existing cell populations in the body to cause them to regenerate from damage and injuries more effectively than is presently the case? Most likely so, though it is a fair distance from present early explorations to a safe and effective therapy. Here is an example of work presently underway in the laboratory:

"We found that the activity of the Meis1 gene increases significantly in heart cells soon after birth, right around the time heart muscle cells stop dividing. Based on this observation we asked a simple question: If the Meis1 gene is deleted from the heart, will heart cells continue to divide through adulthood? The answer is 'yes.'"

The research team demonstrated that deletion of Meis1 extended the proliferation period in the hearts of newborn mice, and also re-activated the regenerative process in the adult mouse heart without harmful effect on cardiac functions. This new finding demonstrates that Meis1 is a key factor in the regeneration process, and the understanding of the gene's function may lead to new therapeutic options for adult heart regeneration. The findings also provide a possible alternative to current adult heart regeneration research, which focuses on the use of stem cells to replace damaged heart cells.

"Meis1 is a transcription factor, which acts like a software program that has the ability to control the function of other genes. In this case, we found that Meis1 controls several genes that normally act as brakes on cell division. As such, Meis1 could possibly be used as an on/off switch for making adult heart cells divide. If done successfully, this ability could introduce a new era in treatment for heart failure."

Link: http://www.utsouthwestern.edu/newsroom/news-releases/year-2013/april/heart-sadek.html

Today I thought it time to one again say something about the Fight Aging! audience data. I am occasionally asked about this, so I'm given to think that some of the other folk who run similar sites may benefit from this very infrequent series of posts. Other regular readers may take the information below as a data point to add to what is known about the size and scope of the longevity science community: researchers, advocates, and supporters. As is always the case, I should note that Fight Aging! is a niche concern: any hard science site is already a low traffic venture, and this is even more the case for specialist hard science sites that focus on small fields. Much as I would like to say otherwise, longevity science is a small subfield of aging research, which in turn is a small field within the medical life sciences, tiny in comparison to many of its peers. Neither human longevity nor aging research in general have the funding or attention they merit, given the possibilities for rejuvenation biotechnology that lie ahead and the level of harm caused by aging. We'd all like to see this change - and it needs to change if we are going to anything other than age to death like our ancestors did.

It has been a little over two years since I last wrote anything on this topic of site audience data. That happened right after the present site design was first deployed and the Longevity Meme merged into Fight Aging!, so it is a useful little exercise to look back and see what has changed since then. Fight Aging! has remained fairly constant over that time, with only minor improvements to the showcasing of important content and readability, but this present design is far more attractive and professional than the wall of green and text that preceded it. Did that have a beneficial effect? I think so, but see below.

Bear Consumption

"Bear consumption" is an ambiguous phrase in the context of an internet search. I know what folk are getting if they click through to the page in the Fight Aging! archives that, against all common sense given the far better listings below it, is at the top of Google's rankings for "bear consumption." I have no idea what they might be after, however. Misspelled beer? Bears afflicted with Victorian era diseases? Bear food or bears as food? We may never know for sure.

Any sort of inspection of website analytics turns up things of this nature; little oddities and mysteries for which no-one can really justify the time required to obtain a deeper understanding and certain answers. You don't even have to be the owner of the website in question these days to look at this sort of data. Services like Alexa have expanded out to provide a public record of this and other interesting information about any given website above a certain level of traffic. If you browse the Alexa entry for Fight Aging! you can see the whole bear consumption thing for yourself under the search analytics tab.

Though one has to take this data with a grain of salt for smaller sites like this Fight Aging! - artifacts are common, and seeking corroboration with other sources is a good plan. For example, the audience breakdown provided by Alexa suggests that a large portion of the readership are men over the age of 45 who don't have children. That seems a pretty narrow and unlikely demographic, all things considered, even given that each of those line items could be argued as plausible on its own given the topic of this site.

Comparing 2013 With 2011

Based on the data from Alexa (which is improving) and the data from Google Analytics (which is getting steadily worse), I can put forward the following items.

I am inclined to ascribe this growth in traffic, which has occurred in a very steady and consistent manner these past two years, to the improved site design. That seems to be the one obvious line item separating the fairly consistent traffic of the years prior to the present state of affairs. Judging a book by its cover is a going concern, it seems, and the same content in a more attractive package is apparently much better at holding attention. That said, it's very hard to determine whether or not this translates into anything meaningful in terms of the things I care about - which is to say engagement with the SENS vision for rejuvenation biotechnology, funds given to longevity science and related research initiatives, and so forth. This is ever the challenge of a web site; you have lots of numbers at your fingertips but they'll never tell you what you want to know. There is always that slippery and wishful step of interpretation.

The number of newsletter subscribers remains steady at a little over 3000, the same as it was two years ago, which is another reason for questioning the meaning of increased traffic, and the site presently holds 9500 posts versus the 7600 back then.

The Longest of Long Tails

Closing in on ten thousand web pages, without counting the archives, makes for a very big website for a single webmaster. I'm still finding the occasional orphan page left over from the Longevity Meme merge two years ago, disconnected from the site by some quirk of the page name that was allowed in the old host but not in this one - one can only be caring in the aggregate, as they say.

Traffic in a site like this follows a long tail distribution, the top of which is shown below:

You can look back to the Q1 2011 post to see how this compares; I'm pleased to have successfully directed more visitors to the Take Action! and Introduction pages - since one of the principal goals of this website is to convey the information on those pages - but here I mainly want to point out the scale of the fall-off in traffic after the home page. In fact the top 100 most viewed pages at Fight Aging! only account for 35% of the total traffic, with the home page accounting for most of that. This is what you might expect for a blog that updates a couple of times a day. Most of the traffic to Fight Aging! is scatted across the long tail of its nearly ten thousand posts, a couple of views here, a couple there.

From my viewpoint this manifests as a slow trickle of comments and emails relating to old, old posts. For the most part these are from people, often patients and their relatives, interested in specific medical technologies that are working their way through the labs and which I have linked to or discussed. They are often enough looking for hope and miracles, but I can do little but point them to the clinical trial sites or guides on how to research available therapies more effectively. It's a small and ongoing reminder of what is at stake here: sooner or later we'll all be that unfortunate person who will die or become crippled and frail without the benefit of medical technology that is in the labs and tantalizingly close - but for most of us it will be the general progression of aging that does this.

The only way out of this hole we find ourselves in is faster progress towards the rejuvenation biotechnologies of the SENS vision or other repair-based approaches to the damage of aging, and the best way to obtain that faster progress at this point is through more effective fundraising.

CD47 is a cell surface marker that tells immune cells to leave a cell alone. Researchers are presently using CD47 as a target for next-generation cancer therapies - and quite effectively. The marker seems to be present to a greater level that usual in all cancers examined to date, and blocking it frees the immune system to attack the cancer cells.

I noticed another research item today in which a group found that removing CD47 triggers the set of genes known to cause normal adult cells to become induced pluripotent stem (iPS) cells. This is a very interesting result given the cancer connection, and given that this manipulation doesn't seem to make cells prone to generating cancer:

In 2008 [researchers] were using agents that block a membrane protein called CD47 to explore their effects on blood vessels. When cells from the lining of the lungs, called endothelium, had been treated with a CD47 blocker, they stayed healthy and maintained their growth and function for months. [The] team continued to experiment with CD47 blockade, focusing on defining the underlying molecular mechanisms that control cell growth.

They found that endothelial cells obtained from mice lacking CD47 multiplied readily and thrived in a culture dish, unlike those from control mice. [The researchers] discovered that this resulted from increased expression of four genes that are regarded to be essential for formation of iPS cells. When placed into a defined growth medium, cells lacking CD47 spontaneously formed clusters characteristic of iPS cells. By then introducing various growth factors into the culture medium, these cells could be directed to become cells of other tissue types. Despite their vigorous growth, they didn't form tumors when injected into mice, a major disadvantage when using existing iPS cells.

"Stem cells prepared by this new procedure should be much safer to use in patients. Also, the technique opens up opportunities to treat various illnesses by injecting a drug that stimulates patients to make more of their own stem cells. These experiments indicate that we can take a primary human or other mammalian cell, even a mature adult cell, and by targeting CD47 turn on its pluripotent capability. We can get brain cells, liver cells, muscle cells and more. In the short term, they could be a boon for a variety of research questions in the lab."

Link: http://www.eurekalert.org/pub_releases/2013-04/uops-rfl041613.php

A great deal of work in the aging research community focuses on trying to untangle the relationship between genes, epigenetic patterns of gene expression, metabolism, and natural variations in human longevity. It's an enormously complex task, far harder than just trying to repair the known biochemical damage of aging - analogous to producing a general theory and full mathematical model of paint peeling rather than just repainting a wall.

In the dimly lit, chilly hallway outside Passarino's university office stand several freezers full of tubes containing centenarian blood. The DNA from this blood and other tissue samples has revealed additional information about the [study population]. For example, people who live into their 90s and beyond tend to possess a particular version, or allele, of a gene important to taste and digestion. This allele not only gives people a taste for bitter foods like broccoli and field greens, which are typically rich in compounds known as polyphenols that promote cellular health, but also allows cells in the intestine to extract nutrients more efficiently from food as it's being digested.

Passarino has also found in his centenarians a revved-up version of a gene for what is called an uncoupling protein. The protein plays a central role in metabolism - the way a person consumes energy and regulates body heat - which in turn affects the rate of aging.

"We have dissected five or six pathways that most influence longevity," says Passarino. "Most of them involve the response to stress, the metabolism of nutrients, or metabolism in general - the storage and use of energy." His group is currently examining how environmental influences - everything from childhood diet to how long a person attends school - might modify the activity of genes in a way that either promotes or curtails longevity.

If nothing else, the plethora of new studies indicates that longevity researchers are pushing the scientific conversation to a new level. [But] genes alone are unlikely to explain all the secrets of longevity. Passarino made the point while driving back to his laboratory after visiting the centenarians in Molochio. "It's not that there are good genes and bad genes," he said. "It's certain genes at certain times. And in the end, genes probably account for only 25 percent of longevity. It's the environment too, but that doesn't explain all of it either. And don't forget chance."

Link: http://ngm.nationalgeographic.com/2013/05/longevity/hall-text

João Pedro de Magalhães is the researcher behind the excellent senescence.info site, the Animal Aging and Longevity Database, the Aging Gene Database, and sundry other projects. He presently heads the Integrative Genomics of Ageing Group at the University of Liverpool, and is one of the modern generation of life scientists unafraid to declare in public that the goal of the field should be nothing less than to cure aging. Many more people of this vision and drive are needed in the field of aging research if we are to see more rapid progress towards rejuvenation biotechnology.

I noticed an interview with de Magalhães in the Argentinian Spanish language press today that gives an executive summary of some of his views; the English version is quoted below, tidied up from its machine translation to make things a little more clear.

João Pedro de Magalhães: "I do not see why we could not abolish old age"

When asked about the scientific evidence supporting current theories on aging, João Pedro de Magalhães, a professor and researcher at the University of Liverpool, does not depart from the scientific literature. But this "scientist, philosopher and dreamer" as he defines himself chooses also to imagine a future in which we can manipulate the biological machinery of aging. Via email, de Magalhães provided the following answers to our questions.

[Lanacion]: What, in his opinion, is the most likely explanation for the causes of aging?

[de Magalhães]: Possibly the theory of DNA damage is the most accepted, although not proven. The hypothesis explaining this progresses due to free radicals [unstable atoms that damage our cells] has been widely attacked. The process of telomere shortening could also contribute to aging, but is far from proven. In fact, almost all the important discoveries of cellular or molecular biology have led to a new family of hypotheses about aging. But the difficulties inherent in the study of this stage of life - such as the lack of suitable models - make it costly. Moreover, the results are often controversial, and discriminating between cause and effect is often impossible ...

[Lanacion]: Do all organisms age?

[de Magalhães]: Actually, no. It's fascinating, but some species appear not to age. For example, turtles are showing no signs of aging: some live up to 138 years and, in particular, the Galapagos reach the 177. There are fish that live more than one hundred and bats that weigh 10 grams and are 34 years old.

[Lanacion]: Is it an oxymoron to talk about healthy aging?

[de Magalhães]: For me it is only possible to a certain degree, because aging will end in death and that will never be nice or pleasant. Personally, I think we can improve health in older and delay aging, but unless you fully mend our biology, health and aging will always be opposites.

[Lanacion]: Why do you have to try to keep prolonging life? To what extent? Is there a limit?

[de Magalhães]: Yes. Preserving life and health should be the main goal of biomedical research, and already we have benefited tremendously from it in recent decades. Today, there are obvious limitations to how much we can delay aging and extend life, but with the current scientific and technological progress I see no reason why we can not abolish aging. As the researcher and advocate Aubrey de Grey says, aging is "a barbaric phenomenon that should not be tolerated in polite society." However, the current anti-aging treatments do not reduce the rate of the aging process or extend the life expectancy by any more than quitting smoking, physical activity, or having a good diet and access to modern medicine. The only way to achieve a further 50% increase in longevity is to find ways to stop the aging process in itself.

For the goal of stopping the aging process, I favor the SENS vision: a set of biotechnologies that can be described in some detail today, and which - once realized - will repair or make irrelevant the known forms of fundamental biological damage present in old tissue but not in young tissue. The only thing holding the various labs and researchers involved in SENS to a slow pace is a comparative lack of funding - money is absolutely the limiting factor on progress in therapies to repair aging at this time.

Work on nanoparticles and artificial cell structures for use in medicine is becoming more sophisticated. There is an emerging generation of simple but effective medical micro- and nanomachines, devices that will be manufactured in their millions and infused into the body to perform useful tasks, such as killing specific cells, or delivering specific signals to cells to cause them to regenerate more effectively, or clearing out unwanted metabolic byproducts that contribute to aging. A lot of interesting projects are presently underway, and this article is a good illustration of one branch of this work and its utility:

Nanoparticles could be used to neutralize toxins produced by many bacteria, including some that are antibiotic-resistant, and could counteract the toxicity of venom from a snake or scorpion attack. [The] "nanosponges" work by targeting so-called pore-forming toxins, which kill cells by poking holes in them. There are a range of existing therapies designed to target the molecular structure of pore-forming toxins and disable their cell-killing functions. But they must be customized for different diseases and conditions, and there are over 80 families of these harmful proteins, each with a different structure. Using the new nanosponge therapy [researchers] can neutralize every single one, regardless of their molecular structure.

[Researchers] wrapped real red blood cell membranes around biocompatible polymeric nanoparticles. A single red blood cell supplies enough membrane material to produce over 3,000 nanosponges, each around 85 nanometers (a nanometer is a billionth of a meter) in diameter. Since red blood cells are a primary target of pore-forming toxins, the nanosponges act as decoys once in the bloodstream, absorbing the damaging proteins and neutralizing their toxicity. And because they are so small, the nanosponges will vastly outnumber the real red blood cells in the system. This means they have a much higher chance of interacting with and absorbing toxins, and thus can divert the toxins away from their natural targets.

In animal tests, the researchers showed that the new therapy greatly increased the survival rate of mice given a lethal dose of one of the most potent pore-forming toxins. Liver biopsies several days following the injection revealed no damage, indicating that the nanosponges, along with the sequestered toxins, were safely digested after accumulating in the liver.

Link: http://www.technologyreview.com/news/513461/nanoparticle-disguised-as-a-blood-cell-fights-bacterial-infection/

Here at Fight Aging! the most recent update on protofection, a possible basis for a way to replace damaged mitochondrial DNA (mtDNA) and remove its contribution to degenerative aging, was late last year. Since the first publication on protofection back in 2005 a number of other potential mechanisms for mitochondrial DNA repair or replacement have emerged, but none of these, protofection included, are moving as rapidly as would be liked. One problem is the regulatory environment in the biggest markets: you are only allowed to develop commercial therapies for named diseases, not for aging, and comparatively few people suffer from named diseases that involve specific, characteristic forms of mitochondrial mutation - as opposed to the general stochastic damage of aging. So there is little funding, and it's actually effectively illegal to try to treat aging this way, despite the great possibilities of this research.

One of the potential target diseases is Leber's hereditary optic neuropathy (LHON), and if you have a good memory you might recall that one of the researchers involved in work on the SENS approach to mitochondrial DNA damage - move the vulnerable genes into the cell nucleus to create a secondary source of the necessary proteins - is primarily concerned with LHON rather than aging.

Here is an open access paper on the use of protofection (among other options) as a LHON therapy, which is also of general interest to anyone looking at this sort of approach to mitochondrial gene therapy for aging or other conditions:

An optimal cure [for LHON] would be gene therapy, which involves introducing the missing gene(s) into the mitochondria to complement the defect. Our recent research results indicate the feasibility of an innovative protein-transduction ("protofection") technology, consisting of a recombinant mitochondrial transcription factor A (TFAM) that avidly binds mtDNA and permits efficient targeting into mitochondria in situ and in vivo. Thus, the development of gene therapy for treating mitochondrial disease offers promise, because it may circumvent the clinical abnormalities and the current inability to treat individual disorders in affected individuals.

We successfully demonstrated introduction of labeled rhTFAM and healthy mtDNA complexed with rhTFAM into homoplasmic LHON cybrid cells containing the G11778A mutation. [Further] results in LHON cybrid cells, demonstrated an increase in mitochondrial genome replication, transcription, translation, and respiration initiated within a week when the complex was introduced into the mitochondria. We also observed the activation of the mitochondrial biogenesis (creation of new mitochondria) program in these human LHON cybrid cells. [It] is expected that this mitochondrial genome manipulation approach based on introduction of exogenous normal or pathogenic mtDNA provides hope for LHON patients afflicted with other mutations in the mitochondrial genome.

The current studies indicate that the mitochondrial genome can be manipulated and lead to improvement in mitochondrial function in in vitro and in vivo models. Future coordinated efforts between scientists and clinicians are necessary to translate these findings towards development of therapies for LHON patients.

This is far from a niche study, despite being related to a niche disease; mitochondrial DNA damage arguably causes a fairly large fraction of degenerative aging. It is incredible to think that regulators actively work to prevent greater funding and more work on this and other items that could help to reverse the effects of aging in the old.

Link: http://www.discoverymedicine.com/Shilpa-Iyer/2013/03/22/novel-therapeutic-approaches-for-leber-s-hereditary-optic-neuropathy/

Longevity and wealth go hand in hand. This association is very evident in many periods of history, such as the century leading up to the industrial revolution in England, or the more recent and very rapid transformation of South Korean society from rural poverty to industrialized wealth, accompanied by an equally rapid rise in life expectancy.

Thus economics should be a topic of at least passing interest for everyone who follows longevity science, or looks forward to a future of extended healthy life provided by new medical biotechnologies. Frankly, economics in the broadest sense of human action and its explanations should be of at least passing interest to everyone: societies rise and fall based upon the public understanding or lack of understanding regarding the origins of wealth and economic growth. There seem to be cycles in which those who understand dominate and thus build prosperity, only for their descendants to give it all back to waste and destruction because they fail to grasp why it is that their society is prosperous. Comparative wealth is very good at sheltering people from the realities of how the world works, sadly. These days the US seems to be on the downward slope of that cycle: there is a lot more of eating of seed corn and corruption than even as recently as twenty years ago.

On the grand scale this will slow down progress in technology across the board in comparison to what might have been. Corruption manifests itself most evidently as centralization of power and resulting regulation, which in turn attracts those who live to propagate control for the sake of control. Medicine and biotechnology are being choked beneath a mountain of red tape. One can hope that other regions of the world will take up the slack as the grand medical research community of the US is slowly crushed into an inability to produce and commercialize anything truly new and innovative.

But I hadn't intend this to be a gloomy post, and the very readable paper I want to bring to your attention today is, ultimately, an optimistic take on human progress - both in longevity and in wealth. And indeed, I am optimistic for the long term; empires rise and fall, the US only different in detail from those that came before, and humanity nonetheless marches onward, building new technologies at what seems to be an every-increasing pace, despite the politics, politicians, and parasites. What gloom there is stems from that fact that you and I don't have forever to wait for the just-around-the-corner biotechnologies that will enhance human longevity - there is plenty of room for ugly economic or political collapse to delay matters long enough to produce a poor outcome for us, while still winding up as just another fiddling detail of early 21st century history to the ageless folk of the 2100s and later

But take a look at the paper I mentioned; I think you'll find it interesting:

Population aging and endogenous economic growth

We investigate the consequences of population aging for long-run economic growth perspectives. [We] show that (1) increases in longevity have a positive impact on per capita output growth, (2) decreases in fertility have a negative impact on per capita output growth, (3) the positive longevity effect dominates the negative fertility effect in [our models], and (4) population aging fosters long-run growth.

Just to get an impression of the severity of the demographic changes, we are facing the following: on the global scale, the total fertility rate has dropped from five children per woman in 1950 to 2.5 children per woman today, while life expectancy has increased from 48 years in 1950 to 68 years today. [We] are interested in the implications of population aging for per capita output growth over a long time horizon. Since technological progress has been identified as the main determinant of long-run economic prosperity, we are particularly concerned with the effects of changing age [distributions in society] on research and development (R&D) intensities.

Our main conclusion is that currently ongoing demographic changes do not necessarily hamper technological progress and therefore economic prosperity. Simultaneously decreasing birth and death rates can even lead to an increase in the economic growth rate.

As I've argued in the past, technological progress is really the only yardstick that matters when you're looking at the long view.

Like many, I think that Ray Kurzweil is overly optimistic on the timeline for progress in technology. I don't think he's wrong in terms of his high level view on where our technology is going, just a few decades on the early side - which is unfortunate for those of us who will age to death before the advent of rejuvenation biotechnology. It is certainly the case that the first draft of technologies to repair the underlying biological damage that causes aging could arrive fairly soon, within two decades - but it's not just a matter of building them, even though there are detailed research and development plans for doing so.

The issues are persuasion and fundraising; when it comes to aging, the mainstream of the research community is set on goals that either have nothing to do with human longevity, or will do very little to extend life even after being realized at great cost. So the comparatively tiny and underfunded shard of the scientific community whose members are interested in realizing effective means of rejuvenating the old will likely spend the next twenty years on laying the groundwork, prototyping the biotechnologies, proving their case ever more completely, growing funding, and persuading ever more researchers to do the same. If there were hundreds of millions of dollars devoted to this cause today, we could leap ahead twenty years in this timeline - but there are not. The money and large supportive community still has to be bootstrapped, building on the present early phase in the growth of modern rejuvenation research, underway successfully but slowly for the past decade or so, giving rise to organizations like the Methuselah Foundation and SENS Research Foundation.

Here is Kurzweil's take on timelines, which are derived from his analysis of trends in technological capabilities:

To listen to Mr. Kurzweil or read his several books is to be flummoxed by a series of forecasts that hardly seem realizable in the next 40 years. But this is merely a flaw in my brain, he assures me. Humans are wired to expect "linear" change from their world. They have a hard time grasping the "accelerating, exponential" change that is the nature of information technology. "A kid in Africa with a smartphone is walking around with a trillion dollars of computation circa 1970," he says. Project that rate forward, and everything will change dramatically in the next few decades.

"I'm right on the cusp," he adds. "I think some of us will make it through" - he means baby boomers, who can hope to experience practical immortality if they hang on for another 15 years. By then, Mr. Kurzweil expects medical technology to be adding a year of life expectancy every year. We will start to outrun our own deaths. And then the wonders really begin.

Mr. Kurzweil's ideas on death and immortality, not his impressive record as an entrepreneur, are what bring TV newsmagazines and print reporters to his door these days. I suggest to him he's discovered the power of the prophetic voice and is borne forward by the rewarding feelings that come from giving people hope in the face of their profoundest fears. My insight does not impress him. He says he just gets satisfaction from seeing his ideas, like his inventions, wield a positive force in the world. People blame technology for humanity's problems, he says. They are much too pessimistic about its power to solve poverty, disease and pollution in our lifetimes.

Link: http://online.wsj.com/article/SB10001424127887324504704578412581386515510.html

Decellularization is the process of taking donor tissue, such as a complete organ, stripping out its cells to leave the extracellular matrix structure, and then repopulating that structure with another individual's cells to reform a functional organ. This produces donor tissue that will not be rejected by a transplant recipient, and has been successfully used in a few human transplants of less complicated tissue structures such as the trachea.

This technology is an important stepping stone on the way towards organs created from scratch; it works around the present inability to build a sufficiently detailed and functional framework for complex tissue. The extracellular matrix from existing tissue provides chemical cues and other necessary items that allow cells to correctly form the many intricate structures, such as blood vessel networks, needed for a fully functional organ.

In the laboratory, a number of complete animal organs have been successfully decellularized and transplanted - and kidneys are now included in that list, albeit only partially functional kidneys, a starting point for better results in years ahead:

[Researchers have] engineered functional rat kidneys by stripping donor kidneys of their cells and then repopulating the remaining collagen substructures with new cells. The bioengineered kidneys produced urine in laboratory dishes and when implanted in living animals. The advance could be good news for the 100,000 Americans waiting for donor kidneys for transplant, because it suggests that someday scientists might be able to grow custom-made kidneys for people, using a patient's own cells to seed tissues.

The process at the center of his team's approach is called "decellularization." In a carefully calibrated process, researchers removed a kidney from a cadaver and then introduced a series of washing agents into its vascular system to remove the organ's cells. [Then] they introduced immature cells that could form kidney tissues and blood vessels into the acellular scaffold.

After a short time, the new kidneys could produce urine. They didn't work as well as normal, healthy kidneys would - in the laboratory dish, they cleared creatinine (a blood component filtered by the kidneys) 23% as well as a native kidney; once implanted in animals, about 5% to 10% as well. But "the bottom line is, we saw urine production."

Link: http://www.latimes.com/news/science/sciencenow/la-sci-sn-bioengineered-kidney-20130414,0,4202332.story

When it comes to medical procedures, everyone has their own definition of acceptable risk. Sadly we're then overruled by faceless bureaucrats at the US Food and Drug Administration (FDA) and similar government bodies - people who have only their own interests in mind, and suffer no consequences from making useful medical technologies illegal or too expensive for commercial use. Fortunately, the FDA doesn't rule the world: there are regions in which medical regulations are less onerous and therapies less costly, and these locations are only a plane flight away.

People who undertake medical tourism for stem cell therapies are demonstrating their own risk preferences: balancing the plausible expected benefits based on what is presently known of the science and the outcomes (in the absence of rigorous trials) against the cost and estimated risk. For stem cell treatments perhaps the largest inherent risk for early stage therapies is that of cancer resulting from the activities of transplanted cells. Work in the laboratory suggests that this risk is generally lower than first thought, but it still exists.

The world of cancer treatments is, meanwhile, changing profoundly, gearing up for a new generation of therapies that will displace chemotherapy and radiotherapy. Reprogramming immune cells or introducing targeted viruses and nanoparticles to seek out and kill cancer cells with few side-effects will be the standard operating procedure twenty years from now - and probably available outside the US in a decade. In early trials and the laboratory, these technologies are already showing impressive results.

Improvements in cancer treatment - leading to the introduction of robust therapies that can clear most common forms of cancer quickly and without accompanying illness - will, I think, go hand in hand with a far greater demand for and use of very aggressive stem cell treatments. Things like periodic infusions of massive numbers of immune cells cloned from a patient's own cells, done not just for people with medical conditions, but for the healthy as a beneficial preventative measure. Similarly, why boost regeneration and tissue maintenance via stem cell therapies only in the sick and the wounded? That makes sense if there is a significant risk associated with treatment, but in a world in which cancer is merely troublesome, why not make stem cell therapies a part of general health maintenance?

These are the sort of shifts in the cost-benefit picture of regenerative medicine that will emerge over the next couple of decades, driven by a growing ability to control the undesirable aspects of cellular biology, such as cancer.

Researchers here examine the published literature on hormesis via heat shock, one of the ways shown to induce modest gains in longevity in laboratory animals, and find less support for positive outcomes than was thought. This may or may not be significant - the goal for researchers, as for calorie restriction and other means of extending longevity, is to find the underlying mechanism of action and build a therapy that triggers it with minimal side-effects. So long as heat shock can be demonstrated to improve long term health and longevity under at least some conditions, then there is a mechanism to be found and exploited.

Hormesis is the response of organisms to a mild stressor resulting in improved health and longevity. Mild heat shocks have been thought to induce hormetic response because they promote increased activity of heat shock proteins (HSPs), which may extend lifespan. Using data from 27 studies on 12 animal species, we performed a comparative meta-analysis to quantify the effect of heat shock exposure on longevity. Contrary to our expectations, heat shock did not measurably increase longevity in the overall meta-analysis, although we observed much heterogeneity among studies.

Thus, we explored the relative contributions of different experimental variables (i.e. moderators). Higher temperatures, longer durations of heat shock exposure, increased shock repeat and less time between repeat shocks, all decreased the likelihood of a life-extending effect, as would be expected when a hormetic response crosses the threshold to being a damaging exposure. We conclude that there is limited evidence that mild heat stress is a universal way of promoting longevity at the whole-organism level. Life extension via heat-induced hormesis is likely to be constrained to a narrow parameter window of experimental conditions.

Link: http://www.ncbi.nlm.nih.gov/pubmed/23570942

The clam species Arctica islandica is very long-lived, reaching at least four centuries in the wild. Researchers are comparing its biochemistry with similar but shorter-lived species to see if they can pinpoint the mechanisms that lead to its exceptional longevity. Here is recent research on this topic:

The observation of an inverse relationship between lifespan and mitochondrial H2 O2 production rate would represent strong evidence for the disputed oxidative stress theory of aging. Studies on this subject using invertebrates are surprisingly lacking, despite their significance in both taxonomic richness and biomass. Bivalve molluscs represent an interesting taxonomic group to challenge this relationship. They are exposed to environmental constraints such as microbial H2 S, anoxia/reoxygenation, and temperature variations known to elicit oxidative stress. Their mitochondrial electron transport system is also connected to an alternative oxidase that might improve their ability to modulate [the reactive oxygen species (ROS) generated by mitochondria and which produce oxidative stress].

Here we compared H2 O2 production rates in isolated mantle mitochondria between the longest living metazoan - the bivalve Arctica islandica - and two taxonomically related species of comparable size. In an attempt to test mechanisms previously proposed to account for a reduction of ROS production in long-lived species, we compared oxygen consumption of isolated mitochondria and enzymatic activity of different complexes of the electron transport system in the two species with the greatest difference in longevity.

We found that A. islandica mitochondria produced significantly less [of the reactive oxygen species] H2 O2 than those of the two short-lived species in nearly all conditions of mitochondrial respiration tested, including forward, reverse, and convergent electron flow. Alternative oxidase activity does not seem to explain these differences. However, our data suggest that reduced complex I and III activity can contribute to the lower ROS production of A. islandica mitochondria, in accordance with previous studies.

Reduced activity within mitochondria in this sense shows up in some longevity-inducing mutations in laboratory animals. Mitochondrial activity and composition (how much damage they cause per unit time, and how resistant they are to damage) appears to be very important as a determinant of longevity differences between species. This should increase our interest in ways to repair mitochondrial damage in humans as a potential rejuvenation therapy.

Link: http://www.ncbi.nlm.nih.gov/pubmed/23566066

A fair number of research groups worldwide are gathering and processing data in search of associations between minor genetic variations and human longevity. As for all studies of long-term human health, this a challenging process: statistics become involved, it is costly to gather data of even moderate quality, and the underlying biology is exceedingly complex. This is illustrated by the fact that comparatively few genetic associations can be validated across different study populations: if you find a genetic polymorphism with a statistically significant association with longevity in Italian lineages, the odds are very good that it won't show up in Asian populations, or even in other Italian study populations, for that matter. The range of minor variation in the human genome is very large, and it seems to be the case that there are many, many tiny genetic contributions to the way in which metabolism interacts with environment to determine natural longevity, most of which differ widely in different populations.

So while the funding lasts, this is a deep well for researchers to work on - just not one likely to produce more than knowledge for the foreseeable future. If you want actual results in terms of therapies to reverse the course of aging, then look to the programs described in the SENS research outline. The research community already knows what needs to be repaired in aged tissue, as the low-level differences between old and young tissue are well enumerated - it is the intricate, enormously complex metabolic dance of progressing from undamaged to damaged that remains an open field of work. The difference between SENS and the mainstream efforts to fully understand aging is the difference between on the one hand making the effort to rust-proof a metal surface and on the other producing a complete and detailed model of how rust progresses and interacts with metal structures at every level, from chemistry through to the physics of forces acting on structures and material strengths. The latter isn't necessary to achieve the goal of prevention once you know what rust is, and indeed will probably prove to cost far more than just preventing the rust.

Here are a couple of illustrative papers from the steady flow of new associative studies of genetics and aging in humans. There will be many more similar results arriving in the years ahead: a lot more money goes towards this sort of work than to any effort to do something about aging.

The functional VNTR MNS16A of the TERT gene is associated with human longevity in a population of Central Italy

Telomerase, encoded by TERT, is the ribonucleoprotein polymerase that maintains telomere ends and it plays a crucial role in cellular senescence. TERT single nucleotide polymorphisms (SNPs) have been associated both with various malignancies and telomere length (TL). The association of TERT SNPs with longevity remains uncertain and varies with ethnicity. Aim of this study was to investigate whether the functional variable number of tandem repeat (VNTR) MNS16A of TERT is associated with longevity.

MNS16A genotypes have been determined for 1072 unrelated healthy individuals from Central Italy (18-106 years old) divided into three gender-specific age classes defined according to demographic information and accounting for the different survivals between sexes. MNS16A appears associated to longevity. The MNS16A*L allele is significantly underrepresented in Age Class 3 compared to Age Class 2. The concomitant significant telomere cross sectional attrition rate observed for L*/L* genotype suggests that this polymorphism could influences human longevity by affecting TL.

Common polymorphisms in nitric oxide synthase (NOS) genes influence quality of aging and longevity in humans

Nitric oxide (NO) triggers multiple signal transduction pathways and contributes to the control of numerous cellular functions. Previous studies have shown in model organisms that the alteration of NO production has important effects on aging and lifespan. We studied in a large sample (763 subjects, age range 19-107 years) the variability of the three human genes (NOS1, -2, -3) coding for the three isoforms of the NADPH-dependent enzymes named NO synthases (NOS) which are responsible of NO synthesis.

We found that gene variation of NOS1 and NOS2 was associated with longevity. In addition NOS1 rs1879417 was also found to be associated with a lower cognitive performance, while NOS2 rs2297518 polymorphism showed to be associated with physical performance. Moreover, SNPs in the NOS1 and NOS3 genes were respectively associated with the presence of depression symptoms and disability, two of the main factors affecting quality of life in older individuals. On the whole, our study shows that genetic variability of NOS genes has an effect on common age related phenotypes and longevity in humans as well as previously reported for model organisms.

Here is a popular science article on intermittent fasting, something that extends life in mice, but which is not as well researched as calorie restriction, the gold standard for science on healthy life extension. There appears to be considerable overlap in the mechanisms involved in calorie restriction and intermittent fasting, but it's not all exactly the same when gene expression patterns are examined, to pick one example.

Many diet and exercise trends have origins in legitimate science, though the facts tend to get distorted by the time they achieve mainstream popularity. Benefits are exaggerated. Risks are downplayed. Science takes a backseat to marketing. One needn't look any further than the emerging trend of intermittent fasting for a prime example.

There is indeed a large body of research to support the health benefits of fasting, though most of it has been conducted on animals, not humans. Still, the results have been promising. Fasting has been shown to improve biomarkers of disease, reduce oxidative stress and preserve learning and memory functioning. [There] are several theories about why fasting provides physiological benefits. "The one that we've studied a lot, and designed experiments to test, is the hypothesis that during the fasting period, cells are under a mild stress. And they respond to the stress adaptively by enhancing their ability to cope with stress and, maybe, to resist disease."

But perhaps it isn't so much the fasting that produces health benefits, per se, as the resulting overall reduction in calorie intake (if, that is, you don't overeat on nonfasting days, which could create a caloric surplus instead of a deficit). That appears, at least, to be the case in slowing diseases such as cancer in mice. "Caloric restriction, undernutrition without malnutrition, is the only experimental approach consistently shown to prolong survival in animal models," In [a] study, mice fasted twice a week for 24 hours, but were otherwise permitted to eat at liberty. During nonfasting days, the mice overate. Overall, they did not lose weight, counteracting whatever benefits they might have seen from fasting. Intermittent fasting with compensatory overeating "did not improve mouse survival nor did it delay prostrate tumor growth," the study concluded.

Equally, there are studies showing that intermittent fasting without calorie restriction does extend life in nematode worms. A lot more research is needed to bring intermittent fasting up to the level of confidence that we can have in calorie restriction.

Link: http://www.cmaj.ca/site/earlyreleases/8apr13_intermittent-fasting-the-science-of-going-without.xhtml

Modest progress is demonstrated in a recent stem cell therapy trial for heart failure, putting some ballpark numbers to the level of benefits obtained by patients in reputable overseas clinics for some years now. It is to be expected that this sort of published result will lend further support for medical tourism while these therapies remain restricted and largely unavailable in countries like the US, thanks to the heavy hand of the FDA and similar regulatory bodies.

This trial also shows the scope of remaining progress yet to be achieved if the goal is complete organ repair, something that will likely prove impossible without an accompanying repair of at least some of the low-level biochemical damage of aging. Heart failure doesn't just randomly happen in the vast majority of cases - it emerges as a consequence of the accumulated damage of aging in heart tissue and other organs.

The multi-center, randomized Cardiopoietic stem cell therapy in heart failure (C-CURE) trial involved heart failure patients from Belgium, Switzerland and Serbia. Patients in the control group received standard care for heart failure in accordance with established guidelines. Patients in the cell therapy arm received, in addition to standard care, cardiopoietic stem cells - a first-in-class biotherapeutic. In this process, bone marrow was harvested from the top of the patient's hip, and isolated stem cells were treated with a protein cocktail to replicate natural cues of heart development. Derived cardiopoietic stem cells were then injected into the patient's heart.

Every patient in the stem cell treatment group improved. Heart pumping function improved in each patient within six months following cardiopoietic stem cell treatment. In addition, patients experienced improved fitness and were able to walk longer distances than before stem cell therapy. "Six months after treatment, the cell therapy group had a 7 percent absolute improvement in EF (ejection fraction) over baseline, versus a non-significant change in the control group. This improvement in EF is dramatic, particularly given the duration between the ischemic injury and cell therapy. It compares favorably with our most potent therapies in heart failure."

Link: http://www.mayoclinic.org/news2013-rst/7416.html

Neural plasticity - the ability of the brain to generate new neurons and make good use of them in its circuitry - is a topic of growing interest in the research community. That adult brains continue to create and assimilate new neurons was a comparatively recent discovery, first made in the 1960s, but lacking conclusive proof until the 1990s. Unfortunately, the pace at which this happens declines with age. Neurogenesis, the creation of neurons, requires an active neural stem cell population, and as appears to be the case for all stem cell populations, those in the brain decline in their activities with age. At the high level this is generally thought to be an evolutionary adaptation related to cancer, a part of the evolved balance between maintaining tissues and suppressing those maintenance activities when cellular damage (which grows with age) raises the odds of spawning a cancer.

It is thought that there are benefits to be gained by boosting the pace at which new neurons are created in old individuals. Aims include restoring the general loss of cognitive function that occurs with aging, developing new types of treatment for the named neurodegenerative diseases, and so forth. This ties into much of the present ongoing work on stem cells and aging: why do they stop performing their tasks; do they decline in number or just stop working; what exactly are the biochemical cues involved? The answers are emerging piece by piece, probably broadly similar but different in detail for every different stem cell population. The best outcome we can hope for is that all stem cell declines are a reaction to growing levels of damage and disarray in cells and cellular machinery - and thus the development of therapies to repair that damage will lead stem cell populations to revert to youthful behaviors without the need for further intervention.

Here are a few recent articles from the research world on the topic of neural plasticity, starting with one that pulls the ever-important processes of autophagy into the picture:

Spring Cleaning in Your Brain's Stem Cells?

Deep inside your brain, a legion of stem cells lies ready to turn into new brain and nerve cells whenever and wherever you need them most. While they wait, they keep themselves in a state of perpetual readiness -- poised to become any type of nerve cell you might need as your cells age or get damaged. [New research reveals] a key way they do this: through a type of internal "spring cleaning" that both clears out garbage within the cells, and keeps them in their stem-cell state.

It is the first time that this cellular self-cleaning process, called autophagy, has been shown to be important to neural stem cells. The findings may help explain why aging brains and nervous systems are more prone to disease or permanent damage, as a slowing rate of self-cleaning autophagy hampers the body's ability to deploy stem cells to replace damaged or diseased cells. If the findings translate from mice to humans, the research could open up new avenues to prevention or treatment of neurological conditions.

Producing New Neurons Under All Circumstances

Improving neuron production in elderly persons presenting with a decline in cognition is a major challenge facing an aging society and the emergence of neurodegenerative conditions such as Alzheimer's disease. [Researchers] recently showed that the pharmacological blocking of the TGFβ molecule improves the production of new neurons in the mouse model. These results incentivise the development of targeted therapies enabling improved neuron production to alleviate cognitive decline in the elderly and reduce the cerebral lesions caused by radiotherapy.

Neither heavy doses of radiation nor aging are responsible for the complete disappearance of the neural stem cells capable of producing neurons (and thus the origin of neurogenesis). Those that survive remain localised in a certain small area of the brain (the sub-ventricular zone (SVZ)). They nevertheless appear not to be capable of working correctly. Additional experiments have made it possible to establish that in both situations, irradiation and aging, high levels of the cytokine TGFβ cause the stem cells to become dormant, increasing their susceptibility to apoptosis [and] reducing the number of new neurons. [Researchers then] demonstrated that pharmacological blocking of TGFβ restores the production of new neurons in irradiated or aging mice.

Assessing brain plasticity across the lifespan with transcranial magnetic stimulation

Sustaining brain and cognitive function across the lifespan must be one of the main biomedical goals of the twenty-first century. We need to aim to prevent neuropsychiatric diseases and, thus, to identify and remediate brain and cognitive dysfunction before clinical symptoms manifest and disability develops. [Therefore], assessing the mechanisms of brain plasticity across the lifespan is critical to gain insight into an individual's brain health.

Indexing brain plasticity in humans is possible with transcranial magnetic stimulation (TMS), which, in combination with neuroimaging, provides a powerful tool for exploring local cortical and brain network plasticity. [Ultimately], TMS measures of plasticity can become the foundation for a brain health index (BHI) to enable objective correlates of an individual's brain health over time, assessment across diseases and disorders, and reliable evaluation of indicators of efficacy of future preventive and therapeutic interventions.

One of the major hurdles in tissue engineering is populating tissue with blood vessels sufficient to support it. This is absolutely essential to enable the growth of anything more than a tiny amount of tissue. Decellularization has proven to be a useful way to work around present limits, but that requires donor tissue in order to obtain the guiding extracellular matrix structure. When it comes to building tissue from scratch, researchers are still working on techniques to create the necessary blood vessel networks.

One of the major obstacles to growing new organs - replacement hearts, lungs and kidneys - is the difficulty researchers face in building blood vessels that keep the tissues alive. "It's not just enough to make a piece of tissue that functions like your desired target. If you don't nourish it with blood by vascularizing it, it's only going to be as big as the head of a pen."

Today, biomedical researchers are taking two main approaches to growing new capillaries, the smallest blood vessels and those responsible for exchanging oxygen, carbon dioxide and nutrients between blood and muscles or organs. One group of researchers is developing drug compounds that would signal existing vessels to branch into new tributaries. These compounds - generally protein growth factors - mimic how cancerous tumor cells recruit blood vessels. The other group [is] using a cell-based method. This technique involves injecting cells within a scaffolding carrier near the spot where you want new capillaries to materialize. [Researchers] deliver endothelial cells, which make up the vessel lining and supporting cells. Their scaffolding carrier is fibrin, a protein in the human body that helps blood clot.

"The cells know what to do. You can take these things and mix them and put them in an animal. Literally, it's as easy as a simple injection and over a few days, they spontaneously form new vessels and the animals' own vasculature connects to them. The adult stem cells from fat and bone marrow both work equally well. If we want to use this clinically in five to 10 years, I think it's crucial for the field to focus on a support cell that actually has some stem cell characteristics."

Link: http://www.sciencedaily.com/releases/2013/04/130404151954.htm

An interesting result here, given that most surveys of the public conducted in recent years show mixed interest or a lack of interest in greatly extending healthy human life via medical biotechnology. Perhaps measurable progress in changing minds and educating the public is occurring now - and certainly such progress should speed up at some point after a slow start - but we need to see more such encouraging surveys before drawing that conclusion:

This paper explores Canadian public perceptions of a hypothetical scenario in which a radical increase in life expectancy results from advances in regenerative medicine. A national sample of 1231 adults completed an online questionnaire on stem cell research and regenerative medicine, including three items relating to the possibility of Canadians' average life expectancy increasing to 120 years by 2050.

Overall, Canadians are strongly supportive of the prospect of extended lifespans, with 59% of the sample indicating a desire to live to 120 if scientific advances made it possible, and 47% of respondents agreeing that such increases in life expectancy are possible by 2050. The strongest predictors of support for radical life extension are individuals' general orientation towards science and technology and their evaluation of its plausibility. These results contrast with previous research, which has suggested public ambivalence for biomedical life extension, and point to the need for more research in this area. They suggest, moreover, that efforts to increase public awareness about anti-aging research are likely to increase support for the life-extending consequences of that research program.

Link: http://www.ncbi.nlm.nih.gov/pubmed/23561280

Here is a thing to consider: as folk grow older they generally grow wealthier at the same time. There's nothing magical about this, of course. The longer you have to save and invest, the more you will have saved and invested. I'd imagine that the freedom and security that comes with not living hand to mouth or as a dependent is one of the more important reasons why older people are generally happier than younger people.

Older people also have the greatest need for the fruits of longevity science: better ways to treat age-related disease, but more importantly ways to reverse the course of aging by repairing its root causes, the various forms of low-level biochemical damage that accumulate over the years. So you might think that there is a fortunate confluence of circumstances here, in the the people who most need rejuvenation biotechnologies are also the people who have more in the way of resources that might help fund its development.

But there are perverse incentives at work here. The older you are, the less time you have to wait for the results of research and development to arrive. If you don't have decades to wait, then you are unlikely to benefit personally - unless you can write a check for a few hundred million dollars to the SENS Research Foundation and later buy yourself a couple of labs and clinics in less regulated Asia-Pacific countries to move directly to clinical application without going through the FDA or other equally hostile regulatory bodies. But most people can't do that, and there are few bold billionaires in this sense; most embody their own businesses and look little beyond them. The Elon Musk or Richard Branson of applied longevity science has yet to emerge.

So for the rest of the elder population, and from the raw self-interest point of view, there is no incentive to give meaningful sums to longevity science when the first rejuvenation therapies are, under the very best scenarios, at least twenty years away. Few people even see that possibility, offered by SENS if large-scale funding arrives soon, as most researchers in the longevity science mainstream tell the world that results are both far further out in time and will not achieve actual rejuvenation when they do arrive. So the old have diminished incentives to do anything to meaningful advance the state of research even as their bodies are constantly reminding them of their ongoing degeneration.

The young, of course, are extremely talented at ignoring the future. Humans, I should say, are extremely talented at ignoring the future - but the young don't yet have the constant nagging pain and lost-function reminders of a failing body, they are usually not on first name terms with the local medical community, and nor do they have as much in the way of money to donate to research into applied longevity science.

So the incentives founder at both ends of the human life span. You need vision if you're likely to benefit personally and selflessness if you are not, and neither of those things are as common as we'd all like them to be.

Being overweight appears to behave much as though you are accumulating damage to your biology. The more time you spend being overweight and the more excess visceral fat tissue you carry, the greater your risk of suffering age-related conditions later in life, the greater your lifetime medical expenditures, and the shorter your life expectancy. The mechanisms that cause these effects may be largely linked to levels of chronic inflammation, which are increased by visceral fat tissue, though there are undoubtedly other things going on under the hood.

Being overweight starting in young adulthood may significantly increase individuals' risks of developing kidney disease by the time they become seniors, according to [a new study]. The findings emphasize the importance of excess weight as a risk factor for chronic kidney disease (CKD). The researchers analyzed information from the Medical Research Council National Survey of Health and Development, a sample of children born in one week in March 1946 in England, Scotland, and Wales. A total of 4,584 participants had available data, including body mass index at ages 20, 26, 36, 43, 53, and 60 to 64 years.

Participants who were overweight beginning early in adulthood (ages 26 or 36 years) were twice as likely to have CKD at age 60 to 64 years compared with those who first became overweight at age 60 to 64 years or never became overweight. The link between overweight and CKD was only in part explained by taking diabetes and hypertension into account. Larger waist-to-hip ratios ("apple-shaped" bodies) at ages 43 and 53 years were also linked with CKD at age 60 to 64 years.

"We estimated that 36% of CKD cases at age 60 to 64 in the current US population could be avoided if nobody became overweight until at least that age, assuming the same associations as in the analysis sample."

Link: http://www.eurekalert.org/pub_releases/2013-04/ason-osi032913.php

Life span in a species is an evolved trait: if longer lives provide a competitive advantage over shorter-lived peers, then a species will tend to become longer lived over time. We humans are long-lived for our size in comparison to other mammals, and the current thinking on that is that it may have to do with our intelligence and social nature - there is a selection effect based on advantages to survival provided by the presence of post-reproductive elders in a collaborative environment.

Salmon provide another example of the impact of evolution on aging, with their unusual aging process driven by levels of predation. The environment in which a species lives has a strong effect on life span. Here is an open access paper that considers another collection of fish species in which life spans evolved to adapt to differing mortality rates caused by environmental factors:

Early evolutionary theories of aging predict that populations which experience low extrinsic mortality evolve a retarded onset of senescence. [Here], we study annual fish of the genus Nothobranchius whose maximum lifespan is dictated by the duration of the water bodies they inhabit. Different populations of annual fish do not experience different strengths of extrinsic mortality throughout their life span, but are subject to differential timing (and predictability) of a sudden habitat cessation. In this respect, our study allows testing how aging evolves in natural environments when populations vary in the prospect of survival, but condition-dependent survival has a limited effect. We use 10 Nothobranchius populations from seasonal pools that differ in their duration to test how this parameter affects longevity and aging in two independent clades of these annual fishes.

We found that replicated populations from a dry region showed markedly shorter captive lifespan than populations from a humid region. Shorter lifespan correlated with accelerated accumulation of lipofuscin (an established age marker) in both clades. Analysis of wild individuals confirmed that fish from drier habitats accumulate lipofuscin faster also under natural conditions. This indicates faster physiological deterioration in shorter-lived populations. [The] characterization of pairs of closely related species with different longevities should provide a powerful paradigm for the identification of genetic variations responsible for evolution of senescence in natural populations.

Link: http://dx.doi.org/10.1186/1471-2148-13-77

The weight of scientific evidence tells use that regular moderate exercise is very beneficial; aside from calorie restriction, it is the best thing that basically healthy people can do for themselves. No presently available medical technology surpasses the benefits of exercise and calorie restriction for long term health for the vast majority of the population - which is a strange thing to be saying in the midst of modern medicine and biotechnology. Strange but nonetheless true. This is a state of affairs we'd all like to see change for the better, via the introduction of new biotechnologies of rejuvenation, therapies that can be envisaged in some detail today, and which (if research and development is well funded) lie only a few decades ahead of us.

Near enough to matter, but still out of reach. So at this point exercise and calorie restriction are all that most of us have to work with to increase the odds of you still being alive to benefit from future rejuvenation therapies. It has to be said that the odds are not going to be moved to anywhere near the degree they would if a very large amount of funding arrived at the SENS Research Foundation, thus speeding up progress towards clinical reversal of age-related degeneration, but most of us are not in a position to make that happen.

The benefits of exercise are very broad, much like those offered by calorie restriction. It impacts mechanisms and the speed of change throughout the body and the aging process. On this topic, I recently noticed a couple of papers that note two small aspects of the interaction of exercise and aging, one in mice, and one in we humans. In mouse studies, it's quite possible to show that exercise causes numerous health benefits: mice are short-lived and thus researchers can follow them all the way through their lives:

Enhanced Diastolic Filling Performance with Lifelong Physical Activity in Aging Mice

Fourteen C57Bl/6J mice (seven male and seven female) were individually housed at eight weeks of age in cages with a running wheel, magnetic sensor and digital odometer. Duration, distance and running velocity were recorded daily. Fourteen additional mice C57Bl/6J mice (seven male and seven female) were placed in individual cages without running wheels at eight weeks of age. [Ultrasound techniques] were used to image the left ventricle every four weeks throughout the lifespan.

Lifelong physical activity resulted in greater diastolic filling parameters by the second quarter of the lifespan highlighting the clinical importance of regular aerobic activity in young adulthood as a mechanism for improved left ventricular performance with aging.

In the case of humans a research group must instead work with shorter snapshots of time, drawing data from existing populations with their quirks and histories. Given that, it is much harder to prove the degree to which exercise causes good health and slower aging versus only being associated with these line items.

The impact of physical activity on endothelial function in middle-aged and elderly subjects: the ikaria study

The study was conducted on a subgroup population of the IKARIA study consisting of 185 middle-aged (40-65 years) and 142 elderly subjects (66-91 years). Endothelial function was evaluated by ultrasound measurement of flow-mediated dilatation (FMD).

In the overall study population FMD was inversely associated with age and middle-aged subjects had higher FMD compared with the elderly. Multiple linear regression analysis revealed that among middle-aged subjects the physically active had higher FMD compared with the physically inactive. Physically active subjects in the middle-aged group showed higher FMD compared with the physically active elderly. However, there was no difference in FMD values between middle-aged inactive subjects and the elderly physically active.

The present study revealed that increased [physical activity] was associated with improved endothelial function in middle-aged subjects and that [physical activity] in elderly subjects can ameliorate the devastating effects of ageing on arterial wall properties.

The full PDF version of the Ikaria study paper quoted above is available, so you can judge for yourself just how justified the authors' conclusion might be. Causation is hard to demonstrate - but the general presumption is that the causation shown in animal studies is also operating in human ones when it comes to things like exercise and cardiovascular health in aging. Proving and then putting numbers to that presumption are the challenges.

You might recall a recent article on transposons as a form of more aggressive genetic damage and disarray in the later stages of aging. It is unclear as to whether this is a secondary effect or whether it does in fact contribute to age-related decline at that stage; the arguments would be much the same as those made for other forms of stochastic DNA damage in aging. Here is another example of recently published research on transposons and aging:

[Researchers] showed that when the activity of a protein called Ago2 (Argonaute 2) was perturbed, so was long-term memory [in fruit flies] - which was tested using a trained Pavolvian response to smell. Since Ago2 is known to be involved in protecting against transposon activity in fruit flies, [the scientists] were compelled to look for transposons. Though transposons have been shown to be active during normal brain development, they are silenced soon afterward. The implication is that they have some functional role in development.

When [the team] looked for transposons they found that there is a marked increase in transposon levels in the brain cells, or neurons, by 21 days of age in normal fruit flies. The levels were observed to increase steadily with age. These transposons, including one in particular called gypsy, were highly active, jumping from place to place in the genome. When they blocked Ago2 from being expressed in fruit flies, transposons accumulated at a much younger age.

Accompanying this transposon accumulation were defects in long-term memory that mirrored those usually seen in much older flies, as well as a much-reduced lifespan. "Essentially the Ago2 knock out flies have no long-term memory by the time they are 20 days old, while normal flies have a normal long-term memory at the same age." [The researchers propose] that a "transposon storm" may be responsible for age-related neurodegeneration as well as the pathology seen in some neurodegenerative disorders.

However, [the] studies so far don't address whether transposons are the cause or an effect of aging-related brain defects. "The next step will be to activate transposons by genetically manipulating fruit flies and ask whether they are a direct cause of neurodegeneration."

The challenge with this sort of research is that it's easy to exhibit reduced life span by pulling out necessary parts of an animal's biochemistry, but very hard to show that this is actually relevant to aging versus just another form of causing damage. The real test in this case would be to find a way to suppress transposons with minimal other changes to biochemistry and show extended life - or at least preserved cognitive function - as a result. That would be compelling.

Link: http://www.eurekalert.org/pub_releases/2013-04/cshl-cns040513.php

Immune cells can be engineered to selectively target cancer cells for destruction via use of chimeric antigen receptors that match up with proteins that are more common on the exterior of a cancer cell. This strategy has been in the news of late with impressive successes against leukemia. Here researchers show that better results can be obtained by chaining together two marginal targets, each of which is only slightly discriminating for cancer cells if used on its own.

T cells made to express a protein called CAR, for chimeric antigen receptor, are engineered by grafting a portion of a tumor-specific antibody onto an immune cell, allowing them to recognize antigens on the cell surface. Early first-generation CARs had one signaling domain for T-cell activation. Second-generation CARs are more commonly used and have two signaling domains within the immune cell, one for T-cell activation and another for T- cell costimulation to boost the T cell's function.

Importantly, CARs allow patients' T cells to recognize tumor antigens and kill certain tumor cells. A large number of tumor-specific, cancer-fighting CAR T cells can be generated in a specialized lab using patients' own T cells, which are then infused back into them for therapy. Despite promising clinical results, it is now recognized that some CAR-based therapies may involve toxicity against normal tissues that express low amounts of the targeted tumor-associated antigen.

To address this issue [researchers] developed an innovative dual CAR approach in which the activation signal for T cells is physically dissociated from a second costimulatory signal for immune cells. The two CARs carry different antigen specificity - mesothelin and a-folate receptor. Mesothelin is primarily associated with mesothelioma and ovarian cancer, and a-folate receptor with ovarian cancer. [Dual] CAR T cells are more selective for tumor cells since their full activity requires interaction with both antigens, which are only co-expressed on tumor cells, not normal tissue.

Link: http://www.sciencedaily.com/releases/2013/04/130407133235.htm

Few people seem terribly interested in noting the opportunity costs of aging, for all that a great deal of work goes into trying to build models for the direct costs. Insurers, government program administrators, and so forth, are all eager to put numbers to their potential future outlays - but they have fewer incentives to work on better numbers for the lost ability to earn that comes with advancing age. Here are some figures from a recent paper on dementia in the US, for example:

The estimated prevalence of dementia among persons older than 70 years of age in the United States in 2010 was 14.7%. The yearly monetary cost per person that was attributable to dementia was either $56,290 (95% confidence interval [CI], $42,746 to $69,834) or $41,689 (95% CI, $31,017 to $52,362), depending on the method used to value informal care. These individual costs suggest that the total monetary cost of dementia in 2010 was between $157 billion and $215 billion. Dementia represents a substantial financial burden on society, one that is similar to the financial burden of heart disease and cancer.

If you go digging around in US census data on income, or the quick summaries thereof, you'll see that median income sits somewhere a little under $40,000/year in the prime earning years of life. It tapers off to a little more than half of that for surviving members of the 75 and older demographic. So while one of seven completely median older people incurs costs of roughly $40,000/year for dementia, all seven completely median older people suffer an opportunity cost of roughly $20,000/year as a result of becoming old. A range of income that might have been earned if still healthy and vigorous is no longer within reach.

These are very rough and ready comparisons, but you can see that even piling in a bunch of other direct medical costs for the rest of the population - cancer, diabetes, cardiovascular disease, and the other common foes - the opportunity costs of being old still look sizable in comparison. In another study that gives average medical costs over time for people in Japan aged between 40 and 80 followed over 13 years, the average yearly expenditure was in the ~$3,500 range, rising to more like ~$25,000 in the last year prior to death. The error bars for casual use of any of the numbers mentioned in this post is large - probably a factor of two, given all of the oddities and politics that goes into medical expenditures and recording of income, and especially when comparing data between different regions on the world. But you can still draw very rough conclusions about relative sizes.

Lastly, I should note that all of the above only considers the living. Once you get to the age 75 demographic in the US, half of the original population is dead, give or take. The dead accrue even higher opportunity costs than those mentioned above, as they have (for the most part) lost all ability to earn or contribute to building new things.

So aging causes a largely unseen cost to go along with what is seen, the cost of what might have been but for disability and death. As is often the case, the cost of research and development to build the means of rejuvenation is small in comparison to what is lost to aging - and also in comparison to what is spent in coping with the aftermath of loss rather than trying to prevent it.

It is worth keeping an eye on progress towards the creation of artificial cells and cell-like structures, as they are potentially useful in a very broad range of biotechnologies relevant to longevity science, regenerative medicine, and so forth. The first swarms of medical microrobots will quite likely be modified cells or artificial cells, packed with specific forms of molecular machinery to achieve some sort of effect in the body - such as manufacturing signaling compounds in response to local conditions, so as to steer the activities of surrounding cells.

A custom-built programmable 3D printer can create materials with several of the properties of living tissues. The new type of material consists of thousands of connected water droplets, encapsulated within lipid films. Because droplet networks are entirely synthetic, have no genome and do not replicate, they avoid some of the problems associated with other approaches to creating artificial tissues - such as those that use stem cells. Each droplet is an aqueous compartment about 50 microns in diameter. Although this is around five times larger than living cells the researchers believe there is no reason why they could not be made smaller. The networks remain stable for weeks.

"We aren't trying to make materials that faithfully resemble tissues but rather structures that can carry out the functions of tissues. We've shown that it is possible to create networks of tens of thousands of connected droplets. The droplets can be printed with protein pores to form pathways through the network that mimic nerves and are able to transmit electrical signals from one side of a network to the other."

Link: http://www.sciencedaily.com/releases/2013/04/130404142457.htm

This article looks past the immediate challenges of aging and early medical biotechnologies aimed at extending human longevity, and into the future of merged molecular manufacturing and biotechnology, when it will become possible to replace our biology with far more robust and long-lasting machinery:

If we're talking far-future, non-biological approaches to life-extension will win out over biological approaches, due mainly to their comparative advantages (e.g. ease of repair and modification). [I] think that the distinction between non-biological and biological systems (especially if Drexlerian nanotech - that is, using mechanosynthesis - is implemented with any ubiquity) will increasingly dissolve. If a system exhibits the structural, functional and operational modalities of a biological cell, tissue, organ or organism, yet consists of wholly inorganic materials, is it not closer to a biological system than to what we would typically consider a non-biological system? Either the distinction between the two will eventually dissolve, or we will use the term "biological" to designate systems exhibiting the structural, functional, and/or operational modalities of biological systems.

I make a distinction between life-extension therapies and indefinite-longevity therapies, and I'd like to elaborate more on this distinction here. Life-extension therapies extend longevity, but for various reasons fail to make it necessarily indefinite or unlimited. Often this is because such therapies aren't comprehensive - a given therapy solves one contributing factor of aging, but not all of them. Others, like SENS (which I'm in no way discounting), fix the major causes of damage, but use a different methodology for each respective source of damage or aging; the drawback of this approach is that if previously overshadowed causes of aging now begin to make a non-negligible impact on aging, in the absence of the more predominant causes, then we have no methodology to combat it. Because each strategy is tied intimately to the cause it seeks to ameliorate, the techniques often cannot be applied to the new source of molecular damage.

Indefinite or unlimited longevity therapies, on the other hand, use one comprehensive approach to mitigate all sources of aging. One example is Drexlerian nanotech (and to a shared but somewhat lesser extent Robert Freitas's nanomedicine - only because it has specifically-tailored strategies not dependent on the feasibility of Drexlerian molecular assembly or "mechanosynthesis", in addition to the more comprehensive ones). This approach fixes not the source of the damage but the damage itself, iteratively, and can thus be used to combat any source of molecular damage using the same tools, technologies and techniques. With such therapies we wouldn't need to come up with a second wave of strategies to combat those sources of aging that might crop up in the future, and which remained unnoticed until such a time only because their impact couldn't be seen (or allowed to take effect) while the first wave of sources was still predominant.

I'm not totally convinced that this last point is the case; I think it's more that a designed replacement for tissue can be made to have far fewer and more comprehensibly understood forms of aging (which can be repaired on an ongoing basis). But there will still be the unknowns, pushed into an ever-smaller corner, and ever less important. Yet by the time it is possible to build artificial tissue and cell replacements in this way, will we not have come to understand biology so well that the unknowns in biological aging are already equally small?

Link: http://lifeboat.com/blog/2013/04/longer-life-or-unlimited-life

Without the biotechnologies of human rejuvenation that could be created over the next twenty years given a fully funded crash program of development, we and our immediate descendants will all die due to the effects of aging, exactly as did our ancestors. Aging to death has never been a choice - but now it is, and every needless day of delay comes at a cost of 100,000 lives. Everyone presently alive will suffer greatly due to aging and age-related conditions unless new medical technologies of the sort envisaged by the SENS Research Foundation are developed to repair and reverse the low-level biological damage that causes of aging. So why isn't this front and center on everyone's list of concerns? Why does longevity science and the elimination of age-related suffering barely even register in the public eye?

Here is a talk on this subject given at the Stanford Advancing Humanity Symposium last month by Maria Konovalenko of the Russian Science For Life Extension Foundation, an advocacy initiative:

In this talk I am sharing our wonder about why haven't the ideas of life extension won. It is not clear why isn't every person on Earth concerned with their longevity. There are several serious reasons that I mention in my presentation, but even all of them combined don't give the answer to this question. I am also looking at different possible scenarios of how the extending longevity ideas could rise to power.

You might look at this research on size and longevity in the context of what is known of growth hormone and aging. The presently longest lived mice, for example, are those in which growth hormone is removed or blocked, and they are small in comparison to their peers. Also worth considering are analogous rare human lineages with non-functional growth hormone receptors, such as those exhibiting Laron-type dwarfism.

Large body size is one of the best predictors of long life span across species of mammals. In marked contrast, there is considerable evidence that, within species, larger individuals are actually shorter lived. This apparent cost of larger size is especially evident in the domestic dog, where artificial selection has led to breeds that vary in body size by almost two orders of magnitude and in average life expectancy by a factor of two.

Survival costs of large size might be paid at different stages of the life cycle: a higher early mortality, an early onset of senescence, an elevated baseline mortality, or an increased rate of aging. After fitting different mortality hazard models to death data from 74 breeds of dogs, we describe the relationship between size and several mortality components. We did not find a clear correlation between body size and the onset of senescence. The baseline hazard is slightly higher in large dogs, but the driving force behind the trade-off between size and life span is apparently a strong positive relationship between size and aging rate. We conclude that large dogs die young mainly because they age quickly.

Link: http://www.ncbi.nlm.nih.gov/pubmed/23535614

Mitohormesis is a process by which a low dose of some toxic substance or environmental effect causes mitochondria in cells to emit a little more in the way of damaging reactive oxygen species, which in turn causes cellular maintenance mechanisms to ramp up their efforts. The end result is a net gain in health and longevity:

Arsenite is one of the most toxic chemical substances known and is assumed to exert detrimental effects on viability even at lowest concentrations. By contrast and unlike higher concentrations, we here find that exposure to low-dose arsenite promotes growth of cultured mammalian cells. In the nematode C. elegans, low-dose arsenite promotes resistance against thermal and chemical stressors, and extends lifespan of this metazoan, whereas higher concentrations reduce longevity.

While arsenite causes a transient increase in reactive oxygen species (ROS) levels in C. elegans, co-exposure to ROS scavengers prevents the lifespan-extending capabilities of arsenite, indicating that transiently increased ROS levels act as transducers of arsenite effects on lifespan, a process known as mitohormesis. This requires two transcription factors, namely DAF-16 and SKN-1, which employ the metallothionein MTL-2 as well as the mitochondrial transporter TIN-9.1 to extend life span. Taken together, low-dose arsenite extends lifespan, providing evidence for non-linear dose-response characteristics of toxin-mediated stress resistance and longevity in a multicellular organism.

SKN-1 and DAF-16 are already well known as longevity-related genes in nematodes - more data for the importance of mitochondria in aging.

Link: http://www.ncbi.nlm.nih.gov/pubmed/23534459

Arguments from authority are frowned upon in most forms of formal debate, since the purpose of said debate is to argue and build upon facts firsthand - as opposed to merely repeating other people's consideration of those facts. But for the purposes of advocacy and informal discussion, invoking authority is tremendously useful for getting past knee-jerk rejection of new ideas. Most people are quick to bypass anything that they are unfamiliar with; in this information-dense age some sort of filter is needed to keep a focus on important matters, but folk in every era have been reluctant to engage with the new and the unusual.

Thus one of the necessary activities for any growing concern in any field of human endeavor is to convince influential, knowledgeable people to publicly provide their blessing. On the one hand this is all part and parcel of networking: if you're working on a disruptive new approach to aging research, say, then at some point you have to convince a sizable fraction of the existing research community leadership that you are right, and that your approach is indeed better than the established dogma. You need to build a network, and bootstrap your support.

In most cases, great new ideas can be easily discerned in hindsight, but in the early days it's a matter of a hundred rejections for every cautious expression of interest. You have to kick down a lot of doors. No good idea is accepted without a fight - and that is the human condition for you.

The disruptive and vastly better new approaches to aging research and extending human longevity that I favor are (as I'm sure you all know by now) collectively known as SENS: the Strategies for Engineered Negligible Senescence. SENS is is an assembly of tremendously good ideas expressed in the form of detailed research plans for medical biotechnology, and is (to my eyes) enormously better than the sort of work presently undertaken by the mainstream of longevity science. I say this meaning that it will most likely produce better outcomes at far lower cost in time and money. The present mainstream seeks only to slightly slow aging, and is moving glacially and at great expense. SENS aims to achieve rejuvenation of the old, and can be proven to work or not for a fraction of the amount it would take for the mainstream to develop a single drug to safely and modestly slow down aging through metabolic reprogramming.

Needless to say, with SENS being such a great idea and better plan of action, it's been a struggle this past decade to get it to its present level of respect and adoption. No good plan goes unchallenged in this madhouse world of ours. Congratulations should go to the Methuselah Foundation and SENS Research Foundation teams over the years, most of whom have worked tirelessly behind the scenes and for little recognition. The public at large, however, lagging behind some years in following the scientific conversation, remain suspicious of anything that presents itself as SENS does - new ideas, involving only a small portion of the scientific community at first, talking about human longevity, the existence of public scientific debates over validity in past years, and so forth. It's easy for the fellow in the street to knee-jerk and reject, just as he does for any new idea that has yet to take over the mainstream.

This is where the argument from authority is useful and indeed often necessary in the real world give and take of advocacy for a cause. It launches you past the first hurdle of immediate rejection, to a point at which people might actually start to consider factual arguments - i.e. start to give any sort of fair consideration to your position at all. For SENS, the resource of first recourse for the argument from authority is the SENS Research Foundation scientific advisory board. Again, this is not primarily why the advisory board exists: an initiative grows by networking. But it is enormously helpful when in casual discussion or debate for someone like such like myself to be able to point to that advisory board and say "look at these leading scientists in the fields of aging research, genetics, regenerative medicine, cancer research, and others: they have evaluated the scientific merits and goals of SENS and support it."

It is suspected that some fraction of the benefits of calorie restriction for health and longevity are keyed to the hunger response in some way - i.e. that being hungry more often is necessary to gain the full effects. There's not all that much work on this so far as I'm aware, however. You might look at one study suggesting increased levels of ghrelin, the hunger hormone, are linked to an improved immune system response, for example. Studies investigating the contribution of hunger to the benefits of calorie restriction would have to run by manipulating the hunger response separately from calorie intake to try to isolate its effects.

Here is one recently published example of such a study. It is unfortunately focused only on aspects of Alzheimer's disease rather than on longevity, but it is still intriguing. The reduced inflammation is a sign that the researchers might be on the right track:

It has been shown that caloric restriction (CR) delays aging and possibly delays the development of Alzheimer's disease (AD). We conjecture that the mechanism may involve interoceptive cues, rather than reduced energy intake per se. We determined that hunger alone, induced by a ghrelin agonist, reduces AD pathology and improves cognition in [a] mouse model of AD.

Long-term treatment with a ghrelin agonist was sufficient to improve the performance in the water maze. The treatment also reduced levels of amyloid beta (Aβ) and inflammation (microglial activation) at 6 months of age compared to the control group, similar to the effect of CR. Thus, a hunger-inducing drug attenuates AD pathology, in the absence of CR, and the neuroendocrine aspects of hunger also prevent age-related cognitive decline.

Link: http://dx.doi.org/10.1371/journal.pone.0060437

"Very small embryonic-like stem cells" (VSELs) is one name given to populations of stem cells in the adult body that appear to share some characteristics with embryonic stem cells - such as the ability to differentiate into multiple cell types. If this pans out, these cells will be useful in therapy - and here is news of an upcoming trial:

Preparations are underway for the first known human trial to use embryonic-like stem cells collected from adult cells to grow bone. [The] research partners hypothesize that the VSEL stem cells, which mimic properties of embryonic stem cells, can provide a minimally invasive way to speed painful bone regeneration for dental patients and others with bone trauma.

Within a year, researchers hope to begin recruiting roughly 50 patients who need a tooth extraction and a dental implant. Before extracting the tooth, [researchers] harvest the patient's cells, and then NeoStem's VSEL technology is used to purify and isolate those VSEL stem cells from the patient's other cells. This allows [researchers] to implant pure populations of the VSEL stem cells back into test patients. Control patients receive their own cells, not the VSELs. After the new bone grows, researchers remove a small portion of it to analyze, and replace it with an implant.

"We're taking advantage of the time between extraction and implant to see if these cells will expedite healing time and produce better quality bone. They are natural cells that are already in your body, but NeoStem's technology concentrates them so that we can place a higher quantity of them onto the wound site."

Link: http://www.sciencedaily.com/releases/2013/04/130402090826.htm

Does Aging Stop? was published a couple of years back, and provides a good grounding in the research and viewpoints of evolutionary biologist Michael Rose, whose work is mentioned here and there in the Fight Aging! archives. He and fellow researchers have assembled a compelling set of data regarding increased longevity in flies by selective breeding, and on the late life mortality plateau in flies: if aging is defined as an increasing chance of death per unit time, there comes at point at which aging ceases. In flies at least it's quite clearly the case that their mortality rate flattens out in very late life.

Human data is much less definitive, unfortunately, with a study published last year showing no signs of mortality rates leveling out in in the oldest surviving portions of the population.

The Rose view of aging that emerges from this and related work shares some aspects in common with programmed aging theories (aging is an errant continuation of youthful genetic programs that cause damage and dysfunction) and some with damage based theories (aging is caused directly by accumulated damage at the level of cells and protein machinery). Rose is, for example, not opposed to damage repair initiatives like SENS, but argues that the late-life mortality plateau data has to indicate that damage is not the whole story. Thus by this logic, damage repair biotechnologies cannot produce a comprehensive form of rejuvenation.

(At this point, as I've argued before, I'll say that the cost of proving SENS right or wrong is probably about a billion dollars and ten years, which is far less time and money than any other approach to extending longevity will require to even get started. Proving SENS right is essentially the same as proving one class of theories of aging right and the rest wrong: most of the big ongoing debates in aging research could be solved or bypassed by creating a demonstration of SENS in old laboratory mice).

Here is a review of Does Aging Stop?

The work reported with fruit flies (Drosophila melanogaster) was long and extensive, covering 18 years and 465 generations, supplemented by a lesser amount of work with a related, also shortlived insect, the medfly (Cerititis capitata). The fruit flies averaged about 14 days per generation and lived up to a little past 100 days. Roughly, the length of generations and maximum life-span of the fruit flies in days equaled these data for humans in years, which thus are scaled several hundred times longer.

As for the results, it is consistently shown that the mortality of fruit flies, measured in terms of a probability density function giving the chance of dying in a short time interval, does not indefinitely increase. Instead it levels off or plateaus in later life, approaching a roughly constant value in which about 15-30% of the flies die per day, the variations depending on such factors as whether the flies have been specially bred for longevity. Though this is a substantial attrition rate, it is significant that it does not change much from this point on and particularly does not approach 100%, contrary to the thinking of earlier times. Instead, following the period of "aging" in which mortality rates rise, there is a period of indefinite if still finite length that the authors call "late life" when the organism does not age any further, though the aging that has already occurred is not reversed.

The whole thing is worth reading.

This is a somewhat obvious point, but seems worth making once or twice. The primary methods of extending life in laboratory animals involve genetic engineering and environmental line items such as calorie restriction - these are how new metabolic states that lead to increased longevity are discovered in the research mainstream. The process of then developing drugs to try to recapture some of these effects inevitably lags behind in effectiveness: it's a complex process with many dead ends and only partial successes, whereas testing new genetic alterations in lower animals proceeds fairly rapidly these days. This recent paper illustrates the point:

The regulation of animal longevity shows remarkable plasticity, in that a variety of genetic lesions are able to extend lifespan by as much as 10-fold. Such studies have implicated several key signaling pathways that must normally limit longevity, since their disruption prolongs life. Little is known, however, about the proximal effectors of aging on which these pathways are presumed to converge, and to date, no pharmacologic agents even approach the life-extending effects of genetic mutation.

In the present study, we have sought to define the downstream consequences of age-1 nonsense mutations, which confer 10-fold life extension to the nematode Caenorhabditis elegans - the largest effect documented for any single mutation. Such mutations insert a premature stop codon upstream of the catalytic domain of the AGE-1/p110α subunit of class-I PI3K. As expected, we do not detect class-I PI3K, [nor] do we find any PI3K activity as judged by immunodetection of phosphorylated AKT, which strongly requires PIP3 for activation by upstream kinases, or immunodetection of its product, PIP3.

We tested a variety of commercially available PI3K inhibitors, as well as three phosphatidylinositol analogs (PIAs) that are most active in inhibiting AKT activation, for effects on longevity and survival of oxidative stress. Of these, GDC-0941, PIA6, and PIA24 [extended] lifespan by 7-14%, while PIAs 6, 12, and 24 (at 1 or 10 μM) increased survival time [under oxidative stress] by 12-52%. These effects may have been conferred by insulinlike signaling.

Link: http://www.ncbi.nlm.nih.gov/pubmed/23543623

The programmed aging camp points to experiments such as this as supportive of their view that aging is a genetic program that gives rise to damage and change, rather than resulting from damage that causes epigenetic changes to arise in reaction. The data could be interpreted either way, however, and there are other reasons to believe that aging is caused by damage:

In a 2005 experiment, one old mouse and one young mouse became artificial Siamese twins. For control, [researchers] also paired two old mice and two young mice. After the surgery, they injured one mouse from each pair, and monitored the healing process at a cellular level. As expected, the young mice recovered from injury much more efficiently than old mice. The surprise was that old mice that were paired with young mice healed as if they were young. "Importantly, the enhanced regeneration of aged muscle was due almost exclusively to the activation of resident, aged progenitor cells, not to the engraftment of circulating progenitor cells from the young partner." In other words, it was not young cells that implanted themselves in the old mice; it was signal proteins in the blood that told the old mouse tissue to go ahead and heal as if it were young.

[A recent paper] culminates in a proposal for whole-body rejuvenation that might be practical in the near term. Fortuitously, its safety in humans has already been established, so people might be willing to try it if a course of animal experiments shows promise. The idea is simply to transfuse older subjects with blood plasma from a young donor, repeated often enough to sustain levels of signaling proteins that control gene expression.

The mainstream view on why stem cells and tissue maintenance decline with age is that it is an evolved response to rising levels of damage that reduces cancer risk. Flooding an old system with young signaling overrides that response, but would probably be accompanied by an increased risk of cancer - though in the case of a short-term signal change as a therapy to promote regeneration of a specific injury, that may be an acceptable risk. In the long term, however, the underlying damage has to be repaired, rather than just forcing our biochemistry to continue as though it didn't exist.

Link: http://joshmitteldorf.scienceblog.com/2013/03/25/young-blood/

Forecasting is really hard, especially when it involves the future - or so they say. One of Ray Kurzweil's more noteworthy achievements has been, I think, to help popularize the idea that technological progress can be predicted fairly well at the level of general capabilities (as opposed to specific implementations). This is not a new idea, but despite - or because of - the sweeping, glittering changes transforming our society, at a pace that is only getting faster, it hasn't achieved any great adoption in the public eye, at least beyond some few narrow and often misquoted instances such as Moore's law for computing power.

If the outcome of technological progress only meant smaller widgets and brighter lights, then I probably wouldn't be as interested in it as I am. In the grand scheme of things, does it much matter that you can be modestly confident in predicting whether widgets will be half the size and a tenth of the cost in twenty years versus forty years? If you're in the widget business for the long haul, it matters. If not ... well, everyone has their own specialty to attend to.

There is one branch of technology which is now of great importance to everyone, however, and that is medicine. We stand on the verge of being able to extend human life by reversing the underlying biological damage that causes aging. "On the verge" means that either you die just a little later than your parents, or you live for centuries or longer, depending on whether or not you live long enough to benefit from the first therapies capable of actual rejuvenation. The early rejuvenation therapies will be poor in comparison to what comes afterwards, but they will give you time to wait for better treatments: you just have to be young enough at the outset to stay ahead of the curve of improvement.

This is vastly more important than widgets: being able to more or less predict the course of electronics, computing, or space flight gives you an idea of what you might see before you die. Predicting the course of capacities in medicine even at a very high level may show you whether you will have to age to death at all, should things progress as expected. On this topic, here is an open access paper that delves into historical technologies to suggest that progress is predictable:

Statistical Basis for Predicting Technological Progress

Forecasting technological progress is of great interest to engineers, policy makers, and private investors. Several models have been proposed for predicting technological improvement, but how well do these models perform? An early hypothesis made by Theodore Wright in 1936 is that cost decreases as a power law of cumulative production. An alternative hypothesis is Moore's law, which can be generalized to say that technologies improve exponentially with time. Other alternatives were proposed by Goddard, Sinclair et al., and Nordhaus.

These hypotheses have not previously been rigorously tested. Using a new database on the cost and production of 62 different technologies, which is the most expansive of its kind, we test the ability of six different postulated laws to predict future costs. Our approach involves hindcasting and developing a statistical model to rank the performance of the postulated laws. Wright's law produces the best forecasts, but Moore's law is not far behind. We discover a previously unobserved regularity that production tends to increase exponentially. A combination of an exponential decrease in cost and an exponential increase in production would make Moore's law and Wright's law indistinguishable, as originally pointed out by Sahal.

We show for the first time that these regularities are observed in data to such a degree that the performance of these two laws is nearly the same. Our results show that technological progress is forecastable, with the square root of the logarithmic error growing linearly with the forecasting horizon at a typical rate of 2.5% per year.

I point you to the research quoted above as a form of reassurance: progress will continue in medicine, and via efforts such as the Methuselah Foundation and SENS Research Foundation the medical research community is presently being brought around to the idea of extending human life via rejuvenation biotechnology. The uncertainty in timelines at present all lies in how long it will take for SENS-style rejuvenation research to gather a firm, mainstream, well-funded position: once that happens then progress is inevitable and tends to unfold as outlined above. Prior to that point there is much uncertainty, with things progressing in fits and starts - the standard tyranny of progress under minimal funding and participation.

Thus the present goal for advocates is to persuade enough people and funds to make progress inevitable from that point on. The sooner that happens, the higher the fraction of those presently alive who will live to see and benefit from human rejuvenation. If you're in mid-life like I am, you only have forty years or so of grace - and less if you're not taking care of your health, or are just plain unlucky in the cancer lottery. Four decades is probably only enough time if things go very well over the next ten to twenty years, and SENS or SENS-like programs colonize a large enough chunk of the life science research community in a short enough space of time.

So: hope or help. One of the two, but the letter is generally a better plan.

Mitochondria are the powerplants of the cell, bacteria-like entities that produce chemical stores of energy to power cellular processes. The accumulation of damaged mitochondria is thought to cause a fair portion of degenerative aging, and differences in the ability of mitochondria to resist damage appear to play an important role in determining variation in life span between similar species.

Autophagy is one of the processes by which damaged mitochondria are removed from consideration, in this case by destroying them and freeing up the materials for recycling. Autophagy also removes other damaged cell components and unwanted metabolic byproducts. Mitochondria-specific autophagy is often called mitophagy or macromitophagy, and a large pile of evidence suggests that it is this aspect of autophagy that is most responsible for the association between increased levels of autophagy and increased longevity in a range of laboratory species and different methods of life extension.

At some point in the near future, development will be underway in earnest on drugs to boost autophagy. Here researchers add more evidence to considerations of autophagy and longevity while examining mitophagy in yeast under calorie restriction (CR), a well-known method of life extension:

In this study, we provide the first evidence that selective macroautophagic mitochondrial removal plays a pivotal role in longevity extension by a CR diet in chronologically aging yeast; such a diet was implemented by culturing yeast cells in a nutrient-rich medium initially containing low (0.2%) concentration of glucose, a fermentable carbon source. It should be emphasized that under these longevity-extending CR conditions yeast cells are not starving but undergo an extensive remodeling of their metabolism in order to match the level of ATP produced under longevity-shortening non-CR conditions.

Moreover, our study also reveals that in chronologically aging yeast limited in calorie supply macromitophagy is essential for longevity extension by LCA. This bile acid is a potent anti-aging intervention previously shown to act in synergy with CR to enable a significant further extension of yeast lifespan under CR conditions by modulating so-called "housekeeping" longevity pathways.

In sum, these findings imply that macromitophagy is a longevity assurance process that in chronologically aging yeast underlies the synergistic beneficial effects of anti-aging dietary and pharmacological interventions (i.e., CR and LCA) on lifespan. Our data suggest that macromitophagy can maintain survival of chronologically aging yeast limited in calorie supply by controlling a compendium of vital cellular processes known for their essential roles in defining longevity. [It] is conceivable that in chronologically aging yeast limited in calorie supply macromitophagy selectively eliminates dysfunctional mitochondria impaired in vital mitochondrial functions that define longevity.

Link: http://impactaging.com/papers/v5/n4/full/100547.html

Aging is a global phenomenon throughout the body, and thus we should expect the pace of progression of any one aspect to correlate well with the others. So it is for height loss - meaning that you have the same modest level of control via lifestyle choices such as exercise and calorie restriction as is the case for aging in general:

Using unique data from a new massive longitudinal survey of 17,708 adults beginning at age 45, the researchers show for the first time that lifestyle choices we make in adulthood - and not just the hand we're dealt as children - influence how tall we stand as we age. While prior work has looked for the connection between height and health - both in childhood and adulthood - the researchers are the first to examine height loss as we age. They show that regardless of your maximum height, the loss of height over time is also an important indicator for other health issues as we age.

For example, the research reveals an especially strong relationship between height loss and cognitive health. Those who had lost more height were also much more likely to perform poorly on standard tests of cognitive health such as short-term memory, ability to perform basic arithmetic and awareness of the date. All humans go through physical changes with age, including an increase in body fat and decrease in bone mass. But a decrease in height can be further exacerbated by certain kinds of arthritis, inflammation of spine joints or osteoporosis, which other studies have shown are associated with such lifestyle choices as diet, exercise and smoking.

Link: http://www.eurekalert.org/pub_releases/2013-04/uosc-gsa032913.php